WO2024121349A1 - Therapeutic treatment for haematological cancer based on the level of t-cell function - Google Patents

Therapeutic treatment for haematological cancer based on the level of t-cell function Download PDF

Info

Publication number
WO2024121349A1
WO2024121349A1 PCT/EP2023/084808 EP2023084808W WO2024121349A1 WO 2024121349 A1 WO2024121349 A1 WO 2024121349A1 EP 2023084808 W EP2023084808 W EP 2023084808W WO 2024121349 A1 WO2024121349 A1 WO 2024121349A1
Authority
WO
WIPO (PCT)
Prior art keywords
patient
age
imid
cell function
years
Prior art date
Application number
PCT/EP2023/084808
Other languages
French (fr)
Inventor
Jakob LINDBERG
Original Assignee
Oncopeptides Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB2218510.2A external-priority patent/GB202218510D0/en
Priority claimed from GBGB2313014.9A external-priority patent/GB202313014D0/en
Application filed by Oncopeptides Ab filed Critical Oncopeptides Ab
Publication of WO2024121349A1 publication Critical patent/WO2024121349A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/505—Cells of the immune system involving T-cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/70—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving creatine or creatinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention concerns the treatment of multiple myeloma. More particularly, this invention concerns an improved way of using the available multiple myeloma treatments by more effectively selecting the most appropriate treatment for a given patient.
  • myeloma is a plasma cell malignancy characterized by the production of monoclonal protein, anemia, and disordered bone remodeling with lytic bone disease.
  • myeloma primarily consisting of corticosteroids, melphalan, the VAD regimen (vincristine, doxorubicin, dexamethasone), and autologous stem cell transplant.
  • Median survival during that era was 2-3 years (Holstein and McCarthy, Drugs. 2017 April; 77(5): 505-520. doi:10.1007/s40265-017-0689-l; and Raza et al., Current Cancer Drug Targets, 2017, 17(9), 846-857).
  • IMDs immunomodulatory drugs
  • Pls proteasome inhibitors
  • the first IMiD to be authorised for use in multiple myeloma was thalidomide (first authorised for in 2006).
  • Lenalidomide is a more potent second generation IMiD with fewer side effects than thalidomide. It was also first authorised in 2006. It is commonly used in combination with dexamethasone in newly-diagnosed multiple myeloma, relapsed refractory myeloma and as maintenance therapy after autologous stem cell transplantation (ASCT).
  • ASCT autologous stem cell transplantation
  • Pomalidomide is sometimes referred to as a third generation IMiD and it is 10 times more potent than lenalidomide. It was first authorised in 2013 and it has shown good results in relapsed MM patients and in those refractory to both lenalidomide and bortezomib. All three agents have been studied in combination with multiple different agents, including alkylating agents (e.g. low-dose cyclophosphamide, bendamustine, melphalan), proteasome inhibitors (e.g. bortezomib, carfilzomib, ixazomib), HDAC inhibitors (e.g.
  • alkylating agents e.g. low-dose cyclophosphamide, bendamustine, melphalan
  • proteasome inhibitors e.g. bortezomib, carfilzomib, ixazomib
  • HDAC inhibitors e.g.
  • panobinostat panobinostat, ricolinostat
  • monoclonal antibodies e.g.elotuzumab, daratumumab, pembrolizumab, isatuximab.
  • CELMoDs cereblon E3 ligase modulatory drugs
  • IMiDs and combinations of IMiDs with other agents have brought, there remains a need for further improved therapies for certain patient groups.
  • the present invention seeks to meet the aforementioned need.
  • the present invention provides, in a first aspect, a method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
  • the current inventors have found that by following the methods of the current invention, treatment outcomes overall can be improved. In particular, it is possible to avoid giving health-impacting treatments to patients who do not benefit from them.
  • the invention also provides, in a second aspect, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the level T-cell function of the patient is poor, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the level T-cell function of the patient is poor, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
  • IIMiD immunomodulatory imide drug
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD ; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
  • IIMiD immunomodulatory imide drug
  • Figure 1 shows progression-free survival (PFS, primary endpoint) for a Phase III trial comparing melphalan flufenamide (melflufen) + dexamethasone (“Mel+dex”) with pomalidomide + dexamethasone (“Pom+dex”) (Example 1 study), assessed by independent review committee. Data cut-off: 3 February 2021.
  • FIG. 2 shows overall survival (OS) for the same Phase III trial as described in Figure 1 (Example 1 study).
  • OS overall survival
  • Mel+dex melphalan flufenamide (melflufen) + dexamethasone;
  • Pom+dex pomalidomide + dexamethasone.
  • Figure 3A a forest plot showing progression free survival
  • Figure 3B is a forest plot showing overall survival outcomes by patient age subgroup in the same Phase III trial as in Figure 1 (Example 1 study).
  • Mel+dex melphalan flufenamide (melflufen) + dexamethasone
  • pom+dex pomalidomide + dexamethasone.
  • Figure 4 is a spline plot showing the hazard of death as a function of age per treatment arm in the Example 1 study (3 February 2023 data cut off). The grey area depicts the underlying prognostic value of age in itself for the patient study population.
  • Figure 5 is a scatter plot of overall survival hazard ratio (OS log HR) by age, for IMiDs in Phase III multiple myeloma trials. Correlation coefficient: 0.92.
  • Figure 6 is a forest plot showing age subgroup data in Phase III studies allowing for the isolation of the IMiD treatment effect in multiple myeloma and where overall survival hazard ratio data by age are available (including OCEANZExample 1 study - data cut off 3 February 2023).
  • Figure 7 is a scatter plot of overall survival hazard ratio (OS log HR) by age, for IMiDs in Phase III trials for indications other than multiple myeloma. Correlation coefficient: 0.86.
  • Figure 8 is a scatter plot of overall survival hazard ratio (OS log HR) by age, for non-IMiDs, in Phase III trials for multiple myeloma. Correlation coefficient: 0.36.
  • Figure 9 is a forest plot showing age subgroup data in Phase III studies of non-IMiDs in multiple myeloma and where overall survival hazard ratio data by age are available.
  • the present invention provides, in a first aspect, a method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD; if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
  • Sub-group analysis by age of data from a clinical trial described hereinbelow in Example 1 revealed a significant interaction between patient age and overall survival (“OS”) in relapsed/refractory MM patients treated with pomalidomide + dexamethasone.
  • OS overall survival
  • the risk of death increased significantly with age, with the effect being most pronounced in patients >75 years of age. This effect is surprising, and has not been previously reported for pomalidomide, as illustrated by the fact that it is not reflected in current indications or prescribing instructions for this drug, or any other IMiD.
  • Table A PFS and OS in newly diagnosed multiple myeloma (NDMM) studies that isolates the lenalidomide treatment effect (ASCT: autologous stem cell transplant; ITT, intention to treat; PFS, progression free survival; OS, overall survival; HR, hazard ratio.)
  • ASCT autologous stem cell transplant
  • ITT intention to treat
  • PFS progression free survival
  • OS overall survival
  • HR hazard ratio
  • lenalidomide treatment has significant survival effect modification by one or more age-related factors that is not reflected by surrogate endpoints.
  • OS HR There is not a single lenalidomide trial with OS HR demonstrating anything else than absolute OS harm or detriment for elderly ASCT ineligible MM patients, while younger ASCT eligible patients get a survival benefit that is greater than what the surrogates indicate.
  • This pattern is identical to that of pomalidomide.
  • the OS harm/detriment signal is consistent from the age of 70-75. To date, this has not lead to a change of regime prescribing practice in older patients, which is especially concerning given the median age of patients currently on IMiD treatment of around 74.
  • IMiD treatment is currently shortening the life-expectancy for MM patients over 70 years of age.
  • the median age of myeloma patients currently on treatment is 74 years, the patient group over 70 years of age is a significant portion of myeloma patients.
  • the majority of myeloma patients are 70+ years of age and are not in sufficiently good physical condition to be eligible for clinical trials. As a consequence, the real-world impact is likely to be worse than what is observed in the trials that provide the data analysed herein.
  • HDex high- dose dexamethasone
  • the detrimental effect of HDex as a function of patient age would have masked the OS interaction between patient age and the IMiD treatment effect in MM009, MM010 and MM003.
  • those trials had patient groups with low median ages. In the overall study populations investigated, the detrimental effect on survival in elderly would therefore not have impacted on the OS result in a noticeable way.
  • the quantification of T-cell function in step i. can be carried out in many different ways.
  • the quantification of T-cell function in step i. can be carried out by assessing the patient’s biological age and/or gender.
  • a low biological age is indicative of a high level of T cell function.
  • Female gender is also indicative of a high level of T cell function.
  • a female patient has a higher level of T cell function than a male patient of the same age.
  • a patient’s biological age can be assessed.
  • One or more of the following factors may be used as a proxy for biological age: chronological age, transplant eligibility, cardiovascular function and renal function.
  • Cardiovascular function is determined by the level of renal function and other age-related aspects and it is therefore also useful as a proxy for biological age. Algorithms have also been developed for the estimation of biological age. In the method of the invention, a low biological age is indicative of high level of T cell function.
  • step i the method comprises an assessment of the patient’s chronological age.
  • An age of less than 70 years is generally indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the chronological age of the patient is less than 70 years.
  • An alternative treatment is administered if the chronological age of the patient is 70 years or older.
  • a cut-off of 71, 72 or 73 years can be used in place of the cut-off of 70 years, which is appropriate for a male patient.
  • step ii. comprises administering the IMiD if the chronological age of the patient is less than 75 years, and administering an alternative treatment if the chronological age of the patient is 75 years or older.
  • the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, administering an IMiD; or if the chronological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 75 years, administering an IMiD; or if the chronological age of the patient is 75 years or more, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the chronological age of the patient is 70 years or more, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the chronological age of the patient is 70 years or more, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
  • IIMiD immunomodulatory imide drug
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, administering an IMiD, administering the IMiD; or if the chronological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD.
  • IIMiD immunomodulatory imide drug
  • transplant eligibility may be used as a proxy for biological age.
  • a patient who is considered eligible for a transplant is considered sufficiently biologically young to have high T-cell function.
  • step (i) may be quantifying the level of T-cell function of the patient by determining if a patient is eligible for stem cell transplantation. If a patient is considered eligible for stem cell transplantation, then they can be considered to have high T- cell function in the context of the current invention.
  • Eligibility for stem cell transplant is something that is often determined for multiple myeloma patients, as stem cell transplantation is an effective treatment for the condition in certain patients.
  • the UK’s National Institute of Health and Care Excellence set out that Bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high- dose chemotherapy with haematopoietic stem cell transplantation.
  • Eligibility for stem cell transplantation is generally determined by the physician. The factors that are taken into account include chronological age and gender. In some settings, an age cut-off of 65 years is used.
  • the cut-off can be 70 years.
  • Belotti et al. (American Journal of Hematology, Vol 95(7), 759-765) noted that IMWG frailty score was a good predictor of successful stem cell transplant in patients aged 70 or over.
  • the International Myeloma Working Group (IMWG) frailty score is based on age ( ⁇ 75, 75-80, >80 years, score 0, 1, 2 respectively), Charlson Comorbidity Index ( ⁇ 1 or >2, score 0 or 1) and (instrumental) Activities Daily Living score (ADL >4 or ⁇ 4, score 0 or 1, iADL >5 or ⁇ 5, score 0 or 1). They concluded that the IMWG frailty score was a good guide for identifying those patients aged >70 years who can safely and effectively be treated with ASCT.
  • Cardiovascular function is commonly used as a proxy for biological age in various medical settings and it is considered to be a stronger predictor of biological age than chronological age in elderly patients. Cardiovascular function is influenced by a patient’s level of heart function, the performance of their vascular system and the level of renal function. Renal function is the simplest and most commonly assessed of those.
  • the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, administering an IMiD; or if the patient is not considered eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the patient is not considered eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the patient is not considered eligible for stem cell transplantation, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
  • IIMiD immunomodulatory imide drug
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, administering an IMiD; or if the patient is not considered eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an IMiD.
  • IIMiD immunomodulatory imide drug
  • level of cardiovascular function As noted above, an important factor that is taken into account when determining eligibility for stem cell transplantation is a patient’s level of cardiovascular function, and level of renal function is the simplest and most commonly assessed parameter to determine cardiovascular function.
  • GFR glomerular filtration rate
  • the level of renal function for a patient can be assessed in various ways, for example by measuring plasma level of creatinine and determining the patient’s estimated GFR by the Cockcroft-Gault formula (Cockcroft D. W., Gault M. H., Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16(1):31-41), 24 hour urine creatinine collection or other estimation methods (for example Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations).
  • MDRD Modification of Diet in Renal Disease
  • CKD-EPI Chronic Kidney Disease Epidemiology Collaboration
  • a GFR of 90 mL/min or more as determined by any method is indicative of normal renal function, normal cardiovascular function, transplant eligibility and/or low biological age.
  • a GFR of less than 90 mL/min as determined by any method is indicative of renal impairment (for example, minor, moderate or severe renal impairment), cardiovascular dysfunction/impairment of cardiovascular function (for example, minor, moderate or severe cardiovascular dysfunction/impairment of cardiovascular function), transplant ineligibility and/or high biological age.
  • a GFR of 60 mL/min or more as determined by any method is indicative of normal renal function (90 mL/min or more) or minor renal impairment (60 mL/min or more to less than 90 mL/min), normal cardiovascular function (90 mL/min or more) or minor cardiovascular dysfunction/impairment of cardiovascular function (60 mL/min or more to less than 90 mL/min), and/or low biological age (90 mL/min or more) or moderate biological age (60 mL/min or more to less than 90 mL/min).
  • a GFR of less than 60 mL/min as determined by any method is indicative of moderate or severe renal impairment, moderate or severe cardiovascular dysfunction/impairment of cardiovascular function, transplant ineligibility, and/or high or very high biological age.
  • a GFR of 45 mL/min or more as determined by any method is indicative of normal renal function (90 mL/min or more), minor renal impairment (60 mL/min or more to less than 90 mL/min) or moderate renal impairment (45 mL/min or more to less than 60 mL/min); normal cardiovascular function (90 mL/min or more), minor cardiovascular dysfunction/impairment of cardiovascular function (60 mL/min or more to less than 90 mL/min) or moderate cardiovascular function (45 mL/min or more to less than 60 mL/min); and/or low biological age (90 mL/min or more), moderate biological age (60 mL/min or more to less than 90 mL/min) or high biological age (45 mL/min or more to less than 60 mL/min).
  • a GFR of less than 45 mL/min as determined by any method is indicative of severe renal impairment
  • the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 90 mL/min or more administering an IMiD; or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention also provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 60 mL/min or more administering an IMiD; or if the patient has a GFR of less than 60 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention also provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 45 mL/min or more administering an IMiD; or if the patient has a GFR of less than 45 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 90 mL/min or more, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the patient has a GFR of less than 90 mL/min, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
  • GFR for example determining the patient’s GFR by the Cockcroft-Gault formula
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii.
  • IMD immunomodulatory imide drug
  • the patient has a GFR of 90 mL/min or more, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the patient has a GFR of less than 90 mL/min, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 90 mL/min or more, administering an IMiD; or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
  • IIMiD immunomodulatory imide drug
  • Renal function/cardiovascular function/transplant eligibility and chronological age In one especially preferred embodiment, eligibility for stem cell transplantation and chronological age of the patient are used in combination to assess/quantify/determine T-cell function of the patient.
  • the present invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the chronological age of the patient is less than 70 years, and if the patient is considered eligible for stem cell transplantation, administering an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient is considered not eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an ImiD.
  • the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii.
  • the chronological age of the patient is less than 70 years, and if the patient is considered eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an ImiD; or if the chronological age of the patient is 70 years or more, and/or if the patient is considered not eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an ImiD.
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (ImiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii.
  • ImiD immunomodulatory imide drug
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (ImiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii.
  • ImiD immunomodulatory imide drug
  • the chronological age of the patient is less than 70 years, and if the patient is considered eligible for stem cell transplantation, administering an ImiD; or if the chronological age of the patient is 70 years or more, and/or if the patient is considered not eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an ImiD.
  • renal function which is an indicator of cardiovascular function
  • chronological age of the patient are used in combination to assess/quantify/determine T-cell function of the patient.
  • the present invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, administering an ImiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an ImiD.
  • the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii.
  • the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii.
  • IMD immunomodulatory imide drug
  • the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii.
  • IMD immunomodulatory imide drug
  • the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, administering an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
  • a patient is considered to have a high level of T cell function if they have a biological age of less than 70 years. That is to say that in step i, the method comprises an assessment of the patient’s biological age and a biological age of less than 70 years is generally indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the biological age of the patient is less than 70 years.
  • An alternative treatment is administered if the biological age of the patient is 70 years or older.
  • step ii. comprises administering the IMiD if the biological age of the patient is less than 75 years, and administering an alternative treatment if the biological age of the patient is 75 years or older.
  • Biomarkers can be, but are not excluded to: C-reactive protein, serum creatinine, glycated haemoglobin, serum albumin, serum total cholesterol, cytomegalovirus optical density, serum urea nitrogen, serum alkaline phosphatase, renal function, forced expiratory volume, and systolic blood pressure.
  • the Pearson Correlation with chronological age is greater than ⁇ 0.10.
  • Other biomarkers can be used as long as their Pearson Correlation with chronological age is known and preferably, if it is high (> 0.10).
  • the Biological Age (BEC) estimate is based upon minimising the distance between m regression lines and m biomarker points with a value %j, within an m dimensional space of all biomarkers: Where C is the chronological age of the subject and Sj is the root mean squared error from the regressions between each biomarker and chronological age. To calculate the value the following equations are used sequentially:
  • the Klemera and Doubal method provides an improvement over other algorithms for calculating Biological Age.
  • Alternative algorithms include Principal Component Analysis or Factor Analysis.
  • Multiple Linear Regression can be used, by applying the equation below:
  • An alternative approach is to use the epigenetic clock. It has been known for a some time that DNA methylation associates with age, but recently supervised machine learning methods have been used to calculate the DNA methylation age, also referred to as the epigenetic clock, as a viable Biological Age predictor.
  • the two seminal epigenetic clocks are the Hannum Clock (G. Hannum, Mol. Cell., 2013, 49, 2, 359-367; WO 2014/075083 Al) and the Horvath Clock (S. Bocklandt et al., PLoS One, 2011, 6, 6, el4821; S. Horvath, Genome Biology, 2013, 14, R115; WO 2015/048665 A2).
  • the Horvath clock is a multi -tissue predictor based on methylation levels of 353 Cytosine- phosphate-Guanine (CpG) sites on the Illumina 27 k array.
  • the Hannum clock uses 71 CpG sites from the Illumina 450 k array and performs best using whole blood samples.
  • a free version of the calculator for DNA methylation age based on the Illumina Infmium platforms can be found on: https://dnamage.genetics.ucla.edu/, provided by S. Hovarth and the University of California, Los Angeles.
  • Other models of the epigenetic clock can also be used to calculate DNA methylation age, such as the PhenoAge clock (M. E. Levine et al., Aging, 2018, 10, 4, 573-591; WO 2019/143845 Al) and the GrimAge clock (A. T. Lu et al., Aging, 2019, 11, 2, 303-327; WO 2020/076983 Al). These also use Illumina Infmium technology.
  • Telomere length is a further indicator of age. Telomeres are repetitive DNA sequences that cap chromosomes and shorten every time the cell divide; thus, leukocyte telomere length (LTL) is a popular marker for biological ageing. LTL correlates less well with chronological age than the epigenetic clocks and is therefore a less accurate predictor of Biological Age, however it offers a more practical biomarker to measure. For example, a method to calculate the telomeric brink age (TB age ) was reported by T. Steenstrup et al. in 2017, who measured the LTL by southern blots of the terminal restriction measurements as previously described (T. Steenstrup et al., Aging, 2017, 9, 4, 1130-1142):
  • the rate of telomere shortening can be between 15-45 bp/year.
  • the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 70 years, administering an IMiD; or if the biological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 75 years, administering an IMiD; or if the biological age of the patient is 75 years or more, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 70 years, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the biological age of the patient is 70 years or more, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 70 years, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the biological age of the patient is 70 years or more, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
  • IIMiD immunomodulatory imide drug
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method);; ii. if the chronological age of the patient is less than 70 years, administering an IMiD, administering the IMiD; or if the chronological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD. (and similarly for a 75 year cut-off)
  • T-cell function in a patient can be assessed by carrying out direct measurement using established assays.
  • the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
  • the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the level T-cell function of the patient is poor, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
  • the invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the level T-cell function of the patient is poor, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
  • IIMiD immunomodulatory imide drug
  • the invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
  • IIMiD immunomodulatory imide drug
  • one outcome is the use of an IMiD in treatment.
  • IMiDs include thalidomide, pomalidomide, or lenalidomide.
  • Other IMiDs include cereblon E3 ligase modulatory drugs (CELMoDs).
  • CELMoDs include avadoimide, iberdomide, and mezigdomide.
  • the IMiD is thus preferably selected from the group consisting of thalidomide, pomalidomide, lenalidomide, avadoimide, iberdomide, and mezigdomide.
  • the IMiD is more preferably selected from the group consisting of thalidomide, pomalidomide, lenalidomide and mezigdomide.
  • the IMiD is more preferably selected from the group consisting of thalidomide, pomalidomide, or lenalidomide.
  • the IMiD is pomalidomide.
  • an alternative outcome is the administration of an alternative therapeutic agent and not the administration of an IMiD.
  • the alternative therapeutic agent is preferably selected from the group consisting of: alkylator, anti-CD38 agents and proteasome inhibitors.
  • alkylator include melflufen, melphalan, bendamustine, and cyclophosphamide.
  • suitable alkylators are N-mustard containing alkylators, for example melflufen, melphalan and an alkylator as described in WO2022/263679, for example any one of Example Compounds 1 to 51 of WO2022/263679, the contents of which are incorporated herein by reference.
  • Suitable anti-CD38 agents include anti-CD38 antibodies, for example daratumumab and isatuximab, elotuzumab and belantamab, in particular daratumumab.
  • Suitable proteasome inhibitors include bortezomib, carfilzomib and ixazomib.
  • the alternative therapeutic agent is an alkylator, for example melflufen, melphalan, bendamustine, cyclophosphamide, or an alkylator as described in WO2022/263679 (for example melflufen, melphalan, bendamustine, or cyclophosphamide); and more preferably an N-mustard containing alkylator; and even more preferably melflufen, melphalan or an alkylator as described in WO2022/263679, for example melflufen, melphalan or any one of Example Compounds 1 to 51 of WO2022/263679; and even more especially melflufen.
  • WO2022/263679 for example melflufen, melphalan, bendamustine, cyclophosphamide
  • an alkylator as described in WO2022/263679 (for example melflufen, melphalan, bendamustine, or cyclophosphamide
  • the alternative therapeutic agent is an alkylator and a steroid, for example an alkylator and dexamethasone.
  • melflufen and dexamethasone and in particular 40 mg melflufen on Day 1 and dexamethasone 40 mg or 20mg on Days 1, 8, 15 and 22 of each 28- day cycle.
  • Haematological cancers may include for example plasma cell neoplasms and myelomas (for example MGUS, plasmacytoma, smouldering myeloma, multiple myeloma, relapsed/refractory multiple myeloma, light chain myeloma, or non-secretory myeloma), B-cell leukaemias (for example, acute lymphoblastic leukaemia including adult and childhood acute lymphoblastic leukemia; chronic lymphocytic leukemia; and hairy cell leukemia), and B-cell derived lymphoid malignancies (for example AIDS-related lymphoma; Hodgkin's lymphoma including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma during pregnancy; nonHodgkin's lymphoma including adult and childhood non-Hodgkin's lymphoma and nonHo
  • Haematological cancers may for example be selected from the group consisting of a plasma cell neoplasm or myeloma, a B-cell leukaemia, or a B-cell derived lymphoid malignancy, for example multiple myeloma, chronic lymphocytic leukaemia (CLL), or diffuse large B-cell lymphoma.
  • the haematological cancer is multiple myeloma (for example relapsed/refractory multiple myeloma) or diffuse large B-cell lymphoma.
  • the invention has particular application in the treatment of multiple myeloma.
  • the present invention is directed to each individual feature, system, article, material, kit, and/or method described herein.
  • any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.
  • each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.
  • Example 1 Subgroup analysis from a Phase III trial comparing melphalan flufenamide + dexamethasone with pomalidomide + dexamethasone
  • NCT03151811 A randomized, controlled, open-label, Phase 3 multicenter study (NCT03151811) which enrolled patients with relapsed/refractory multiple myeloma (RRMM) following 2-4 lines of prior therapy and who were refractory to both the last line of therapy and to lenalidomide (>10 mg) administered within 18 months prior to randomization as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients received either melphalan flufenamide + dexamethasone (melflufen- dex) or pomalidomide + dexamethasone (pomalidomide-dex).
  • melphalan flufenamide + dexamethasone melflufen- dex
  • pomalidomide + dexamethasone pomalidomide-dex
  • Arm B Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
  • Table 1 Summary of treatment arms in the Example 1 study.
  • PFS Progression Free Survival
  • ORR Overall Response Rate
  • DOR Duration of Response
  • Safety and Tolerability Number of patients with treatment-emergent adverse events, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 [Time Frame: From start of dosing until 30 days after last dose]: To assess and compare safety and tolerability in Arm A versus Arm B. Number of patients with treatment-emergent adverse events, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 will be presented. No formal statistical analysis will be performed for safety endpoints.
  • Measurable disease defined as any of the following: o Serum monoclonal protein > 0.5 g/dL by protein electrophoresis. o > 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis o Serum free light chain > 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
  • FCBP child bearing potential
  • Active hepatitis B viral infection (defined as HBsAg+) o Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-) o Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation
  • cytotoxic therapies including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization.
  • IMiDs, Pls and or corticosteroids within 2 weeks prior to randomization.
  • Other investigational therapies and monoclonal antibodies within 4 weeks of randomization.
  • Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to randomization
  • Table 2 Patient characteristics in Example 1 study. Key: ASCT, autologous stem cell transplant; dex, dexamethasone; ECOG, Eastern Cooperative Oncology Group; EMD, extramedullary disease; IQR, interquartile range; ISS, International Staging System; melflufen, melphalan flufenamide; pom, pomalidomide; PS, performance status.
  • ASCT autologous stem cell transplant
  • dex dexamethasone
  • ECOG Eastern Cooperative Oncology Group
  • EMD extramedullary disease
  • IQR interquartile range
  • ISS International Staging System
  • melflufen melphalan flufenamide
  • pom pomalidomide
  • PS performance status.
  • a Defined as t(4; 14), t(14; 16), t(14;20), del(17p), gain(lq21), or gain 1 q(+l q) by fluorescence in situ hybridization.
  • PFS Progression-free survival
  • OS overall survival
  • the PFS was longer in the melfufen-dex group than in the pomalidomide-dex comparator group, showing that the Example 1 study met its primary endpoint.
  • Median OS in all patients at the 3 February 2021 and 3 February 2023 data cut-off is shown in Table 3.
  • OS overall survival
  • CI confidence interval
  • the OS hazard ratio is a measure of the relative risk of death at each time point during follow-up when receiving melflufen+dex in relation to pomalidomide+dex: a value below 1 indicates a better treatment effect for melflufen+dex, and a value above 1 indicates a better treatment effect for pomalidomide+dex.
  • Table 4 A shows OS hazard ratios in the pre-specified age groups of the Example 1 trial, i.e. ⁇ 65 years, 65-74 years, and >75 years. Hazard ratios were calculated for all patients in each age group regardless of treatment arm. As seen in Table 4 A, the OS hazard ratios were highly heterogeneous in the predefined age groups overall. Further subgroup analysis, comparing the melflufen+dex and pomalidomide+dex arms in each subgroup, revealed significantly heterogeneous OS outcomes by patient age in the pomalidomide+dex arm but similar OS outcomes by patient age in the melflufen+dex arm.
  • OS overall survival
  • CI confidence interval
  • Table 4B OS Hazard Ratio Per Age Group in MM Patients with 1+ Prior Line of Therapy Key: HR, hazard ratio; MM, multiple myeloma; OS, overall survival.
  • the OS hazard ratios were also highly heterogeneous in the predefined creatinine clearance level groups (see Table 5), which as noted above is an estimate of glomerular filtration rate (GFR) and indicator of renal function, as well as an indicator of cardiovascular function and/or stem cell transplant eligibility, and as such is a proxy for biological age and T-cell function.
  • GFR glomerular filtration rate
  • indicator of renal function as well as an indicator of cardiovascular function and/or stem cell transplant eligibility, and as such is a proxy for biological age and T-cell function.
  • the PFS in the pomalidomide+dex arm were much more homogenous across subgroups, meaning that PFS did not predict the age-related effect on OS seen for pomalidomide i.e, PFS did not act as a survival surrogate for the pomalidomide+dex treatment effect (see Figure 3A).
  • the median OS in months for the 75+ age group was 17.5 months
  • for the 65 - 74 age group was 20.2 months
  • for the ⁇ 65 age group was 32.0 months (see Table 6 below).
  • the hazard ratios for OS and PFS results within the melflufen arm were similar across both 75+ versus ⁇ 65 and 65-74 versus ⁇ 65 age group comparisons (Table 6). Looking also at the median PFS and OS in months for each age group illustrates that PFS was predictive of OS: i.e. the highest median PFS in months in the melflufen+dex arm was in the 75+ age group, and highest median OS in months was seen in this age group; and the lowest median PFS in months was in the ⁇ 65 age group, and lowest median OS in months was seen in this group.
  • HR hazard ratio
  • OS overall survival
  • PFS progression-free survival
  • Figure 4 shows a spline analysis of the hazard of death within each treatment arm in the Example 1 study, as a function of age.
  • the hazard of death in the pomalidomide arm rapidly accelerated in patients older than 65 years of age, and becomes over two times higher in elderly patients (>75 years) compared with younger patients ( ⁇ 65 years of age).
  • Example 2 OS variability as a function of age in other studies
  • Study MM002 was a phase II trial evaluating safety and efficacy of pomalidomide with/without low-dose dexamethasone in RRMM patients who had received at least 2 prior therapies (i.e. the same indication and number of prior therapies as the Example 1 trial), published in Jagannath S et al. (2012) Blood 120 (21):450 (https://doi.org/10.1182/blood.V120.21.450.450).
  • patients ⁇ 65 years of age had a median OS of 19.7 months compared with 11.8 months in patients >65 years of age.
  • the ICARIA study a phase III study in RRMM patients, evaluated isatuximab, pomalidomide and low-dose dex (IsaPd) versus pomalidomide and low-dose dex (Pd) in patients who had received at least 2 prior lines of therapy (Richardson P et al. (2022) Lancet Oncology 23 (3) :416-427).
  • IsaPd pomalidomide and low-dose dex
  • Pd low-dose dex
  • FAS Full Analysis Set
  • HR hazard ratio
  • isa isatuximab
  • OS overall survival
  • pd pomalidomide
  • PFS progression-free survival.
  • Example 2B Analysis of effect modification by age in Phase III MM trials that isolate an IMiD treatment effect
  • Table 8 Summary of hypothesis testing Phase III trials that allow for isolation of lenalidomide or pomalidomide treatment effect in multiple myeloma.
  • MM multiple myeloma
  • OS overall survival
  • CSR clinical study report.
  • Pomalidomide' For pomalidomide, there were three Phase III trials that allowed, in principle, for isolation of the pomalidomide treatment effect and assessment of the effect modification by age subgroup. These were: MM007 (2016) with pomalidomide/bortezomib/dexamethasone vs bortezomib/dexamethasone, OCEAN (Example 1 study) (2021) with melflufen/dexamethasone vs pomalidomide/dexamethasone, and DREAMM-3 (2022) with belantamab mafodotin vs pomalidomide/dexamethasone.
  • Table 9 Summary of data from phase III trials isolating the IMiD treatment effect in MM (including available age subgroups) Key: CSR, clinical study report; HR, hazard ratio; IMiD, immunomodulatory agent; ITT, intent-to-treat; MM, multiple myeloma; NA, not analyzed; OS, overall survival; PFS, progression-free survival.
  • ITT intention to treat
  • OS overall survival
  • pomalidomide behaved identically across the OCEAN and Takeda trial head-to-head comparisons, regardless of the drug class being tested.
  • the OS benefit was significantly heterogeneous, as can be seen from the PFS and OS hazard ratios.
  • each drug class tested conferred an OS benefit that was greater than the PFS benefit in the ITT population (i.e. which included younger patients and therefore had a lower median age).
  • the pomalidomide OS benefit in these trials varied by age, with an OS benefit that was greater than the PFS benefit in the younger patients and worse than the PFS benefit in the older patients. Lenalidomide'.
  • MM015 with lenalidomide/melphalan/ prednisolone vs melphalan/prednisolone (2012) the CALGB/ALLIANCE trial (2018) with lenalidomide vs no lenalidomide and Myeloma XI (2019) with lenalidomide vs no lenalidomide (summarized in Tables 8 and 9).
  • the MM015 trial only included non-transplant eligible patients in a single 65+ age bracket, making it unsuitable for studying detailed effect modification across a range of age brackets within the study.
  • the CALGB/ALLIANCE trial only included younger transplant-eligible patients, again making it unsuitable for studying detailed effect modification by age across a range of age brackets within the study.
  • Lenalidomide therefore behaved similarly to the pomalidomide results described above, with a significant heterogeneity of OS results as a function by patient age.
  • the data for lenalidomide in newly diagnosed MM patients in Table 11 was in line with the observations for pomalidomide in the OCEAN (Example 1 study) trial.
  • the OS benefit from lenalidomide therapy significantly exceeded the PFS benefit in the younger ASCT-eligible patients and was significantly less than the PFS benefit in the older non-ASCT eligible patients. Consequently, the post-progression hazard of death was modulated by the IMiD therapy, namely, to be reduced in the young ASCT-eligible patients and increased in the older non-ASCT eligible patients.
  • the effect of IMiD therapy by age was bi-directional i.e., the post-progression hazard of death was not only increased in older patients but also reduced in younger patients after IMiD intervention.
  • Figure 5 shows the correlation between the IMiD-OS treatment effect and median patient age.
  • the correlation coefficient for the OS IMiD treatment effect and median age in MM studies that allow for the isolation of the IMiD treatment effect was found to be 0.92 (log OS HR and median age).
  • the immunomodulatory agent OS treatment effect and patient age was found to be 0.92 (log OS HR and median age).
  • Figure 6 shows the age subgroup data as a forest plot in studies that allowed for the isolation of the IMiD treatment effect in multiple myeloma and where OS HR subgroup data by age was available (including the Example 1 study, OCEAN).
  • OS HR subgroup data by age including the Example 1 study, OCEAN.
  • Study MM015 investigated melphalan-prednisone (MP) vs. melphalan-prednisone- lenalidomide (MPR) vs. MPR with lenalidomide maintenance (MPR+R(continuous)) in ASCT ineligible NDMM patients 65+ (Palumbo A., et al, N Engl J Med. 2012 May 10;366 (19): 1759-69.) and consequently isolated the lenalidomide treatment effect in elderly NDMM patients. The results from the comparison with MPR vs.
  • MM015 demonstrated a positive relationship between duration of exposure to lenalidomide and efficacy (continuous therapy was more beneficial than fixed duration therapy in the study population), it also simultaneously demonstrated that IMiD-free therapy (i.e., only MP) had the best benefit-risk profile for ASCT ineligible elderly patients.
  • Lenalidomide caused absolute OS harm to these patients.
  • MM015 results were made available they caused a lot of confusion in the scientific community. How was it possible to have both a positive relationship between duration of lenalidomide exposure and efficacy and simultaneous absolute OS harm? At the time the clinical research community believed the unexplainable observed OS harm was due to the combination of lenalidomide with the alkylator, i.e.
  • the MM015 study results adequately describe the lenalidomide treatment effect in elderly patients, and also shows that it is not possible for study MM020 (mentioned above) to provide information on whether elderly ASCT ineligible NDMM patients should receive IMiD-based therapy or not.
  • Thalidomide Phase 3 trials studying thalidomide in ASCT ineligible 65+ NDMM patients demonstrated positive PFS results. However, they generally failed to show OS benefit. The results from the three main thalidomide trials (melphalan + prednisolone (MP) vs. melphalan + prednisolone + thalidomide (MPT)) are presented in Table 12 below.
  • IFM99-06 and IFM01-01 have significantly confounded the entire IMiD myeloma field.
  • the two trials have been discussed and treated as if the benefit-risk profile of thalidomide can be generalized from those results without taking sufficient note of the very specific patient selection in those two studies.
  • the clinical trial results with thalidomide demonstrate the exact same phenomena as in pomalidomide and lenalidomide studies i.e., highly significant survival effect modification by patient age and age-related factors. Because the biological age of the patient group is significantly lowered by the enrolment criteria in IFM99-06 and IFM01-01, the survival data became positive with only minor differences in surrogate activity compared to the other thalidomide studies.
  • Example 2C Analysis of effect modification by age in Phase III non-MM trials that isolate an IMiD treatment effect
  • Table 13 Summary of data from phase 3 clinical trials that isolate the IMiD treatment in non-MM indications, sorted by median patient age (including available age subgroups)
  • CLL chronic lymphocytic leukemia
  • DLBCL diffuse large B-cell lymphoma
  • HR hazard ratio
  • IMiD immunomodulatory agent
  • ITT intent-to-treat
  • NA not analyzed
  • OS overall survival
  • PFS progression-free survival
  • Example 2D Analysis of overall survival data by age in Phase III MM trials with other drug classes OS data as a function of age was also gathered from Phase III MM trials that isolate the treatment effect of other non-IMiD drug classes (proteasome inhibitors (Pls), anti-CD38 and anti-CSl) (shown in Table 15 below).
  • Pls proteasome inhibitors
  • Table 15 shows a correlation between the drug OS treatment effect and median age of 0.36 (log OS HR and median age).
  • Studies with available OS HR age subgroup data are shown in Figures 8 and 9. There was no correlation between patient age and the OS treatment effect of Pls, anti-CD38s and anti-CSl based therapy; instead, there was a consistent survival benefit across the age spectrum.
  • Table 15 Summary of data from phase III clinical trials isolating the treatment effect of non-IMiDs in MM, sorted by clinical study (including available age subgroups).
  • FU follow-up
  • HR hazard ratio
  • ITT intent-to-treat
  • MM multiple myeloma
  • NA not analyzed
  • OS overall survival
  • PFS progression- free survival
  • PI proteasome inhibitor
  • Example 2E 3 rd party analysis and summary of findings
  • the pomalidomide treatment effect indeed has a statistical interaction between age and OS. This conclusion is based on identical behavior for pomalidomide across all trials where the pomalidomide treatment effect can be isolated or where detailed survival data exists for an individual pomalidomide/dex treatment arm (e.g. in OCEAN (Example 1 study), MM002, ICARIA, and MM007). Furthermore, no trial datasets could be identified that supported evidence to the contrary. The Applicant further concludes that the analyses show that immunomodulatory agents as a drug class have significant OS effect modification as a function of patient age. Similar analyses were conducted for PFS, but did not identify a material age differential for PFS outcomes.
  • the homogenous PFS treatment effect and at the same time heterogenous OS treatment effect indicate that PFS as a surrogate endpoint does not capture the full benefitrisk profile of immunomodulatory agents.
  • the observed OS benefit is greater than the observed PFS benefit in young patients and less than the observed PFS benefit in older patients i.e., the post-progression hazard of death is modulated by the IMiD intervention and can both be reduced or increased as a function of primarily patient age.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Cell Biology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Toxicology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD. The invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, and an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient.

Description

THERAPEUTIC TREATMENT FOR HAEMATOLOGICAL CANCER BASED ON THE LEVEL OF T-CELL FUNCTION
Field of the Invention
The present invention concerns the treatment of multiple myeloma. More particularly, this invention concerns an improved way of using the available multiple myeloma treatments by more effectively selecting the most appropriate treatment for a given patient.
Background of the Invention
Multiple myeloma is a plasma cell malignancy characterized by the production of monoclonal protein, anemia, and disordered bone remodeling with lytic bone disease. Until the 2000s, there were very limited treatment options for myeloma, primarily consisting of corticosteroids, melphalan, the VAD regimen (vincristine, doxorubicin, dexamethasone), and autologous stem cell transplant. Median survival during that era was 2-3 years (Holstein and McCarthy, Drugs. 2017 April; 77(5): 505-520. doi:10.1007/s40265-017-0689-l; and Raza et al., Current Cancer Drug Targets, 2017, 17(9), 846-857).
Treatment options were expanded in the early 2000s by the introduction of the immunomodulatory drugs (IMiDs) and the proteasome inhibitors (Pls). They led to an improvement of outcomes for patients, such that many patients now live with the disease for over 10 years. IMiDs are widely used as induction therapy for both transplant eligible and ineligible patients, in the post-transplant setting and for relapsed/refractory disease.
The first IMiD to be authorised for use in multiple myeloma was thalidomide (first authorised for in 2006). Lenalidomide is a more potent second generation IMiD with fewer side effects than thalidomide. It was also first authorised in 2006. It is commonly used in combination with dexamethasone in newly-diagnosed multiple myeloma, relapsed refractory myeloma and as maintenance therapy after autologous stem cell transplantation (ASCT).
Pomalidomide is sometimes referred to as a third generation IMiD and it is 10 times more potent than lenalidomide. It was first authorised in 2013 and it has shown good results in relapsed MM patients and in those refractory to both lenalidomide and bortezomib. All three agents have been studied in combination with multiple different agents, including alkylating agents (e.g. low-dose cyclophosphamide, bendamustine, melphalan), proteasome inhibitors (e.g. bortezomib, carfilzomib, ixazomib), HDAC inhibitors (e.g. panobinostat, ricolinostat), and monoclonal antibodies (e.g.elotuzumab, daratumumab, pembrolizumab, isatuximab). A group of next-generation IMiD agents, the cereblon E3 ligase modulatory drugs (CELMoDs), are currently in development and include avadoimide, iberdomide, and mezigdomide.
Despite the advances that IMiDs and combinations of IMiDs with other agents have brought, there remains a need for further improved therapies for certain patient groups. The present invention seeks to meet the aforementioned need.
Summary of the Invention
The present invention provides, in a first aspect, a method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
The current inventors have found that by following the methods of the current invention, treatment outcomes overall can be improved. In particular, it is possible to avoid giving health-impacting treatments to patients who do not benefit from them.
The invention also provides, in a second aspect, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the level T-cell function of the patient is poor, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD. The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the level T-cell function of the patient is poor, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
The invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD ; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
To date, the most commonly used proxy to estimate the level of T-cell function of a patient is chronological age.
Description of the Figures
Figure 1 shows progression-free survival (PFS, primary endpoint) for a Phase III trial comparing melphalan flufenamide (melflufen) + dexamethasone (“Mel+dex”) with pomalidomide + dexamethasone ("Pom+dex”) (Example 1 study), assessed by independent review committee. Data cut-off: 3 February 2021.
Figure 2 shows overall survival (OS) for the same Phase III trial as described in Figure 1 (Example 1 study). (Mel+dex = melphalan flufenamide (melflufen) + dexamethasone;
Pom+dex = pomalidomide + dexamethasone.) Data cut-off: 3 February 2023. Figure 3A a forest plot showing progression free survival and Figure 3B is a forest plot showing overall survival outcomes by patient age subgroup in the same Phase III trial as in Figure 1 (Example 1 study). (Mel+dex = melphalan flufenamide (melflufen) + dexamethasone; pom+dex = pomalidomide + dexamethasone.) Data cut-off 3 February 2021 (PFS) and 3 February 2023 (OS).
Figure 4 is a spline plot showing the hazard of death as a function of age per treatment arm in the Example 1 study (3 February 2023 data cut off). The grey area depicts the underlying prognostic value of age in itself for the patient study population.
Figure 5 is a scatter plot of overall survival hazard ratio (OS log HR) by age, for IMiDs in Phase III multiple myeloma trials. Correlation coefficient: 0.92.
Figure 6 is a forest plot showing age subgroup data in Phase III studies allowing for the isolation of the IMiD treatment effect in multiple myeloma and where overall survival hazard ratio data by age are available (including OCEANZExample 1 study - data cut off 3 February 2023).
Figure 7 is a scatter plot of overall survival hazard ratio (OS log HR) by age, for IMiDs in Phase III trials for indications other than multiple myeloma. Correlation coefficient: 0.86.
Figure 8 is a scatter plot of overall survival hazard ratio (OS log HR) by age, for non-IMiDs, in Phase III trials for multiple myeloma. Correlation coefficient: 0.36.
Figure 9 is a forest plot showing age subgroup data in Phase III studies of non-IMiDs in multiple myeloma and where overall survival hazard ratio data by age are available.
Detailed Description
As described above, the present invention provides, in a first aspect, a method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD;
Figure imgf000006_0001
if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
All cancer therapies are accompanied by side effects and, in many instances, those are severe. The present inventors have noted a significant age-related decline in the effectiveness of IMiD agents that has not previously been appreciated. The findings show that for a patient aged over 70, the lack of drug efficacy leads to the treatment being detrimental to the patient. Whilst treatment with an IMiD results in significantly reduced post-progression hazard of death in young and fit patients, in old and frail patients there is a significantly increased postprogression hazard of death.
The clinical research community has for well over a decade considered the question regarding betterment of treatment in certain patient groups in view of the inconsistent improvements in treatment outcomes across patient groups, in particular focussing on tolerability and/or co-morbidity of existing treatments. For example, Zweegman et al. (Current Opinion in Oncology, 2017, vol. 29, no. 5, p. 315-321) discussed a frailty-based assessment of elderly multiple myeloma patients in order to define subpopulations who would benefit from treatment. Zweegman et al reported that proteasome inhibitors and IMiDs substantially extended both progression free survival and overall survival in patients including elderly patients and that for 10 years the prognosis of elderly patients had improved due to the introduction and use of IMiDs. Zweegman et al further noted that the very elderly appeared to benefit less, and concluded that this was due to the fact that in general practice the majority of elderly patients either do not receive therapy, or therapy is given but without the addition of proteasome inhibitors or IMiDs, or with a lower dose of such agents. Pozzi et al (British Journal of Haematology, 2013 vol. 163, p. 40-46) describes a population-based analysis of the impact of the ‘novel therapies’ thalidomide, lenalidomide and bortezomib on survival of multiple myeloma patients over three time periods, 1988-96, 1997-05, and 2006- 09 based on data collected by the Modena Cancer Registry. Pozzi et al examined both overall and relative survival by age (<65; 65-74; and >75 years) to determine if the introduction of ‘novel agents’ affected survival in each age group. They reported that both relative survival and overall survival improved over the years, but not equally in the three groups. More specifically, they found that the ‘novel agents’ time-period of 2006-2009 showed a trend to improvement from the previous period for patients <65 years, although this was not statistically significant, and a significant improvement in relative survival compared to both previous periods for the 65-74 year age group. For patients 75+ years of age they found that relative survival did not change over time. Pozzoli et al therefore concluded that the group that seemed to benefit more from the introduction of novel agents (thalidomide, lenalidomide and bortezomib) in the clinical practice was the sub-group of patients aged 65-74, stating that this represented a major therapeutic change. They also concluded that the lack of benefit observed for subject aged 75+ years was due to older age being an important factor influencing survival, and the authors recommended that new therapeutic strategies for elderly patients were needed, without suggesting what such strategies could be.
Sub-group analysis by age of data from a clinical trial described hereinbelow in Example 1 revealed a significant interaction between patient age and overall survival (“OS”) in relapsed/refractory MM patients treated with pomalidomide + dexamethasone. The risk of death (compared with patients of the same age treated with melflufen + dexamethasone) increased significantly with age, with the effect being most pronounced in patients >75 years of age. This effect is surprising, and has not been previously reported for pomalidomide, as illustrated by the fact that it is not reflected in current indications or prescribing instructions for this drug, or any other IMiD.
Looking at the outcomes of other published studies of IMiDs in MM patients with the knowledge of the present invention, the same effect can in fact be discerned if the data are analysed appropriately. For example, the table below summarises the PFS and OS hazard ratios in Phase III MM trials from first line lenalidomide therapy. The 5 studies are presented in order of median age and stem cell transplant eligibility:
Figure imgf000008_0001
Figure imgf000009_0001
Table A: PFS and OS in newly diagnosed multiple myeloma (NDMM) studies that isolates the lenalidomide treatment effect (ASCT: autologous stem cell transplant; ITT, intention to treat; PFS, progression free survival; OS, overall survival; HR, hazard ratio.)
Considering that these studies reported in Table A were conducted during a 10-year period, the data are remarkably consistent in showing a reduction in OS benefit as a function of patient age/ASCT eligibility. This OS heterogeneity is not reflected at all by PFS, which is identical regardless of ASCT eligibility and age. The data for lenalidomide in NDMM is completely in line with the data with pomalidomide in RRMM mentioned above and described in Example 2B below in more detail.
It is noted that the studies that enrolled elderly non-ASCT patients - Myeloma XI and MM015 - demonstrate consistent absolute OS harm from lenalidomide therapy in elderly ASCT ineligible NDMM patients, completely in line with the studies that isolate the pomalidomide treatment effect. The majority of elderly ASCT ineligible MM patients are not eligible for clinical trials primarily due to poor cardiovascular/renal function, factors that consistently worsen the observed absolute OS harm in studies Myeloma XI and MM015 (as well as for pomalidomide in Example 1 described below). It is therefore reasonable to assume that the clinical studies underestimate the risk to elderly ASCT ineligible patients in the real- world clinical setting.
It is also noted that a randomized Phase 3 trial (NCT03829371) studying lenalidomide plus low dose dex (“Rd”) (continuous) vs. bortezomib, melphalan and prednisolone (“VMP”) in ASCT ineligible NDMM patients was reported and halted in 2022 (Bringhen S, et al., Blood (2022) 140 (Supplement 1): 1814-1816). The trial was stopped, and the protocol changed, after the results demonstrated similar PFS results but an OS HR of 1.89 (0.93-3.85) for Rd (continuous) in comparison with VMP. This result is completely in line with the lenalidomide data shown in Table A above.
In addition to the NDMM trials listed above there are seven Phase 3 trials that isolate the lenalidomide treatment effect in other oncology indications. It is worth mentioning that two of these trials - ORIGIN in Chronic Lymphocytic Leukemia (CLL) and MAINSAIL in prostate cancer both had to be halted due to poor OS results in elderly patients despite positive surrogate activity (Chanan-Khan, A., et al, Leukemia 2017, 31(5): 1240-1243; Petrylak, D., et al, Lancet Oncol. 2015;16(4):417-425). They show the same pattern of dissociation between surrogate endpoints and OS as observed in MM as a function of patient age and age-related factors (Petrylak, D., et al, Lancet Oncol. 2015;16(4):417-425; Foa , R., et al, Blood (2016) 128 (22) : 230.; Chanan-Khan, A., et al, Leukemia 2017, 31(5): 1240- 1243; Thieblemont, C., et al, J Clin Oncol. 2017 Aug 1;35(22):2473-2481; Morschhauser, F. et al, N Engl J Med. 2018;379:934-947.; Leonard, J., et al, J Clin Oncol. 2019 May 10;37(14): 1188-1199.; Nowakowski, G., et al, Clinical Oncology 39, no 12 (April 20, 2021), 1317-132).
In conclusion, lenalidomide treatment has significant survival effect modification by one or more age-related factors that is not reflected by surrogate endpoints. There is not a single lenalidomide trial with OS HR demonstrating anything else than absolute OS harm or detriment for elderly ASCT ineligible MM patients, while younger ASCT eligible patients get a survival benefit that is greater than what the surrogates indicate. This pattern is identical to that of pomalidomide. The OS harm/detriment signal is consistent from the age of 70-75. To date, this has not lead to a change of regime prescribing practice in older patients, which is especially concerning given the median age of patients currently on IMiD treatment of around 74.
In summary, it is seen in Table A that the OS benefit from lenalidomide therapy significantly exceeded the PFS benefit in the younger ASCT-eligible patients and was significantly less than the PFS benefit in the older non-ASCT eligible patients. That is to say that the postprogression hazard of death was modulated by the IMiD therapy, namely, to be reduced in the young ASCT-eligible patients and increased in the older non-ASCT eligible patients. The effect of IMiD therapy by age was bi-directional i.e., the post-progression hazard of death was not only increased in older patients but also reduced in younger patients after IMiD intervention.
Sub-group analysis of data from a clinical trial described hereinbelow in Example 1 by creatinine clearance levels, which is an estimate of glomerular filtration rate (GFR) and indicator of renal function and cardiovascular function and a proxy for biological age (and thus level of T-cell function), also revealed a significant interaction between patient age and overall survival (“OS”) in relapsed/refractory MM patients treated with pomalidomide + dexamethasone. The risk of death (compared with patients treated with melflufen + dexamethasone) increased significantly in patients with reduced creatinine clearance levels (and thus reduced GFR and renal function), with the effect being most pronounced in patients having creatinine clearance levels/GFR of less than 90 mL/min, and especially less than 60 mL/min. This effect is surprising, and not been previously reported for pomalidomide, as illustrated by the fact it is not reflected in current indications or prescribing instructions for this drug, nor any other iMiD.
Without being bound by a particular theory, the inventors hypothesise that the age-related effect observed in the data is grounded in decreased T-cell function in older patients. Poor T cell function can also be termed low T cell function.
Based on the data described herein, the current inventors show that IMiD treatment is currently shortening the life-expectancy for MM patients over 70 years of age. Considering that the median age of myeloma patients currently on treatment is 74 years, the patient group over 70 years of age is a significant portion of myeloma patients. In addition, the majority of myeloma patients are 70+ years of age and are not in sufficiently good physical condition to be eligible for clinical trials. As a consequence, the real-world impact is likely to be worse than what is observed in the trials that provide the data analysed herein.
It is surprising that the influence of T-cell function on the effectiveness of the IMiDs on OS has not been studied. It is also surprising that the influence of age on the effectiveness of the IMiDs on OS has not been studied in detail. Similarly, the labels for their use contain no information regarding possible differential efficacy of safety among different patient age groups. The prevailing view, and the current stated view of the FDA, is that there is no interaction between age and treatment with IMiDs on OS.
It is accordingly very surprising that the current inventors have found that OS can be significantly improved by use of a treatment as determined in line with the current invention.
It is possible that the age interaction between use of IMiDs and OS has not previously been noted due to the design of early randomized trials of IMiDs. In the registrational trials for lenalidomide (MM009, MM010) and pomalidomide (MM003), the comparator was high- dose dexamethasone (HDex). HDex is given as a 40 mg dose on Day 1-4, 9-12 and 17-20 in a 28-day cycle as compared to low-dose dexamethasone treatment which is given in the same dose, 40 mg, but less frequently (Day, 1, 8, 15 and 22 in a 28-day cycle). The ECOG group showed in February of 2007 (n=445, Rajkumar et al) that HDex compared to LDex (low-dose dexamethasone) has a highly heterogenous detrimental OS effect as a function of patient age, and that older myeloma patients had a dramatic reduction in overall survival when treated with HDex. When comparing the lenalidomide and pomalidomide treatment groups with the HDex groups in the trials, the detrimental effect of HDex as a function of patient age would have masked the OS interaction between patient age and the IMiD treatment effect in MM009, MM010 and MM003. Furthermore, those trials had patient groups with low median ages. In the overall study populations investigated, the detrimental effect on survival in elderly would therefore not have impacted on the OS result in a noticeable way.
However, if the effectiveness of an IMiD is not compared with HDex, and if more elderly patients are investigated separately, then the differential effectiveness of IMiD treatment in different age groups is revealed. As the median age of myeloma patients currently on treatment is 74 years, it is important to study this age group.
Most studies have focussed on Progression Free Survival as a surrogate end point for OS. The present inventors have now shown unambiguously, and for the first time, that PFS is not, in fact, a surrogate end point for OS in these treatments, and furthermore that IMiDs, as a class, modulate the progressive event as a function of underlying T-cell function in the patient.
Quantification of T-cell function:
The quantification of T-cell function in step i. can be carried out in many different ways. For example, in the method of the invention, the quantification of T-cell function in step i. can be carried out by assessing the patient’s biological age and/or gender. A low biological age is indicative of a high level of T cell function. Female gender is also indicative of a high level of T cell function. In general, a female patient has a higher level of T cell function than a male patient of the same age. There are several ways in which a patient’s biological age can be assessed. One or more of the following factors may be used as a proxy for biological age: chronological age, transplant eligibility, cardiovascular function and renal function. Cardiovascular function is determined by the level of renal function and other age-related aspects and it is therefore also useful as a proxy for biological age. Algorithms have also been developed for the estimation of biological age. In the method of the invention, a low biological age is indicative of high level of T cell function.
Biological age, and use of chronological age, transplant eligibility and cardiovascular function as proxies for biological age are discussed in further detail below.
Chronological age:
The simplest proxy for biological age is chronological age. That is to say that in step i, the method comprises an assessment of the patient’s chronological age. An age of less than 70 years is generally indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the chronological age of the patient is less than 70 years. An alternative treatment is administered if the chronological age of the patient is 70 years or older.
In view of the better general T cell activity in females, in a female patient, a cut-off of 71, 72 or 73 years can be used in place of the cut-off of 70 years, which is appropriate for a male patient.
As T cell function declines further with age, an age of 75 years or more is indicative of a lower level of T cell function. In an embodiment, step ii. comprises administering the IMiD if the chronological age of the patient is less than 75 years, and administering an alternative treatment if the chronological age of the patient is 75 years or older.
In view of the better general T cell activity in females, in a female patient, a cut-off of 76, 77 or 78 years can be used in place of the cut-off of 75 years, which is appropriate for a male patient. Accordingly, the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, administering an IMiD; or if the chronological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD.
Similarly, the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 75 years, administering an IMiD; or if the chronological age of the patient is 75 years or more, administering an alternative therapeutic agent and not administering an IMiD.
Similarly, regarding the other aspects of the invention, the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the chronological age of the patient is 70 years or more, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
(and similarly for a 75 year cut-off)
The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the chronological age of the patient is 70 years or more, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
(and similarly for a 75 year cut-off)
The invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the chronological age of the patient; ii. if the chronological age of the patient is less than 70 years, administering an IMiD, administering the IMiD; or if the chronological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD.
Stem Cell transplant eligibility:
In the method of the invention, transplant eligibility may be used as a proxy for biological age. A patient who is considered eligible for a transplant is considered sufficiently biologically young to have high T-cell function.
That is to say that transplant eligibility can be used indirectly as a method for quantification of T-cell function. Thus, step (i) may be quantifying the level of T-cell function of the patient by determining if a patient is eligible for stem cell transplantation. If a patient is considered eligible for stem cell transplantation, then they can be considered to have high T- cell function in the context of the current invention.
Eligibility for stem cell transplant is something that is often determined for multiple myeloma patients, as stem cell transplantation is an effective treatment for the condition in certain patients. For example, the UK’s National Institute of Health and Care Excellence set out that Bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high- dose chemotherapy with haematopoietic stem cell transplantation. Eligibility for stem cell transplantation is generally determined by the physician. The factors that are taken into account include chronological age and gender. In some settings, an age cut-off of 65 years is used. In others, the cut-off can be 70 years. Belotti et al. (American Journal of Hematology, Vol 95(7), 759-765) noted that IMWG frailty score was a good predictor of successful stem cell transplant in patients aged 70 or over. The International Myeloma Working Group (IMWG) frailty score is based on age (<75, 75-80, >80 years, score 0, 1, 2 respectively), Charlson Comorbidity Index (<1 or >2, score 0 or 1) and (instrumental) Activities Daily Living score (ADL >4 or <4, score 0 or 1, iADL >5 or <5, score 0 or 1). They concluded that the IMWG frailty score was a good guide for identifying those patients aged >70 years who can safely and effectively be treated with ASCT.
Cardiovascular function:
An important factor that is taken into account when determining eligibility for stem cell transplantation is a patient’s level of cardiovascular function. Cardiovascular function is commonly used as a proxy for biological age in various medical settings and it is considered to be a stronger predictor of biological age than chronological age in elderly patients. Cardiovascular function is influenced by a patient’s level of heart function, the performance of their vascular system and the level of renal function. Renal function is the simplest and most commonly assessed of those.
It is common to exclude patients with severe cardiovascular dysfunction from clinical trials in oncology, including in multiple myeloma, and poor cardiovascular function is a predictor of poor outcome in stem cell transplantation.
Accordingly, the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, administering an IMiD; or if the patient is not considered eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an IMiD.
Similarly, regarding the other aspects of the invention, the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the patient is not considered eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the patient is not considered eligible for stem cell transplantation, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered. The invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the patient is considered eligible for stem cell transplantation, administering an IMiD; or if the patient is not considered eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an IMiD.
Renal function:
As noted above, an important factor that is taken into account when determining eligibility for stem cell transplantation is a patient’s level of cardiovascular function, and level of renal function is the simplest and most commonly assessed parameter to determine cardiovascular function.
It is common to exclude patients with poor renal function, as indicated by poor glomerular filtration rate (GFR), from clinical trials in oncology, including in multiple myeloma, as for several reasons such as differences in drug pharmacokinetics and poor patient prognosis (associated comorbidities and high biological patient age).
The level of renal function for a patient can be assessed in various ways, for example by measuring plasma level of creatinine and determining the patient’s estimated GFR by the Cockcroft-Gault formula (Cockcroft D. W., Gault M. H., Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16(1):31-41), 24 hour urine creatinine collection or other estimation methods (for example Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations).
All of the methods to determine a patient’s GFR result in an estimation in mL/min. A GFR of 90 mL/min or more as determined by any method (for example by the Cockcroft-Gault formula) is indicative of normal renal function, normal cardiovascular function, transplant eligibility and/or low biological age. A GFR of less than 90 mL/min as determined by any method (for example by the Cockcroft-Gault formula) is indicative of renal impairment (for example, minor, moderate or severe renal impairment), cardiovascular dysfunction/impairment of cardiovascular function (for example, minor, moderate or severe cardiovascular dysfunction/impairment of cardiovascular function), transplant ineligibility and/or high biological age. A GFR of 60 mL/min or more as determined by any method (for example by the Cockcroft-Gault formula) is indicative of normal renal function (90 mL/min or more) or minor renal impairment (60 mL/min or more to less than 90 mL/min), normal cardiovascular function (90 mL/min or more) or minor cardiovascular dysfunction/impairment of cardiovascular function (60 mL/min or more to less than 90 mL/min), and/or low biological age (90 mL/min or more) or moderate biological age (60 mL/min or more to less than 90 mL/min). A GFR of less than 60 mL/min as determined by any method (for example by the Cockcroft-Gault formula) is indicative of moderate or severe renal impairment, moderate or severe cardiovascular dysfunction/impairment of cardiovascular function, transplant ineligibility, and/or high or very high biological age. A GFR of 45 mL/min or more as determined by any method (for example by the Cockcroft- Gault formula) is indicative of normal renal function (90 mL/min or more), minor renal impairment (60 mL/min or more to less than 90 mL/min) or moderate renal impairment (45 mL/min or more to less than 60 mL/min); normal cardiovascular function (90 mL/min or more), minor cardiovascular dysfunction/impairment of cardiovascular function (60 mL/min or more to less than 90 mL/min) or moderate cardiovascular function (45 mL/min or more to less than 60 mL/min); and/or low biological age (90 mL/min or more), moderate biological age (60 mL/min or more to less than 90 mL/min) or high biological age (45 mL/min or more to less than 60 mL/min). A GFR of less than 45 mL/min as determined by any method (for example by the Cockcroft-Gault formula) is indicative of severe renal impairment, severe cardiovascular dysfunction/impairment of cardiovascular function, transplant ineligibility, and/or very high biological age.
Accordingly, the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 90 mL/min or more administering an IMiD; or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
In an alternative embodiment, the invention also provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 60 mL/min or more administering an IMiD; or if the patient has a GFR of less than 60 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
In an alternative embodiment, the invention also provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 45 mL/min or more administering an IMiD; or if the patient has a GFR of less than 45 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
Similarly, regarding the other aspects of the invention, the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 90 mL/min or more, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the patient has a GFR of less than 90 mL/min, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
(and similarly for a 60 mL/min GFR cut-off or for a 45 mL/min GFR cut-off) The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 90 mL/min or more, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the patient has a GFR of less than 90 mL/min, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
(and similarly for a 60 mL/min GFR rate cut-off or for a 45 mL/min GFR cut-off)
The invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the patient has a GFR of 90 mL/min or more, administering an IMiD; or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
(and similarly for a 60 mL/min GFR cut-off or for a 45 mL/min GFR cut-off)
Renal function/cardiovascular function/transplant eligibility and chronological age: In one especially preferred embodiment, eligibility for stem cell transplantation and chronological age of the patient are used in combination to assess/quantify/determine T-cell function of the patient.
For example, in an especially preferred embodiment, the present invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the chronological age of the patient is less than 70 years, and if the patient is considered eligible for stem cell transplantation, administering an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient is considered not eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an ImiD.
(and similarly for a 75 year cut-off)
Similarly, regarding the other aspects of the invention, the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the chronological age of the patient is less than 70 years, and if the patient is considered eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an ImiD; or if the chronological age of the patient is 70 years or more, and/or if the patient is considered not eligible for stem cell transplantation, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an ImiD.
(and similarly for a 75 year cut-off)
The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (ImiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the chronological age of the patient is less than 70 years, and if the patient is considered eligible for stem cell transplantation, determining that overall survival benefit is likely to be greater for treatment with an ImiD; or if the chronological age of the patient is 70 years or more, and/or if the patient is considered not eligible for stem cell transplantation, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an ImiD should not be administered.
(and similarly for a 75 year cut-off)
The invention also provides, in a fourth aspect, an immunomodulatory imide drug (ImiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the chronological age of the patient, and determining if a patient is considered eligible for stem cell transplantation, taking into account the cardiovascular function of the patient (for example taking into account factors including chronological age, renal function and cardiovascular function of the patient); ii. if the chronological age of the patient is less than 70 years, and if the patient is considered eligible for stem cell transplantation, administering an ImiD; or if the chronological age of the patient is 70 years or more, and/or if the patient is considered not eligible for stem cell transplantation, administering an alternative therapeutic agent and not administering an ImiD.
(and similarly for a 75 year cut-off)
In one very especially preferred embodiment, renal function (which is an indicator of cardiovascular function) and chronological age of the patient are used in combination to assess/quantify/determine T-cell function of the patient.
For example, in especially preferred embodiments, the present invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, administering an ImiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an ImiD.
(and similarly for a 75 year cut-off and/or for a 60 mL/min GFR cut-off and/or for a 45 mL/min GFR cut-off)
Similarly, regarding the other aspects of the invention, the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
(and similarly for a 75 year cut-off and/or for a 60 mL/min GFR cut-off and/or for a 45 mL/min GFR cut-off)
The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
(and similarly for a 75 year cut-off and/or for a 60 mL/min GFR cut-off and/or for a 45 mL/min GFR cut-off)
The invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. assessing the chronological age of the patient, and assessing the renal function of the patient by determining the patient’s GFR (for example determining the patient’s GFR by the Cockcroft-Gault formula); ii. if the chronological age of the patient is less than 70 years, and if the patient has a GFR of 90 mL/min or more, administering an IMiD; or if the chronological age of the patient is 70 years or more, and/or if the patient has a GFR of less than 90 mL/min, administering an alternative therapeutic agent and not administering an IMiD.
(and similarly for a 75 year cut-off and/or for a 60 mL/min GFR cut-off and/or for a 45 mL/min GFR cut-off)
Further assessments of biological age:
Biological age is a concept that is widely used in various areas of medicine. Numerous methods have been developed for assessing it and many were reviewed by Jylhava et al. (J. Jylhava et al., EBioMedicine, 2017, 21, 29-36). A number of methods are discussed below.
In the context of the current invention, a patient is considered to have a high level of T cell function if they have a biological age of less than 70 years. That is to say that in step i, the method comprises an assessment of the patient’s biological age and a biological age of less than 70 years is generally indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the biological age of the patient is less than 70 years.
An alternative treatment is administered if the biological age of the patient is 70 years or older.
As T cell function declines further with age, a biological age of 75 years or more is indicative of a lower level of T cell function. In an embodiment, step ii. comprises administering the IMiD if the biological age of the patient is less than 75 years, and administering an alternative treatment if the biological age of the patient is 75 years or older.
The American Federation for Aging Research set out the following criteria for ageing biomarkers:
1) It must predict the rate of ageing. Meaning it should be able to predict remaining life expectancy better than chronological age.
2) It must monitor mechanisms underlying the ageing process but not a specific disease.
3) It must be able to be tested repeatedly without harming the individual.
4) It must be testable in both laboratory animals and humans.
Many methods for determining biological age use algorithms. Biological age can be calculated according to the algorithm described by Klemera and Doubal using multiple biomarkers (Klemera and Doubal, Mechanisms of Ageing and Development, 2006, 127, 3, 240-248). Biomarkers can be, but are not excluded to: C-reactive protein, serum creatinine, glycated haemoglobin, serum albumin, serum total cholesterol, cytomegalovirus optical density, serum urea nitrogen, serum alkaline phosphatase, renal function, forced expiratory volume, and systolic blood pressure. For all of the biomarkers noted the Pearson Correlation with chronological age is greater than ±0.10. Other biomarkers can be used as long as their Pearson Correlation with chronological age is known and preferably, if it is high (> 0.10).
The Biological Age (BEC) estimate is based upon minimising the distance between m regression lines and m biomarker points with a value %j, within an m dimensional space of all biomarkers:
Figure imgf000026_0001
Where C is the chronological age of the subject and Sj is the root mean squared error from the regressions between each biomarker and chronological age. To calculate the value
Figure imgf000027_0001
the following equations are used sequentially:
Figure imgf000027_0002
Where prefers to the variance explained by regression chronological age on m biomarkers, and is used to calculate the characteristic correlation coefficient, rchar. Estimates BE; represent averages of m values.
The Klemera and Doubal method provides an improvement over other algorithms for calculating Biological Age. Alternative algorithms include Principal Component Analysis or Factor Analysis. Alternatively, Multiple Linear Regression can be used, by applying the equation below:
Figure imgf000027_0003
Where coefficients ao, aj are determined so that the ‘sum of squares’ is a minimum:
Figure imgf000027_0004
Levine and Belsky et al. have validated and compared these ageing algorithms, which showed the Klemera and Doubal algorithm predicts Biological Age, and mortality, most accurately (M.E. Levine, Journals of Gerontology: BIOLOGICAL SCIENCES, 2013, 68, 6, 667-674; D.W. Belsky et al., Proceedings of the National Academy of Sciences, 2015, 112, 30, E4104- E4110).
An alternative approach is to use the epigenetic clock. It has been known for a some time that DNA methylation associates with age, but recently supervised machine learning methods have been used to calculate the DNA methylation age, also referred to as the epigenetic clock, as a viable Biological Age predictor. The two seminal epigenetic clocks are the Hannum Clock (G. Hannum, Mol. Cell., 2013, 49, 2, 359-367; WO 2014/075083 Al) and the Horvath Clock (S. Bocklandt et al., PLoS One, 2011, 6, 6, el4821; S. Horvath, Genome Biology, 2013, 14, R115; WO 2015/048665 A2).
The Horvath clock is a multi -tissue predictor based on methylation levels of 353 Cytosine- phosphate-Guanine (CpG) sites on the Illumina 27 k array. The Hannum clock uses 71 CpG sites from the Illumina 450 k array and performs best using whole blood samples. A free version of the calculator for DNA methylation age based on the Illumina Infmium platforms can be found on: https://dnamage.genetics.ucla.edu/, provided by S. Hovarth and the University of California, Los Angeles.
Other models of the epigenetic clock can also be used to calculate DNA methylation age, such as the PhenoAge clock (M. E. Levine et al., Aging, 2018, 10, 4, 573-591; WO 2019/143845 Al) and the GrimAge clock (A. T. Lu et al., Aging, 2019, 11, 2, 303-327; WO 2020/076983 Al). These also use Illumina Infmium technology.
Weidner et al. reported a more practical way to measure DNA methylation age in blood in 2014, whereby they calculate age from DNA methylation data at just three CpG sites (C. I. Weidner et al., Genome Biology, 2014, 15, R24). The reduction in CpG sites meant that pyrosequencing data could be used. Therefore, it does not require Illumina Infmium technology, and is highly practical and cost-effective; however, this method is less accurate than other epigenetic clocks. A free online calculator can be used for this technology: http://www.molcell.rwth-aachen.de/epigenetic-aging-signature/, provided by W. Wagner and the University of Aachen, Germany. The equation used for the calculator is as follows:
Predicated age (in years) = 38.0 - 26.4a - 23.7p + 164.7y a = beta value at CpG cg02228185
P = beta value at CpG cg25809905 y = beta value at CpG upstream to cgl7861230
Telomere length is a further indicator of age. Telomeres are repetitive DNA sequences that cap chromosomes and shorten every time the cell divide; thus, leukocyte telomere length (LTL) is a popular marker for biological ageing. LTL correlates less well with chronological age than the epigenetic clocks and is therefore a less accurate predictor of Biological Age, however it offers a more practical biomarker to measure. For example, a method to calculate the telomeric brink age (TBage) was reported by T. Steenstrup et al. in 2017, who measured the LTL by southern blots of the terminal restriction measurements as previously described (T. Steenstrup et al., Aging, 2017, 9, 4, 1130-1142):
LTL-5kb
TBMt = age+— — r— —
" atrition
Where attrition, the rate of telomere shortening, can be between 15-45 bp/year.
Accordingly, the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 70 years, administering an IMiD; or if the biological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD.
Similarly, the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 75 years, administering an IMiD; or if the biological age of the patient is 75 years or more, administering an alternative therapeutic agent and not administering an IMiD.
Similarly, regarding the other aspects of the invention, the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 70 years, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the biological age of the patient is 70 years or more, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
(and similarly for a 75 year cut-off)
The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method); ii. if the biological age of the patient is less than 70 years, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the biological age of the patient is 70 years or more, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
(and similarly for a 75 year cut-off)
The invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. determining biological age of the patient (for example using the Klemera and Doubal method, the Hannum Clock method or the Horvath Clock method);; ii. if the chronological age of the patient is less than 70 years, administering an IMiD, administering the IMiD; or if the chronological age of the patient is 70 years or more, administering an alternative therapeutic agent and not administering an IMiD. (and similarly for a 75 year cut-off)
Direct T-cell function measurement:
T-cell function in a patient can be assessed by carrying out direct measurement using established assays.
Accordingly, the invention provides a method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
Similarly, regarding the other aspects of the invention, the invention also provides, a method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the level T-cell function of the patient is poor, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
The invention further provides, in a third aspect, a method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the level T-cell function of the patient is poor, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
The invention also provides, in a fourth aspect, an immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. quantifying the level of T-cell function of the patient by direct T-cell function measurement; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
IMiD Drugs:
In the method of the invention, one outcome is the use of an IMiD in treatment. Currently authorised IMiDs include thalidomide, pomalidomide, or lenalidomide. Other IMiDs include cereblon E3 ligase modulatory drugs (CELMoDs). Examples of CELMoDs include avadoimide, iberdomide, and mezigdomide. The IMiD is thus preferably selected from the group consisting of thalidomide, pomalidomide, lenalidomide, avadoimide, iberdomide, and mezigdomide. The IMiD is more preferably selected from the group consisting of thalidomide, pomalidomide, lenalidomide and mezigdomide. The IMiD is more preferably selected from the group consisting of thalidomide, pomalidomide, or lenalidomide. For example, the IMiD is pomalidomide.
Alternative treatments:
In the method of the invention, an alternative outcome is the administration of an alternative therapeutic agent and not the administration of an IMiD.
Many treatments have been established for multiple myeloma. The alternative therapeutic agent is preferably selected from the group consisting of: alkylator, anti-CD38 agents and proteasome inhibitors. A combination of such agents may be used. Suitable alkylators include melflufen, melphalan, bendamustine, and cyclophosphamide. Especially suitable alkylators are N-mustard containing alkylators, for example melflufen, melphalan and an alkylator as described in WO2022/263679, for example any one of Example Compounds 1 to 51 of WO2022/263679, the contents of which are incorporated herein by reference.
Suitable anti-CD38 agents include anti-CD38 antibodies, for example daratumumab and isatuximab, elotuzumab and belantamab, in particular daratumumab. Suitable proteasome inhibitors include bortezomib, carfilzomib and ixazomib.
In certain preferred embodiments, the alternative therapeutic agent is an alkylator, for example melflufen, melphalan, bendamustine, cyclophosphamide, or an alkylator as described in WO2022/263679 (for example melflufen, melphalan, bendamustine, or cyclophosphamide); and more preferably an N-mustard containing alkylator; and even more preferably melflufen, melphalan or an alkylator as described in WO2022/263679, for example melflufen, melphalan or any one of Example Compounds 1 to 51 of WO2022/263679; and even more especially melflufen. In certain preferred embodiments, the alternative therapeutic agent is an alkylator and a steroid, for example an alkylator and dexamethasone. For example, melflufen and dexamethasone, and in particular 40 mg melflufen on Day 1 and dexamethasone 40 mg or 20mg on Days 1, 8, 15 and 22 of each 28- day cycle.
Haematological cancers:
The invention has application in the treatment of haematological cancers. Haematological cancers may include for example plasma cell neoplasms and myelomas (for example MGUS, plasmacytoma, smouldering myeloma, multiple myeloma, relapsed/refractory multiple myeloma, light chain myeloma, or non-secretory myeloma), B-cell leukaemias (for example, acute lymphoblastic leukaemia including adult and childhood acute lymphoblastic leukemia; chronic lymphocytic leukemia; and hairy cell leukemia), and B-cell derived lymphoid malignancies (for example AIDS-related lymphoma; Hodgkin's lymphoma including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma during pregnancy; nonHodgkin's lymphoma including adult and childhood non-Hodgkin's lymphoma and nonHodgkin's lymphoma during pregnancy; Waldenstrom macroglobulinemia; primary mediastinal large B cell lymphoma; diffuse large B cell lymphoma; follicular lymphoma; mantle cell lymphoma; hairy cell lymphoma; and primary central nervous system lymphoma).
Haematological cancers may for example be selected from the group consisting of a plasma cell neoplasm or myeloma, a B-cell leukaemia, or a B-cell derived lymphoid malignancy, for example multiple myeloma, chronic lymphocytic leukaemia (CLL), or diffuse large B-cell lymphoma. In an embodiment of the invention, the haematological cancer is multiple myeloma (for example relapsed/refractory multiple myeloma) or diffuse large B-cell lymphoma.
The invention has particular application in the treatment of multiple myeloma.
Whilst the present invention has been described and illustrated with reference to particular embodiments, it will be appreciated by those of ordinary skill in the art that the invention lends itself to many different variations not specifically illustrated herein.
Equivalents
The invention has been described broadly and generically herein. Those of ordinary skill in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention. Further, each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.
Incorporation by Reference
The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The applicant reserves the right physically to incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.
The following Examples illustrate the invention.
Examples
Example 1 : Subgroup analysis from a Phase III trial comparing melphalan flufenamide + dexamethasone with pomalidomide + dexamethasone
Study Description
Brief Summary. A randomized, controlled, open-label, Phase 3 multicenter study (NCT03151811) which enrolled patients with relapsed/refractory multiple myeloma (RRMM) following 2-4 lines of prior therapy and who were refractory to both the last line of therapy and to lenalidomide (>10 mg) administered within 18 months prior to randomization as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients received either melphalan flufenamide + dexamethasone (melflufen- dex) or pomalidomide + dexamethasone (pomalidomide-dex).
Detailed Description'. A randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who are refractory to both the last line of therapy and to lenalidomide as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients were randomized to either one of two arms (see Table 1 below): Arm A: Melphalan flufenamide (Melflufen) 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Arm B: Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Patients > 75 years of age had a reduced dose of dexamethasone of 20 mg on Days 1, 8, 15 and 22 for both Arm A and Arm B. Patients received treatment until such time as there is documented disease progression, unacceptable toxicity or the patient/treating physician determines it is not in the patient's best interest to continue. Dose modifications and delays in therapy were implemented based on patient tolerability as detailed in the protocol. In the event of a cycle delay, unrelated to dexamethasone toxicity, it was recommended to continue dexamethasone weekly. Study Design
Study Type: Interventional (Clinical Trial)
Actual Enrollment: 495 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Controlled, Open-label, Phase 3 Study of
Melflufen/Dexamethasone Compared With Pomalidomide/Dexamethasone for Patients With Relapsed Refractory Multiple Myeloma Who Are Refractory to Lenalidomide
Arms and Interventions
Figure imgf000036_0001
Figure imgf000037_0001
Table 1 : Summary of treatment arms in the Example 1 study.
Primary Outcome Measures:
1. Progression Free Survival (PFS) [Time Frame: From randomization to time of progression, or, if no progression, 24 months after end of treatment]: To compare the PFS of melflufen plus dexamethasone (Arm A) versus pomalidomide plus dexamethasone (Arm B) as assessed by the Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). Secondary Outcome Measures:
1. Overall Response Rate (ORR) [Time Frame: From randomization until best response achieved before confirmed progression, or if no progression, 24 months after end of treatment]: To assess and compare the ORR in Arm A versus Arm B. 2. Duration of Response (DOR) [Time Frame: From first evidence of response until confirmed progression, or if no progression, 24 months after end of treatment]: To assess and compare the DOR in Arm A versus Arm B.
3. Overall Survival (OS) [Time Frame: From randomization until end of study (2 years after confirmed progression)]: To assess and compare OS in Arm A versus Arm B.
4. Safety and Tolerability: Number of patients with treatment-emergent adverse events, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 [Time Frame: From start of dosing until 30 days after last dose]: To assess and compare safety and tolerability in Arm A versus Arm B. Number of patients with treatment-emergent adverse events, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 will be presented. No formal statistical analysis will be performed for safety endpoints.
Eligibility Criteria
Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Inclusion Criteria:
1. Male or female, age 18 years or older
2. A prior diagnosis of multiple myeloma with documented disease progression requiring further treatment at time of screening
3. Measurable disease defined as any of the following: o Serum monoclonal protein > 0.5 g/dL by protein electrophoresis. o > 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis o Serum free light chain > 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
4. Received 2-4 prior lines of therapy, including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to both the last line of therapy and to lenalidomide (> 10 mg) administered within 18 months prior to randomization. Refractory to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle
5. Life expectancy of > 6 months
6. Eastern Cooperative Oncology Group (ECOG) performance status < 2
7. Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to start of treatment. Participants must agree to ongoing pregnancy testing. All patients must be willing to comply with all requirements of the USA pomalidomide Risk Evaluation and Mitigation Strategy (REMS) program or the pomalidomide Pregnancy Prevention Plan (PPP)
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of < 470 msec Fridericia Formula
10. The following laboratory results must be met during screening and also immediately before study drug administration on Cycle 1 Day 1 : o Absolute neutrophil count (ANC) > 1,000 cells/mm3 (1.0 x 109/L) o Platelet count > 75,000 cells/mm3 (75 x 109/L) o Hemoglobin > 8.0 g/dl o Total Bilirubin < 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilberts syndrome, that have been reviewed and approved by the medical monitor o Aspartate transaminase (AST /SGOT) and alanine transaminase (ALT/SGPT)
< 3.0 x ULN o Renal function: Estimated creatinine clearance by Cockcroft-Gault formula > 45 mL/min
11. Must be able to take antithrombotic prophylaxis
12. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC-line], or central venous catheter) (Insertion only required if randomized to Arm A)
Exclusion Criteria:
1. Primary refractory disease (i.e. never responded (> MR) to any prior therapy) 2. Evidence of mucosal or internal bleeding or platelet transfusion refractory
3. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study
4. Prior exposure to pomalidomide
5. Known intolerance to IMiDs
6. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization
7. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance
8. Pregnant or breast-feeding females
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
10. Known human immunodeficiency virus or active hepatitis C viral infection
11. Active hepatitis B viral infection (defined as HBsAg+) o Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-) o Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation
12. Concurrent symptomatic amyloidosis or plasma cell leukemia
13. POEMS syndrome
14. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. IMiDs, Pls and or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks of randomization. Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to randomization
15. Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted)
16. Prior peripheral stem cell transplant within 12 weeks of randomization
17. Prior allogeneic stem cell transplantation with active graft-versus-host-disease. 18. Prior major surgical procedure or radiation therapy within 4 weeks of the randomization
19. Known intolerance to steroid therapy Table 2, below, summarises some of the characteristics of the patients included in the Example 1 study.
Figure imgf000041_0001
Table 2: Patient characteristics in Example 1 study. Key: ASCT, autologous stem cell transplant; dex, dexamethasone; ECOG, Eastern Cooperative Oncology Group; EMD, extramedullary disease; IQR, interquartile range; ISS, International Staging System; melflufen, melphalan flufenamide; pom, pomalidomide; PS, performance status. aDefined as t(4; 14), t(14; 16), t(14;20), del(17p), gain(lq21), or gain 1 q(+l q) by fluorescence in situ hybridization. bRefractory to >1 immunomodulatory drug, >1 proteasome inhibitor, and >1 anti-CD38 monoclonal antibody. Tailure to achieve at least a minimal response or progression on therapy within 60 days of the last dose of treatment.
Results
Analysis was performed on data available at two cut-off dates: (1) primary data cut-off of 3 February 2021 (for assessment of progression-free survival (PFS) and initial assessment of overall survival (OS); and (2) updated data cut-off of 3 February 2023 (for final assessment of OS and all subgroup analyses presented below).
Progression-free survival (PFS) and overall survival (OS) in all patients
As shown in Figure 1, the median PFS in all patients was 6.8 months (95% CI 5.0- 8.5; 165 [67%] of 246 patients had an event) in the melflufen-dex group and 4.9 months (4.2-5.7; 190 [76%] of 249 patients had an event) in the pomalidomide-dex group (HR 0.79 [95% CI 0.64-0.98]; 2-sided stratified log-rank p=0.03) at a median follow-up of 15.5 months (IQR 9.4-22.8) in the melflufen-dex group and 16.3 months (10.1-23.2) in the pomalidomide-dex group. Thus, the PFS was longer in the melfufen-dex group than in the pomalidomide-dex comparator group, showing that the Example 1 study met its primary endpoint.
OS in all patients (N=246 in melflufen-dex group; N=249 in pomalidomide-dex group) at the 3 February 2023 data cut-off is shown in Figure 2. Median OS in all patients at the 3 February 2021 and 3 February 2023 data cut-off is shown in Table 3.
Figure imgf000042_0001
Table 3, Overall survival in all patients.
Key: OS, overall survival; CI, confidence interval. As seen in Table 3, the median OS was higher in the pomalidomide-dex group than the melflufen-dex group, in both the 3 February 2021 and 3 February 2023 data cut-offs, with a hazard ratio >1 at each cut-off. OS hazard ratio was 1.10 (95% CI, 0.85-1.44) in the 3 February 2021 data cut-off and 1.09 (95% CI, 0.88-1.35) in the 3 February 2023 data cut-off. The OS hazard ratio is a measure of the relative risk of death at each time point during follow-up when receiving melflufen+dex in relation to pomalidomide+dex: a value below 1 indicates a better treatment effect for melflufen+dex, and a value above 1 indicates a better treatment effect for pomalidomide+dex.
The OS results were surprising given the positive PFS results for the melflufen-dex group and warranted further investigation. Further analysis, including subgroup analyses, were therefore performed for the 3 February 2023 data cut-off to determine if OS heterogeneity in patient sub-populations was contributing to the dissociation between the overall PFS and OS results.
OS heterogeneity by patient sub-group
Table 4 A shows OS hazard ratios in the pre-specified age groups of the Example 1 trial, i.e. <65 years, 65-74 years, and >75 years. Hazard ratios were calculated for all patients in each age group regardless of treatment arm. As seen in Table 4 A, the OS hazard ratios were highly heterogeneous in the predefined age groups overall. Further subgroup analysis, comparing the melflufen+dex and pomalidomide+dex arms in each subgroup, revealed significantly heterogeneous OS outcomes by patient age in the pomalidomide+dex arm but similar OS outcomes by patient age in the melflufen+dex arm. For PFS, however, age was consistent in the pomalidomide+dex arm with 4.9 months of PFS regardless of the age category. This was in contrast to the observations on OS, where age had a major impact on the performance of pomalidomide (shown in the forest plots in Figures 3A and 3B).
At the time of diagnosis, the underlying prognostic value of age in multiple myeloma (MM) is significant, with an OS hazard ratio of around 2 when comparing old and young MM patients. However, the US Food and Drug Administration (FDA) conducted and published a meta-analysis of the prognostic value of age in relapsed/refractory MM patients who had at least 1 prior line of therapy, which demonstrated an OS hazard ratio of only 1.21- 1.25 (N=4,766) when comparing older (65-75, 75-80, or >80 years of age) and young patients (<65 years of age) (Kanapuru et al. 2019, Blood (2019) 134 (Supplement !): 3194; shown in Table 4B below). This study also showed a decrease in the differences in risk of death as a function of age with each subsequent line of therapy (i.e. decreasing from 2 prior lines to 3 prior lines). In other words, the prognostic value of age in terms of survival was reduced by each subsequent line of treatment, and after 2 prior lines of therapy, age is no longer a material prognostic factor for survival. Because the Example 1 study enrolled patients with at least 2 prior lines of treatment, no significant survival differences based on age within each treatment arm were expected in this study. However, as can be seen from the Table 4 A, the OS hazard ratios were highly heterogeneous in the predefined age groups overall.
Figure imgf000044_0001
Table 4A, Overall survival heterogeneity in Example 1 study by age group.
Key: OS, overall survival; CI, confidence interval.
Data cut-off 3 February 2023.
Figure imgf000044_0002
Table 4B: OS Hazard Ratio Per Age Group in MM Patients with 1+ Prior Line of Therapy Key: HR, hazard ratio; MM, multiple myeloma; OS, overall survival.
(Kanapuru et al. 2019, Blood, 134 (Supplement !): 3194)
The OS hazard ratios were also highly heterogeneous in the predefined creatinine clearance level groups (see Table 5), which as noted above is an estimate of glomerular filtration rate (GFR) and indicator of renal function, as well as an indicator of cardiovascular function and/or stem cell transplant eligibility, and as such is a proxy for biological age and T-cell function.
Figure imgf000045_0001
Table 5, Overall survival heterogeneity in Example 1 study by creatinine clearance group. Key: OS, overall survival; CI, confidence interval.
Data cut-off 3 February 2023.
Further comparison by age group within the pomalidomide+dex arm in the Example 1 study revealed an OS hazard ratio of 1.79 (p=0.016) for 75+ versus <65 age groups (as well as an OS hazard ratio of 1.55 for 65-74 versus <65 age groups) (Table 6). In both cases, the OS hazard ratio implied a clinically meaningful OS effect modification based on age in the pomalidomide-dex arm: the magnitude of the increased risk of death was larger than what could be attributed to age alone as a prognostic factor in MM (i.e. a hazard ratio of 1.21-1.25, see Table 4B above). The effect was particularly pronounced for the 75+ versus <65 age groups, with an OS hazard ratio of 1.79.
In contrast to OS, the PFS in the pomalidomide+dex arm were much more homogenous across subgroups, meaning that PFS did not predict the age-related effect on OS seen for pomalidomide i.e, PFS did not act as a survival surrogate for the pomalidomide+dex treatment effect (see Figure 3A). This is illustrated by looking at the median PFS and OS in months for each age group in the pomalidomide+dex arm: the median PFS for the 75+ age group, the 65 - 74 age group, and the <65 age group were all 4.9 months. On the other hand, the median OS in months for the 75+ age group was 17.5 months, for the 65 - 74 age group was 20.2 months, and for the <65 age group was 32.0 months (see Table 6 below).
In addition, within the melflufen-dex arm, the hazard ratios for OS and PFS results within the melflufen arm were similar across both 75+ versus <65 and 65-74 versus <65 age group comparisons (Table 6). Looking also at the median PFS and OS in months for each age group illustrates that PFS was predictive of OS: i.e. the highest median PFS in months in the melflufen+dex arm was in the 75+ age group, and highest median OS in months was seen in this age group; and the lowest median PFS in months was in the <65 age group, and lowest median OS in months was seen in this group.
Figure imgf000046_0001
Table 6, Median PFS and OS in months and OS HR comparison by age group within each treatment arm of the Example 1 study
Key: HR, hazard ratio; OS, overall survival; PFS, progression-free survival. Data cutoff date: 3 February 2023.
It can be seen that the largest contributor to the heterogenous OS hazard ratio result by age in the Example 1 study was the variability in the pomalidomide-dex treatment arm. Figure 4 shows a spline analysis of the hazard of death within each treatment arm in the Example 1 study, as a function of age. The hazard of death in the pomalidomide arm rapidly accelerated in patients older than 65 years of age, and becomes over two times higher in elderly patients (>75 years) compared with younger patients (<65 years of age). Given the underlying prognostic value of age after 1-2 prior lines of therapy , i.e. the OS hazard ratio of 1.21-1.25 (N=4,766) identified by the FDA when comparing older (65-75, 75-80, or >80 years of age) and young patients (<65 years of age) (Kanapuru et al. 2019, Blood, 134 (Supplement l): 3194; see Table 4B). this result was significantly different than expected in an even later line MM patient population. In comparison, the risk of death within the melflufen-dex arm remained essentially level by patient age. In summary: sub-group analysis of the Example 1 study data by age revealed a significant interaction between patient age and overall survival in relapsed/refractory MM patients treated with pomalidomide+dexamethasone. The risk of death (compared with patients of the same age treated with melflufen+dexamethasone) increased significantly with age, with the effect being most pronounced in patients >75 years of age. This effect is surprising and has not been previously reported for pomalidomide, as indicated by the fact that it is not reflected in current indications or prescribing instructions for this drug (or any other iMiD).
Example 2: OS variability as a function of age in other studies
Example 2 A: Initial investigation
To determine if the high degree of variability in OS as a function of age observed in the Example 1 trial was replicated in other studies, an initial examination of two pomalidomide studies where OS data were available was performed.
Study MM002 was a phase II trial evaluating safety and efficacy of pomalidomide with/without low-dose dexamethasone in RRMM patients who had received at least 2 prior therapies (i.e. the same indication and number of prior therapies as the Example 1 trial), published in Jagannath S et al. (2012) Blood 120 (21):450 (https://doi.org/10.1182/blood.V120.21.450.450). In the pomalidomide/low dose dexamethasone arm of study MM002, patients <65 years of age had a median OS of 19.7 months compared with 11.8 months in patients >65 years of age.
The ICARIA study, a phase III study in RRMM patients, evaluated isatuximab, pomalidomide and low-dose dex (IsaPd) versus pomalidomide and low-dose dex (Pd) in patients who had received at least 2 prior lines of therapy (Richardson P et al. (2022) Lancet Oncology 23 (3) :416-427). In the pomalidomide- arm, patients <65 years of age had a median OS of 25.6 months compared with 10.3 months in patients 75+ years of age (shown in Table 7 below). Thus, in both these studies, similarly to the pomalidomide-dex arm of the Example 1 trial, OS also decreased in older patients treated with pomalidomide-low dose dexamethasone.
Figure imgf000048_0001
Key: FAS, Full Analysis Set; HR, hazard ratio; isa, isatuximab; OS, overall survival; pd, pomalidomide; PFS, progression-free survival.
Example 2B: Analysis of effect modification by age in Phase III MM trials that isolate an IMiD treatment effect
To further understand the pomalidomide OS effect modification by age observed in the Example 1 trial, available Phase III clinical data were collected based on published information from other clinical trials that allow for the isolation of the IMiD treatment effect in MM. The search was conducted using the search terms “IMiD”, “thalidomide”, “lenalidomide” and/or “pomalidomide” with the filter “randomized controlled trial”. This resulted in 647 hits that were manually assessed. All trials that did not allow for the isolation of the IMiD agent treatment effect or that were not powered for hypothesis testing were excluded from the final result. The trials that were included in the final analysis for lenalidomide or pomalidomide (excluding thalidomide trials) are summarised in Table 8 below. As can be seen from the table, detailed OS data by subgroup is consistently absent from publications and in some cases also from clinical study reports (CSRs). In addition to published data for these trials, unpublished survival data regarding the potential OS effect modification by lenalidomide was obtained from the National Cancer Research Institute in the UK (NCRI UK) (for Myeloma XI) and unpublished subgroup survival data was obtained from the European Medicines Authority (EMA) (for study MM007).
Figure imgf000049_0001
Table 8, Summary of hypothesis testing Phase III trials that allow for isolation of lenalidomide or pomalidomide treatment effect in multiple myeloma.
Key: MM, multiple myeloma; OS, overall survival; CSR, clinical study report. Three published Phase III MM trials were excluded from the analysis, because they were not usable for investigations regarding the potential relationship between patient age, survival effect and IMiD therapy. These were: MM009 and MM010 (the registrational trials for lenalidomide) and MM003 (the registrational trial for pomalidomide). This was because the comparator arm was high-dose dexamethasone in all three trials. The Eastern Co- operative Oncology Group (ECOG) previously showed that the survival effect (OS) of high- dose dexamethasone is significantly heterogenous by patient age, with significantly worse survival in older patients (65+) in comparison with younger patients (E4A03 as reported in Rajkumar et al. (2010) Lancet Oncology 11 (1) :29-37). Since it is not possible to assess heterogeneity based on a comparator that also has a heterogeneous effect, this rules out any detailed age-related interaction analysis based on MM009, MM010 and MM003. Another Phase III MM trial, the MM020 study, was also excluded as that study also did not isolate the IMiD treatment effect, since all patients received IMiD-based therapy (thalidomide or lenalidomide) and the comparison was between continuous therapy and fixed duration MPT.
Pomalidomide'. For pomalidomide, there were three Phase III trials that allowed, in principle, for isolation of the pomalidomide treatment effect and assessment of the effect modification by age subgroup. These were: MM007 (2018) with pomalidomide/bortezomib/dexamethasone vs bortezomib/dexamethasone, OCEAN (Example 1 study) (2021) with melflufen/dexamethasone vs pomalidomide/dexamethasone, and DREAMM-3 (2022) with belantamab mafodotin vs pomalidomide/dexamethasone. Age subgroup results have not yet been released for DREAMM-3; however, for MM007, the OS hazard ratio was highest for patients >75 years of age at 1.27, dropping to 0.90-1.03 for younger patients (< 65 years or < 75 years). PFS for MM007, in contrast, remained consistently low across all patient subgroups and did not vary by age; see Table 9 below.
Figure imgf000051_0001
Table 9: Summary of data from phase III trials isolating the IMiD treatment effect in MM (including available age subgroups) Key: CSR, clinical study report; HR, hazard ratio; IMiD, immunomodulatory agent; ITT, intent-to-treat; MM, multiple myeloma; NA, not analyzed; OS, overall survival; PFS, progression-free survival.
In addition, three published head-to-head comparisons with pomalidomide/dexamethasone were identified with three different drug classes. These were: OCEAN (Example 1 study) (2021) with melflufen/dexamethasone vs pomalidomide/dexamethasone, Takeda (2018) with ixazomib/dexamethasone (Dimopoulos et al, 2022, Blood Cancer J. 2022, 12, 9), and DREAMM-3 (2022) with belantamab mafodotin vs pomalidomide/dexamethasone. Detailed data by age are not yet available for DREAMM- 3, however intention-to-treat (ITT) PFS and OS hazard ratio data, compared with OS hazard ratio data for patients <75 and 75+ from OCEAN and Takeda are presented in Table 10 below The PFS hazard was homogenous by patient age in both trials (data not shown).
Figure imgf000052_0001
Key: ITT, intention to treat; OS, overall survival.
As can be observed in Table 10, pomalidomide behaved identically across the OCEAN and Takeda trial head-to-head comparisons, regardless of the drug class being tested. In both trials, the OS benefit was significantly heterogeneous, as can be seen from the PFS and OS hazard ratios. In older patients (75+), each drug class tested conferred an OS benefit that was greater than the PFS benefit in the ITT population (i.e. which included younger patients and therefore had a lower median age). In other words, the pomalidomide OS benefit in these trials varied by age, with an OS benefit that was greater than the PFS benefit in the younger patients and worse than the PFS benefit in the older patients. Lenalidomide'. For lenalidomide, there were three phase 3 trials that allowed for the isolation of the treatment effect: MM015 with lenalidomide/melphalan/ prednisolone vs melphalan/prednisolone (2012), the CALGB/ALLIANCE trial (2018) with lenalidomide vs no lenalidomide and Myeloma XI (2019) with lenalidomide vs no lenalidomide (summarized in Tables 8 and 9). The MM015 trial only included non-transplant eligible patients in a single 65+ age bracket, making it unsuitable for studying detailed effect modification across a range of age brackets within the study. The CALGB/ALLIANCE trial only included younger transplant-eligible patients, again making it unsuitable for studying detailed effect modification by age across a range of age brackets within the study.
Nevertheless, since all three studies isolated the lenalidomide treatment effect in newly diagnosed MM patients, the results could still be compared side by side (shown in Table 11 below, with the studies sorted in order of increasing median age of the patient group). This comparison showed that the PFS benefit from lenalidomide treatment remained largely constant, with hazard ratios staying around 0.4-0.6 even as median cohort age increased. In contrast, the OS results were much more heterogeneous, with the OS hazard ratio increasing with median age, i.e. indicating that the overall survival benefit of OS decreased with age. A similar trend in overall survival benefit could be observed in the different age brackets for the Myeloma XI study, where the OS hazard ratio increased from 0.68 in <65s (i.e. less risk of dying with respect to the comparator) to 1.12 (i.e. greater risk of dying with respect to comparator) in the 75+ age group (Table 9). Lenalidomide therefore behaved similarly to the pomalidomide results described above, with a significant heterogeneity of OS results as a function by patient age.
Figure imgf000053_0001
Table 11. PFS and OS hazard ratio in Phase III MM trials from first line lenalidomide therapy (in order of median age and stem cell transplant eligibility) Key: ASCT: autologous stem cell transplant; ITT, intention to treat; PFS, progression free survival; OS, overall survival; HR, hazard ratio.
Importantly, the data for lenalidomide in newly diagnosed MM patients in Table 11 was in line with the observations for pomalidomide in the OCEAN (Example 1 study) trial. The OS benefit from lenalidomide therapy significantly exceeded the PFS benefit in the younger ASCT-eligible patients and was significantly less than the PFS benefit in the older non-ASCT eligible patients. Consequently, the post-progression hazard of death was modulated by the IMiD therapy, namely, to be reduced in the young ASCT-eligible patients and increased in the older non-ASCT eligible patients. Thus, the effect of IMiD therapy by age was bi-directional i.e., the post-progression hazard of death was not only increased in older patients but also reduced in younger patients after IMiD intervention.
If the observations in OCEAN (the Example 1 study described above) are reproducible, there should be a relationship between the age of a patient population and the isolated immunomodulatory agent treatment effect as measured by OS (with no to limited reflection by PFS). A correlation analysis was therefore performed to test this; note that the head-to-head studies (such as the Takeda study (Dimopoulos et al, 2022, Blood Cancer J. 2022, 12, 9), DREAMM-3 and OCEANZExample 1 study) included in Tables 8 and 9 were excluded for the correlation analysis since the OS hazard ratio values in trials with active comparator have a different meaning from in trials with comparison to no treatment/placebo.
Figure 5 shows the correlation between the IMiD-OS treatment effect and median patient age. Despite the limitations in the underlying data, the correlation coefficient for the OS IMiD treatment effect and median age in MM studies that allow for the isolation of the IMiD treatment effect was found to be 0.92 (log OS HR and median age). Thus, there was a strong correlation between the immunomodulatory agent OS treatment effect and patient age.
Figure 6 shows the age subgroup data as a forest plot in studies that allowed for the isolation of the IMiD treatment effect in multiple myeloma and where OS HR subgroup data by age was available (including the Example 1 study, OCEAN). As can be seen from the figure, the IMiD treatment effect was reduced as a function of age and most likely becomes detrimental at some point between patient age 70 and 75.
Study MM015 investigated melphalan-prednisone (MP) vs. melphalan-prednisone- lenalidomide (MPR) vs. MPR with lenalidomide maintenance (MPR+R(continuous)) in ASCT ineligible NDMM patients 65+ (Palumbo A., et al, N Engl J Med. 2012 May 10;366 (19): 1759-69.) and consequently isolated the lenalidomide treatment effect in elderly NDMM patients. The results from the comparison with MPR vs. MP were poor, indicating absolute OS harm from lenalidomide use in elderly ASCT ineligible patients with an ITT OS HR of 1.2 in the original data-cut (Palumbo et al, 2012). The comparison of MPR+R(continuous) vs. MP did not fare much beter with an ITT OS HR result of 0.95 despite very strong PFS results (PFS HR of 0.37 (0.27-0.50)). However, the OS HR result for patients 75+ was around 1.5 (derived from EMA/CHMP EPAR 2012) indicating absolute OS harm for elderly patients treated with lenalidomide in line with the MPR vs. MP comparison as well as heterogeneity by patient age and age-related factors. While MM015 demonstrated a positive relationship between duration of exposure to lenalidomide and efficacy (continuous therapy was more beneficial than fixed duration therapy in the study population), it also simultaneously demonstrated that IMiD-free therapy (i.e., only MP) had the best benefit-risk profile for ASCT ineligible elderly patients. Lenalidomide caused absolute OS harm to these patients. When MM015 results were made available they caused a lot of confusion in the scientific community. How was it possible to have both a positive relationship between duration of lenalidomide exposure and efficacy and simultaneous absolute OS harm? At the time the clinical research community believed the unexplainable observed OS harm was due to the combination of lenalidomide with the alkylator, i.e. the alkylator, or the alkylator with the lenalidomide, leading to the absolute OS harm. It is only in view of the present invention that the results from this study can be understood, and it is clear, based on the evidence from other IMiD studies as described extensively in this application, that the MM015 study result is a true representation of IMiD-based therapy in elderly ASCT ineligible MM patients.
The MM015 study results adequately describe the lenalidomide treatment effect in elderly patients, and also shows that it is not possible for study MM020 (mentioned above) to provide information on whether elderly ASCT ineligible NDMM patients should receive IMiD-based therapy or not.
Thalidomide: Phase 3 trials studying thalidomide in ASCT ineligible 65+ NDMM patients demonstrated positive PFS results. However, they generally failed to show OS benefit. The results from the three main thalidomide trials (melphalan + prednisolone (MP) vs. melphalan + prednisolone + thalidomide (MPT)) are presented in Table 12 below.
Figure imgf000056_0001
Table 12, PFS and OS in ASCT ineligible 65+ years of age patients in Phase 3 thalidomide trials
The results from the three trials reported in Table 12 confused the clinical research community greatly. Material OS heterogeneity across pre-specified subgroups was observed for the thalidomide treatment effect. Interestingly, the HOVON group conducted a detailed multi-variate analysis and saw a clear and statistically significant age interaction with a reduction in OS benefit by 4% per year of patient life (i.e., an interaction factor of 1.04 per numerical patient year with a p-value of 0.04 (Wijermans P, et al., J Clin Oncol 2009 28:3160-3166). This is fundamentally identical to the age interaction factor identified for pomalidomide in the Example 1 study.
In two French thalidomide trials, IFM99-06 and IFM01-01 the OS HR for MPT vs MP were much better compared to the studies above (Facon T. and Darre S., Best Pract Res Clin Haematol. 2007;20(4):737-746.; Hulin C., et al., J Clin Oncol. 2009;27:3664-3670). While the other thalidomide trials studied ASCT ineligible elderly NDMM patients, IFM99- 06 and IFM01-01 fundamentally studied ASCT eligible elderly NDMM patients (with the exception of the numerical age criteria). As an example, IFM99-06 and IFM01-01 used the inclusion criterion “no cardiovascular dysfunction” for enrolment. This is a deviation compared to all other clinical studies in MM, where it is standard to exclude patients only with severe cardiovascular dysfunction (including severe renal impairment). The patients in IFM99-06 and IFM01-01 hardly exist in the real -world clinical setting. In the Nordics, more than half of the elderly RRMM patients have severe cardiovascular/renal dysfunction (discussion with members of the Nordic Myeloma Group).
IFM99-06 and IFM01-01 have significantly confounded the entire IMiD myeloma field. The two trials have been discussed and treated as if the benefit-risk profile of thalidomide can be generalized from those results without taking sufficient note of the very specific patient selection in those two studies. In summary, the clinical trial results with thalidomide demonstrate the exact same phenomena as in pomalidomide and lenalidomide studies i.e., highly significant survival effect modification by patient age and age-related factors. Because the biological age of the patient group is significantly lowered by the enrolment criteria in IFM99-06 and IFM01-01, the survival data became positive with only minor differences in surrogate activity compared to the other thalidomide studies. Unfortunately, the published meta-analyses from these thalidomide trials (Kapoor, P., et al, Leukemia (2011)25, 689-696; Payers, P., et al, Blood (2011) 118 (5) 1239-1247) cannot be utilized for any age or age-related conclusions since the analyses are mixing the patients from the two French studies (ASCT eligible elderly NDMM patients) with patients from the other studies (ASCT ineligible elderly NDMM patients).
Example 2C: Analysis of effect modification by age in Phase III non-MM trials that isolate an IMiD treatment effect
Data from Phase III studies isolating the immunomodulatory agent treatment effect in other indications were also analysed (summary of these data shown in Tables 13 and 14 below). These indications included both haematological cancers other than MM (lymphoma, chronic lymphocytic leukaemia (CLL) and diffuse large B-cell lymphoma), as well as prostate cancer (MAINSAIL study). The analysis was performed using the same methodology as for the phase III MM studies described above. Similarly to the MM analysis already described, and again despite the limitations in the underlying data, the correlation analysis showed a correlation coefficient of 0.86 between the log OS hazard ratio immunomodulatory agent treatment effect and median age across studies. (Again, as for MM, the head-to-head studies (RELEVANCE, ORIGIN) were not included in the correlation analysis.) There was thus a strong correlation between the immunomodulatory agent OS treatment effect and patient age also in indications other than MM, as seen in Figure 7. It should be noted that in the ORIGIN study (lenalidomide versus chlorambucil for older patients with chronic lymphocytic leukemia) the data monitoring committee observed an imbalance in deaths between the treatment arms favoring chlorambucil in the oldest patients and as a result, patients aged >81 years were discontinued from study treatment (Chanan- Khan et al. (2017), Leukemia 31(5): 1240-1243.).
Figure imgf000058_0001
Table 13, Summary of data from phase 3 clinical trials that isolate the IMiD treatment in non-MM indications, sorted by median patient age (including available age subgroups)
Key: CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; HR, hazard ratio; IMiD, immunomodulatory agent; ITT, intent-to-treat;NA, not analyzed; OS, overall survival; PFS, progression-free survival
Figure imgf000059_0001
Table 14, Summary of hypothesis testing trials allowing for isolation of lenalidomide or pomalidomide treatment effect outside MM
Example 2D: Analysis of overall survival data by age in Phase III MM trials with other drug classes OS data as a function of age was also gathered from Phase III MM trials that isolate the treatment effect of other non-IMiD drug classes (proteasome inhibitors (Pls), anti-CD38 and anti-CSl) (shown in Table 15 below). The initial analysis was conducted using the same methodology as for IMiDs and showed a correlation between the drug OS treatment effect and median age of 0.36 (log OS HR and median age). Studies with available OS HR age subgroup data are shown in Figures 8 and 9. There was no correlation between patient age and the OS treatment effect of Pls, anti-CD38s and anti-CSl based therapy; instead, there was a consistent survival benefit across the age spectrum.
Figure imgf000061_0001
Figure imgf000062_0001
Table 15, Summary of data from phase III clinical trials isolating the treatment effect of non-IMiDs in MM, sorted by clinical study (including available age subgroups).
Key. FU, follow-up; HR, hazard ratio; ITT, intent-to-treat; MM, multiple myeloma; NA, not analyzed; OS, overall survival; PFS, progression- free survival; PI, proteasome inhibitor.
Example 2E: 3rd party analysis and summary of findings
A further analysis of post-published data on IMiD-age interactions in MM phase III trials was also carried out by a regulatory authority, the US Food and Drug Administration (FDA). This analysis is described in the Combined FDA and Applicant ODAC Briefing Document for the Oncologic Drugs Advisory Committee (ODAC) Meeting (September 22, 2022) for the drug PEPAXTO (melphalan flufenamide), NDA 214383. Briefly, the FDA conducted an exploratory analysis of trials submitted to the FDA that allowed for the isolation of IMiD effect, using age, treatment, and treatment*age in a model to evaluate the modification of OS effect by age in these IMiD trials. The FDA’s conclusion was that the exploratory analysis did not indicate that there was an interaction term between age and IMiD treatment.
Analysis by the current inventors has uncovered several flaws in this approach, based on the studies selected for the exploratory analysis. The studies chosen were: MM0015, MM003, MM009 MM010 and CALGB. For MM0015 and CALGB (as highlighted in Table 8 of this application), there is no published OS age sub-group data available, which makes these studies less suitable for a detailed analysis of OS treatment effect by age bracket. Importantly, as described in the present inventors’ analysis of effect modification by age in Phase III MM trials, MM003, MM009 and MM010 were not usable for investigations regarding the potential relationship between patient age, survival effect and IMiD therapy. This was because the comparator arm was high-dose dexamethasone in all three trials, which also in itself shows a highly heterogeneous survival effect by patient age (Rajkumar et al. (2010) Lancet Oncology 11 (1) :29-37). Since it is not possible to assess heterogeneity based on a comparator that also has a heterogeneous effect, this rules out any detailed age-related interaction analysis based on MM009, MM010 and MM003. In addition, the FDA’s exploratory analysis did not take the Myeloma XI study into account, for which there is age subgroup data available and which demonstrated similar trends in overall survival benefit to OCEAN (Example 1 study) (see e.g. Table 9 in this application)
For these reasons, and based on the analyses presented in this application, the pomalidomide treatment effect indeed has a statistical interaction between age and OS. This conclusion is based on identical behavior for pomalidomide across all trials where the pomalidomide treatment effect can be isolated or where detailed survival data exists for an individual pomalidomide/dex treatment arm (e.g. in OCEAN (Example 1 study), MM002, ICARIA, and MM007). Furthermore, no trial datasets could be identified that supported evidence to the contrary. The Applicant further concludes that the analyses show that immunomodulatory agents as a drug class have significant OS effect modification as a function of patient age. Similar analyses were conducted for PFS, but did not identify a material age differential for PFS outcomes. The homogenous PFS treatment effect and at the same time heterogenous OS treatment effect indicate that PFS as a surrogate endpoint does not capture the full benefitrisk profile of immunomodulatory agents. Interestingly, the observed OS benefit is greater than the observed PFS benefit in young patients and less than the observed PFS benefit in older patients i.e., the post-progression hazard of death is modulated by the IMiD intervention and can both be reduced or increased as a function of primarily patient age.
In current clinical practice, the observation that the OS IMiD treatment benefit differs significantly by patient age (with limited reflection by surrogate endpoints) is nonetheless currently not part of IMiD drug labels, indications, or prescribing instructions. The current invention provides an overall improvement in clinical outcomes. An update of clinical practice guidelines appears to be appropriate.

Claims

Claims
1. A method of treating a haematological cancer in a patient, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
2. The method according to claim 1, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and/or gender, and wherein a low biological age and/or female gender are indicative of a high level of T cell function.
3. The method according to claim 1 or claim 2, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and wherein one or more of the following factors are used as a proxy for biological age: chronological age, transplant eligibility, cardiovascular function and renal function, and wherein low biological age is indicative of high level of T cell function.
4. The method according to claim 3 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 70 years is indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the chronological age of the patient is less than 70 years, or administering the alternative treatment if the chronological age of the patient is 70 years or older.
5. The method according to claim 3 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 75 years is indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the chronological age of the patient is less than 75 years, or administering the alternative treatment if the chronological age of the patient is 75 years or older.
6. The method according to any of claims 1 to 5, wherein the IMiD is selected from the group consisting of: thalidomide, pomalidomide, lenalidomide, avadoimide, iberdomide, and mezigdomide; and preferably thalidomide, pomalidomide, and lenalidomide.
7. The method according to claim 6, wherein the IMiD is pomalidomide.
8. The method according to any of claims 1 to 7, wherein the alternative therapeutic agent is selected from the group consisting of: an alkylator (for example melphalan or melflufen), an anti-CD38 agent (for example an anti-CD38 antibody, for example daratumumab), or a proteasome inhibitor (for example bortezomib, carfilzomib or ixazomib); and more preferably wherein the alternative therapeutic agent is an alkylator.
9. The method according to any of claims 1 to 8, wherein the haematological cancer is multiple myeloma.
10. A method of determining a treatment regimen for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, proceeding with a treatment regimen in which the patient is administered an IMiD; or if the level T-cell function of the patient is poor, proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD.
11. The method according to claim 10, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and/or gender, and wherein a low biological age and/or female gender are indicative of a high level of T cell function.
12. The method according to claim 10 or claim 11, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and wherein one or more of the following factors are used as a proxy for biological age: chronological age, transplant eligibility, cardiovascular function and renal function, and wherein low biological age is indicative of high level of T cell function.
13. The method according to claim 12 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 70 years is indicative of a high level of T cell function, so that step ii. comprises proceeding with a treatment regimen in which the patient is administered an IMiD if the chronological age of the patient is less than 70 years, or proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD if the chronological age of the patient is 70 years or older.
14. The method according to claim 12 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 75 years is indicative of a high level of T cell function, so that step ii. comprises proceeding with a treatment regimen in which the patient is administered an IMiD if the chronological age of the patient is less than 75 years, or proceeding with a treatment regimen in which the patient is administered an alternative therapeutic agent and not administered an IMiD if the chronological age of the patient is 70 years or older.
15. The method according to any of claims 10 to 14, wherein the IMiD is selected from the group consisting of: thalidomide, pomalidomide, lenalidomide, avadoimide, iberdomide, and mezigdomide; and preferably thalidomide, pomalidomide, and lenalidomide.
16. The method according to claim 15, wherein the IMiD is pomalidomide.
17. The method according to any of claims 10 to 16, wherein the alternative therapeutic agent is selected from the group consisting of: an alkylator (for example melpalan or melflufen), an anti-CD38 agent (for example an anti-CD38 antibody, for example daratumumab), or a proteasome inhibitor (for example bortezomib, carfilzomib or ixazomib); and more preferably wherein the alternative therapeutic agent is an alkylator.
18. The method according to any of claims 10 to 17, wherein the haematological cancer is multiple myeloma.
19. A method for determining the suitability of treatment with an immunomodulatory imide drug (IMiD) for a patient having a haematological cancer, the method comprising the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, determining that overall survival benefit is likely to be greater for treatment with an IMiD; or if the level T-cell function of the patient is poor, determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered.
20. The method according to claim 19, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and/or gender, and wherein a low biological age and/or female gender are indicative of a high level of T cell function.
21. The method according to claim 19 or claim 20, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and wherein one or more of the following factors are used as a proxy for biological age: chronological age, transplant eligibility, cardiovascular function and renal function, and wherein low biological age is indicative of high level of T cell function.
22. The method according to claim 21 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 70 years is indicative of a high level of T cell function, so that step ii. comprises determining that overall survival benefit is likely to be greater for treatment with an IMiD if the chronological age of the patient is less than 70 years, or determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered, if the chronological age of the patient is 70 years or older.
23. The method according to claim 21 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 75 years is indicative of a high level of T cell function, so that step ii. comprises determining that overall survival benefit is likely to be greater for treatment with an IMiD if the chronological age of the patient is less than 75 years, or determining that overall survival benefit is likely to be greater for treatment with an alternative therapeutic agent and that an IMiD should not be administered, if the chronological age of the patient is 75 years or older.
24. The method according to any of claims 19 to 23, wherein the IMiD is selected from the group consisting of: thalidomide, pomalidomide, lenalidomide, avadoimide, iberdomide, and mezigdomide; and preferably thalidomide, pomalidomide, and lenalidomide.
25. The method according to claim 24, wherein the IMiD is pomalidomide.
26. The method according to any of claims 19 to 25, wherein the alternative therapeutic agent is selected from the group consisting of: an alkylator (for example melpalan or melflufen), an anti-CD38 agent (for example an anti-CD38 antibody, for example daratumumab), or a proteasome inhibitor (for example bortezomib, carfilzomib or ixazomib); and more preferably wherein the alternative therapeutic agent is an alkylator.
27. The method according to any of claims 19 to 26, wherein the haematological cancer is multiple myeloma.
28. An immunomodulatory imide drug (IMiD) or an alternative therapeutic agent for use in the treatment of a haematological cancer in a patient, wherein the treatment of the haematological cancer comprises the following steps: i. quantifying the level of T-cell function of the patient; ii. if the level of T-cell function of the patient is high, administering an IMiD; or if the level T-cell function of the patient is poor, administering an alternative therapeutic agent and not administering an IMiD.
29. The IMiD or alternative therapeutic agent for use according to claim 28, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and/or gender, and wherein a low biological age and/or female gender are indicative of a high level of T cell function.
30. The IMiD or alternative therapeutic agent for use according to claim 28 or claim 29, wherein the quantification of T-cell function in step i. is carried out by assessing the patient’s biological age and wherein one or more of the following factors are used as a proxy for biological age: chronological age, cardiovascular function transplant eligibility, and renal function, and wherein low biological age is indicative of high level of T cell function.
31. The IMiD or alternative therapeutic agent for use according to claim 30 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 70 years is indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the chronological age of the patient is less than 70 years, or administering the alternative treatment if the chronological age of the patient is 70 years or older.
32. The IMiD or alternative therapeutic agent for use according to claim 30 wherein chronological age is used as a proxy for biological age, and step i. comprises an assessment of the patient’s chronological age and wherein an age of less than 75 years is indicative of a high level of T cell function, so that step ii. comprises administering the IMiD if the chronological age of the patient is less than 75 years, or administering the alternative treatment if the chronological age of the patient is 75 years or older.
33. The IMiD or alternative therapeutic agent for use according to any of claims 28 to 32, wherein the IMiD is selected from the group consisting of: thalidomide, pomalidomide, lenalidomide, avadoimide, iberdomide, and mezigdomide; and preferably thalidomide, pomalidomide, and lenalidomide.
34. The IMiD or alternative therapeutic agent for use according to claim 33, wherein the IMiD is pomalidomide.
35. The IMiD or alternative therapeutic agent for use according to any of claims 28 to 34, wherein the alternative therapeutic agent is selected from the group consisting of: an alkylator (for example melpalan or melflufen), an anti-CD38 agent (for example an anti-CD38 antibody, for example daratumumab), or a proteasome inhibitor (for example bortezomib, carfilzomib or ixazomib); and more preferably wherein the alternative therapeutic agent is an alkylator.
36. The IMiD or alternative therapeutic agent for use according to any of claims 28 to 35, wherein the haematological cancer is multiple myeloma.
PCT/EP2023/084808 2022-12-08 2023-12-07 Therapeutic treatment for haematological cancer based on the level of t-cell function WO2024121349A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB2218510.2 2022-12-08
GBGB2218510.2A GB202218510D0 (en) 2022-12-08 2022-12-08 Novel therapeutic treatment
GB2313014.9 2023-08-25
GBGB2313014.9A GB202313014D0 (en) 2023-08-25 2023-08-25 Novel therapeutic treatment

Publications (1)

Publication Number Publication Date
WO2024121349A1 true WO2024121349A1 (en) 2024-06-13

Family

ID=89190794

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/084808 WO2024121349A1 (en) 2022-12-08 2023-12-07 Therapeutic treatment for haematological cancer based on the level of t-cell function

Country Status (1)

Country Link
WO (1) WO2024121349A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014075083A1 (en) 2012-11-09 2014-05-15 The Regents Of The University Of California Methods for predicting age and identifying agents that induce or inhibit premature aging
WO2015048665A2 (en) 2013-09-27 2015-04-02 The Regents Of The University Of California Method to estimate the age of tissues and cell types based on epigenetic markers
WO2019143845A1 (en) 2018-01-17 2019-07-25 The Regents Of The University Of California Phenotypic age and dna methylation based biomarkers for life expectancy and morbidity
WO2020076983A1 (en) 2018-10-10 2020-04-16 The Regents Of The University Of California Dna methylation based biomarkers for life expectancy and morbidity
WO2022263679A1 (en) 2021-06-18 2022-12-22 Oncopeptides Ab Peptide drug conjugates
WO2023281007A1 (en) * 2021-07-08 2023-01-12 Oncopeptides Ab Melflufen for use in the treatment of multiple myeloma

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014075083A1 (en) 2012-11-09 2014-05-15 The Regents Of The University Of California Methods for predicting age and identifying agents that induce or inhibit premature aging
WO2015048665A2 (en) 2013-09-27 2015-04-02 The Regents Of The University Of California Method to estimate the age of tissues and cell types based on epigenetic markers
WO2019143845A1 (en) 2018-01-17 2019-07-25 The Regents Of The University Of California Phenotypic age and dna methylation based biomarkers for life expectancy and morbidity
WO2020076983A1 (en) 2018-10-10 2020-04-16 The Regents Of The University Of California Dna methylation based biomarkers for life expectancy and morbidity
WO2022263679A1 (en) 2021-06-18 2022-12-22 Oncopeptides Ab Peptide drug conjugates
WO2023281007A1 (en) * 2021-07-08 2023-01-12 Oncopeptides Ab Melflufen for use in the treatment of multiple myeloma

Non-Patent Citations (46)

* Cited by examiner, † Cited by third party
Title
A. T. LU ET AL., AGING, vol. 11, no. 2, 2019, pages 303 - 327
ANONYMOUS: "Pepaxto (melphalan flufenamide)", 22 November 2022 (2022-11-22), pages 1 - 73, XP093133883, Retrieved from the Internet <URL:https://www.fda.gov/media/161763/download> [retrieved on 20240222] *
BELOTTI ET AL., AMERICAN JOURNAL OF HEMATOLOGY, vol. 95, no. 7, pages 759 - 765
BRINGHEN S ET AL., BLOOD, vol. 140, 2022, pages 1814 - 1816
C. I. WEIDNER ET AL., GENOME BIOLOGY, vol. 15, 2014, pages R24
CHANAN-KHAN A ET AL: "Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial)", BLOOD CANCER JOURNAL, vol. 31, no. 5, 31 January 2017 (2017-01-31), London, pages 1240 - 1243, XP093133772, ISSN: 0887-6924, Retrieved from the Internet <URL:http://www.nature.com/articles/leu201747.pdf> DOI: 10.1038/leu.2017.47 *
CHANAN-KHAN, A. ET AL., LEUKEMIA, vol. 31, no. 5, 2017, pages 1240 - 1243
COCKCROFT D. W.GAULT M. H.: "Prediction of creatinine clearance from serum creatinine", NEPHRON., vol. 16, no. 1, 1976, pages 31 - 41
COMBINED FDA AND APPLICANT ODAC BRIEFING DOCUMENT FOR THE ONCOLOGIC DRUGS ADVISORY COMMITTEE (ODAC) MEETING, 22 September 2022 (2022-09-22)
D.W. BELSKY ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 112, no. 30, 2015, pages E4104 - E4110
DIMOPOULOS ET AL., BLOOD CANCER J., vol. 12, 2022, pages 9
FACON T.DARRE S., BEST PRACT RES CLIN HAEMATOL., vol. 20, no. 4, 2007, pages 737 - 746
FAYERS, P. ET AL., BLOOD, vol. 118, no. 5, 2011, pages 1239 - 1247
FOA , R. ET AL., BLOOD, vol. 128, no. 22, 2016, pages 230
G. HANNUM, MOL. CELL, vol. 49, no. 2, 2013, pages 359 - 367
HOLSTEINMCCARTHY, DRUGS, vol. 77, no. 5, April 2017 (2017-04-01), pages 505 - 520
HULIN C. ET AL., J CLIN ONCOL., vol. 27, 2009, pages 3664 - 3670
JAGANNATH S ET AL., BLOOD, vol. 120, no. 21, 2012, pages 450, Retrieved from the Internet <URL:https://doi.org/10.1182/blood.V120.21.450.450>
JYLHAVA ET AL., EBIOMEDICINE, vol. 21, 2017, pages 29 - 36
KANAPURU ET AL., BLOOD, vol. 134, 2019, pages 3194
KAPOOR, P. ET AL., LEUKEMIA, vol. 25, 2011, pages 689 - 696
KLEMERADOUBAL, MECHANISMS OF AGEING AND DEVELOPMENT, vol. 127, no. 3, 2006, pages 240 - 248
LEONARD, J. ET AL., J CLIN ONCOL., vol. 37, no. 14, 10 May 2019 (2019-05-10), pages 1188 - 1199
M. E. LEVINE ET AL., AGING, vol. 10, no. 4, 2018, pages 573 - 591
M.E. LEVINE, JOURNALS OF GERONTOLOGY: BIOLOGICAL SCIENCES, vol. 68, no. 6, 2013, pages 667 - 674
MATEOS MARIA-VICTORIA ET AL: "OCEAN (OP-103): Melflufen/Dexamethasone Compared with Pomalidomide/Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma-Age Subgroup Analysis of Older Patients", BLOOD, vol. 138, no. Supplement 1, 5 November 2021 (2021-11-05), US, pages 2741 - 2741, XP055973235, ISSN: 0006-4971, Retrieved from the Internet <URL:https://ashpublications.org/blood/article/138/Supplement%201/2741/481361/OCEAN-OP-103-Melflufen-Dexamethasone-Compared-with> DOI: 10.1182/blood-2021-147005 *
MORSCHHAUSER, F. ET AL., N ENGL J MED., vol. 379, 2018, pages 934 - 947
NOWAKOWSKI, G. ET AL., CLINICAL ONCOLOGY, vol. 39, no. 12, 20 April 2021 (2021-04-20), pages 1317 - 132
PALUMBO A. ET AL., N ENGL J MED., vol. 366, no. 19, 10 May 2012 (2012-05-10), pages 1759 - 69
PETRYLAK, D. ET AL., LANCET ONCOL., vol. 16, no. 4, 2015, pages 417 - 425
POZZI ET AL., BRITISH JOURNAL OF HAEMATOLOGY, vol. 163, 2013, pages 40 - 46
POZZI ET AL., MODENA CANCER REGISTRY
RAJKUMAR ET AL., LANCET ONCOLOGY, vol. 11, no. 1, 2010, pages 29 - 37
RAZA ET AL., CURRENT CANCER DRUG TARGETS, vol. 17, no. 9, 2017, pages 846 - 857
RICHARDSON P ET AL., LANCET ONCOLOGY, vol. 23, no. 3, 2022, pages 416 - 427
RICHARDSON PAUL G ET AL: "Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial", THE LANCET ONCOLOGY, vol. 20, no. 6, 1 June 2019 (2019-06-01), AMSTERDAM, NL, pages 781 - 794, XP055951611, DOI: 10.1016/S1470-2045(19)30152-4 *
S. BOCKLANDT ET AL., PLOS ONE, vol. 6, no. 6, 2011, pages e14821
S. HORVATH, GENOME BIOLOGY, vol. 14, 2013, pages R115
SCHJESVOLD FREDRIK H ET AL: "Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study", THE LANCET HAEMATOLOGY, vol. 9, no. 2, 12 January 2022 (2022-01-12), GB, pages e98 - e110, XP093133875, ISSN: 2352-3026, Retrieved from the Internet <URL:https://www.thelancet.com/action/showPdf?pii=S2352-3026(21)00381-1> DOI: 10.1016/S2352-3026(21)00381-1 *
SCHJESVOLD FREDRIK H: "Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study - Supplementary appendix", LANCET HAEMATOL, 12 January 2022 (2022-01-12), pages S2352 - S3026, XP055973683, Retrieved from the Internet <URL:https://www.thelancet.com/cms/10.1016/S2352-3026(21)00381-1/attachment/fc4d173d-f823-4f07-8d0d-b98dbabbac5d/mmc1.pdf> [retrieved on 20221021] *
SONNEVELD PIETER ET AL: "Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies", CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA, vol. 23, no. 9, 1 September 2023 (2023-09-01), NL, pages 687 - 696, XP093133849, ISSN: 2152-2650, Retrieved from the Internet <URL:https://pure.eur.nl/ws/portalfiles/portal/98714930/Benefit_Versus_Risk_Assessment_of_Melflufen_and_Dexamethasone_in_RelapsedRefractory_Multiple_Myeloma.pdf> DOI: 10.1016/j.clml.2023.05.004 *
T. STEENSTRUP ET AL., AGING, vol. 9, no. 4, 2017, pages 1130 - 1142
THIEBLEMONT, C. ET AL., J CLIN ONCOL., vol. 35, no. 22, 1 August 2017 (2017-08-01), pages 2473 - 2481
TRNENÝ MAREK ET AL: "Subgroup Analyses of Elderly Patients Aged >= 70 Years in AUGMENT: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) vs Rituximab Plus Placebo (R-Placebo) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 134, 13 November 2019 (2019-11-13), pages 347, XP086673927, ISSN: 0006-4971, DOI: 10.1182/BLOOD-2019-122461 *
WIJERMANS P ET AL., J CLIN ONCOL, vol. 28, 2009, pages 3160 - 3166
ZWEEGMAN, CURRENT OPINION IN ONCOLOGY, vol. 29, no. 5, 2017, pages 315 - 321

Similar Documents

Publication Publication Date Title
Costa et al. Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma
Fucà et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors
Rogado et al. Immune-related adverse events predict the therapeutic efficacy of anti–PD-1 antibodies in cancer patients
Gadgeel et al. Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC)
Bi et al. Mitochondrial damage‐induced innate immune activation in vascular smooth muscle cells promotes chronic kidney disease‐associated plaque vulnerability
van Anrooij et al. Higher mast cell load decreases the risk of Hymenoptera venom–induced anaphylaxis in patients with mastocytosis
Montero et al. Active kinase profiling, genetic and pharmacological data define mTOR as an important common target in triple-negative breast cancer
AU2017238054B2 (en) T-cell exhaustion state-specific gene expression regulators and uses thereof
Owen et al. Mycophenolate mofetil is an effective and safe option for the management of systemic sclerosis-associated interstitial lung disease: results from the Australian Scleroderma Cohort Study
Ferrara et al. Pseudoprogression in non–small cell lung cancer upon immunotherapy: few drops in the ocean?
KR20140025374A (en) Methods of treating cancer using 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione
DK2742356T3 (en) CANCER TREATMENT PREDICTORS
WO2017007941A2 (en) Compositions and methods for identification, assessment prevention, and treatment of cancer using slncr isoforms
Hitz et al. Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial
JP2024124408A (en) Predicting outcome in subjects with bladder or kidney cancer
Maluf et al. A phase 2 randomized clinical trial of abiraterone plus ADT, apalutamide, or abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone levels (LACOG 0415)
JP2022173299A (en) Use of proteasome inhibitor for the treatment of central nervous system (cns) cancers
Shen et al. BRCA status does not predict synergism of a carboplatin and olaparib combination in high-grade serous ovarian cancer cell lines
Kooijmans et al. The Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 kidney analysis examined long-term glomerular dysfunction in childhood cancer survivors
Seikrit et al. Precision medicine in immunoglobulin A nephropathy: still a journey ahead
Wakita et al. Prognostic value of serum soluble PD-L1 in metastatic renal cell carcinoma patients treated with nivolumab
Ariceta et al. Recommendations for the management of renal involvement in tuberous sclerosis complex
WO2024121349A1 (en) Therapeutic treatment for haematological cancer based on the level of t-cell function
Shea et al. A pilot study of lenalidomide maintenance therapy after autologous transplantation in relapsed or refractory classical Hodgkin lymphoma
White et al. Murine strain differences in hemostasis and thrombosis and tissue factor pathway inhibitor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23821960

Country of ref document: EP

Kind code of ref document: A1