WO2023046304A1 - [6r]-mthf dans une chimiothérapie à base de 5-fu de cancer colorectal à mutation de kras ou braf - Google Patents

[6r]-mthf dans une chimiothérapie à base de 5-fu de cancer colorectal à mutation de kras ou braf Download PDF

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WO2023046304A1
WO2023046304A1 PCT/EP2021/076512 EP2021076512W WO2023046304A1 WO 2023046304 A1 WO2023046304 A1 WO 2023046304A1 EP 2021076512 W EP2021076512 W EP 2021076512W WO 2023046304 A1 WO2023046304 A1 WO 2023046304A1
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treatment
patient
colorectal cancer
positive
braf
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PCT/EP2021/076512
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Roger Ingvar TELL
Lisa Katarina SKINTEMO
Per Emil Jonathan HOLMÉN
Per Lennart Lindberg
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Isofol Medical Ab
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Priority to PCT/EP2022/076606 priority patent/WO2023046940A1/fr
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • CRC Colorectal cancer
  • CRC is not a single type of tumor; its pathogenesis depends on the anatomical location of the tumor and differs between right side and left side of the colon. Further, CRC is a multigenetic disease, as several oncogenes are involved frequently in this process. Oncogenic mutations spread differently, based on specific anatomical regions.
  • Huang and coworkers identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017 were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% Cl 1.05-1.33) and p53 mutations (combined OR 1.49, 95% Cl 1.23-1.80) were associated with CRC metastasis, including lymphatic and distant metastases.
  • CRC patients with a KRAS mutation (combined OR 1.29, 95% Cl 1.13-1.47), p53 mutation (combined OR 1.35, 95% Cl 1.06-1.72) or SMAD4 mutation (combined OR 2.04, 95%CI 1.41- 2.95) were at a higher risk of distant metastasis.
  • BRAF and KRAS both belong to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.
  • B-Raf is a protein encoded by the BRAF gene and is involved in the RAS/MAPK pathway, which regulates cellular growth and division.
  • BRAF mutations are found in 8-12% of cases of mCRC, with the predominance of BRAF V600E in approximately 90% of BRAF-mutant CRC.
  • BRAF V600E is a point mutation at nucleotide 1799 that results in independent activation of its upstream activator protein, RAS, as well as increased stimulation of its downstream effector proteins, MEK and ERK, via phosphorylation.
  • RAS and BRAF mutations are usually mutually exclusive (Tabernero 2020).
  • the KRAS gene encodes for a protein called K-Ras that is also part of the RAS/MAPK pathway.
  • KRAS mutation rates are different among CRC patients belonging to different ethnicities. In Caucasians, the frequency of CRC with KRAS mutations is equal to 38%; in Asians, it is close to 40%; and, in Africans, it is only 21%. Most KRAS mutations in CRC occur within KRAS exon 2, with prevalence ranging from 10% to 47%, typically in codons 12 and 13. In addition, approximately 10% of patients with CRC are characterized by other types of KRAS mutations. Mutations in the KRAS gene are detected in approximately 25% of all human cancers; rates are highest in pancreatic carcinoma, reaching above 80%, while, in CRC, they are found in about 40% of cases (Cefali 2021).
  • the KRAS mutation has been found to have an adverse impact on the prognosis for stage IV CRC patients treated with the FOLFOX regimen (Zocche 2015) or on stage II or III CRC patients treated with adjuvant FOLFOX (Lee 2014).
  • FOLFOX regimen Zocche 2015
  • stage II or III CRC patients treated with adjuvant FOLFOX Lee 2014
  • FOLFOX adjuvant FOLFOX
  • ORR best overall response
  • KRAS mutations have further been found to confer resistance to epidermal growth factor receptor (EGFR) inhibitors, a class of tyrosine kinase inhibitors or monoclonal antibodies designed to slow or halt uncontrolled cell growth (Bai 2015).
  • EGFR epidermal growth factor receptor
  • CRC patients with BRAF-mutations do not benefit, either, from EGFR inhibitors.
  • the current standard therapy in first-line treatment of BRAF-mutated CRC is folate/5-fluorouracil (5-FU) assisted oxaliplatin-based chemotherapy plus bevacizumab, increasingly including the more intensive "triplet" therapy FOLFOXIRI (/.e. leucovorin/5-FU/oxaliplatin/ irinotecan) plus bevacizumab, which however is only a valid option in patients with a good ECOG (Eastern Cooperative Oncology Group) performance status (Caputo 2019).
  • Triplet chemotherapy has thus been found to be a very good option for otherwise fit CRC patients with aggressive tumors, and has also been suggested for KRAS-mutated CRC cases (Glynne-Jones 2020).
  • FOLFOXIRI plus bevacizumab triplet therapy is in general associated with a highly increased level of adverse side effects.
  • FOLFOX or FOLFIRI patients in the triplet group
  • FOLFOXIRI plus bevacizumab triplet therapy therefore remains recommended only for patients whose general condition is very good, estimated to around 40-50% of all mCRC patients; discounting the elderly (Cremolini 2019).
  • Leucovorin® orfolinic acid shall both mean 5-formyl tetrahydrofolic acid, i.e. the 5-formyl derivative of tetrahydrofolic acid.
  • Folinic acid contains 2 asymmetric centers.
  • Commercially available leucovorin (LV) is composed of a 1:1 mixture of the dextrorotary and levo- rotary diastereomers (d-leucovorin (d-LV, (6R,2'S)-configuration) and /-leucovorin (/-LV, (6S,2'S)- configuration), respectively), and may also be referred to as (d,/-LV).
  • Levoleucovorin shall refer to the commercially available product which contains only the pharmacologically active /evo-isomer /-LV (or LLV). In vitro, /-LV has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form c/-LV (DLV) is slowly excreted by the kidneys. Leucovorin and levoleucovorin have however been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, Clin Colorectal Cancer 8 200-6 (2009).
  • MTHF or methyleneTHF shall both refer to 5,10-Methylene-5,6,7,8- tetrahydrofolate.
  • racemic methyleneTHF, CoFactor® or [6R,S]-5,10-methyleneTHF shall all refer to the 1:1 diastereomeric mixture [6R,S]-5,10-Methylene-5,6,7,8-tetrahydrofolate.
  • [6R]-5,10-MTHF shall refer to the single diastereomer, [6R]-5,10- methylenetetrahydrofolate.
  • IV or i.v. shall both mean intravenous.
  • best ORR shall refer to the best overall response rate as per RECIST guideline version 1.1 for the treatment period, where applicable.
  • BSA Body Surface Area
  • CRC refers to colorectal cancer.
  • mCRC shall refer to metastatic colorectal cancer.
  • BRAF mutation-positive patients and KRAS mutation-positive patients shall refer to patients who by genotype testing have been found to harbor either BRAF- or KRAS mutated tumors and/or metastases.
  • ctDNA genotype testing shall refer to genotype testing conducted by analyzing a blood or serum sample for cell-free tumor DNA.
  • Arfolitixorin (Modufolin®) is a new drug developed to increase the efficacy of the cytotoxic agent 5-fluorouracil (5-FU) and as a rescue drug after high-dose methotrexate treatment.
  • Arfolitixorin (Modufolin®) [6R]-5,10-methylenetetrahydrofolate, abbreviated herein as [6R]- 5,10-MTHF, needs to be metabolically formed when using the widely used folate-based drugs leucovorin and levoleucovorin.
  • Arfolitixorin (Modufolin®) does not require metabolic activation to exert its effect and may therefore be suitable for all patients.
  • patients diagnosed with colorectal cancer and further determined by genotype testing to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive, i.e. harboring BRAF mutation- and/or KRAS mutation-positive colorectal cancer tumors may be treated according to a chemotherapeutic protocol over at least 16 weeks involving i.a. administration of multiple, rapid boluses of [6R]-5,10-MTHF, by which treatment best ORRs (objective response rates) of >50% can be achieved.
  • [6R]-5,10-methylenetetrahydrofolate for use in a human patient in the treatment of solid colorectal cancer tumors, which treatment comprises the following steps: a) administering a continuous IV infusion containing 85 mg/m 2 (of BSA) oxaliplatin, followed by b) administering an IV bolus containing 400 mg/m 2 (of BSA) 5-fluorouracil, followed by c) administering an IV bolus containing 60 mg/m 2 [6R]-5,10-methylenetetrahydro- folate, followed by d) administering a continuous IV infusion containing 2400 mg/m 2 5-fluorouracil over 46 hours ⁇ 1 hour followed by e) administering an IV bolus containing 60 mg/m 2 (of BSA) [6R]-5,10-methylenetet- rahydrofolate, wherein said human patient has been found by genotype testing to be either BRAF mutation
  • [6R]-5,10-methylenetetrahydrofolate for use in a human patient in the treatment of solid colorectal cancer tumors, which treatment comprises the following steps: a) administering a continuous IV infusion containing 180 mg/m 2 (of BSA) irinotecan, followed by b) administering an IV bolus containing 400 mg/m 2 (of BSA) 5-fluorouracil, followed by c) administering an IV bolus containing 60 mg/m 2 [6R]-5,10-methylenetetrahydro- folate, followed by d) administering a continuous IV infusion containing 2400 mg/m 2 5-fluorouracil over 46 hours ⁇ 1 hour followed by e) administering an IV bolus containing 60 mg/m 2 (of BSA) [6R]-5,10-methylenetetra- hydrofolate, wherein said human patient has been found by genotype testing to be either BRAF mutationpositive or KRAS mutation
  • the treatment based on the ARFOX or ARFIRI protocol may in principle be terminated "for any reason", such as e.g. by a patient decision or a decision taken by the responsible medical person, i.a. due to disease progression or adverse events. Furthermore, the ARFOX or ARFIRI protocol may be interrupted by treatment holidays and the like. Finally the responsible medical person may decide on a fixed number of treatment cycles.
  • [6R]-5,10-methylene-tetrahydrofolate is therefore provided for use in the retardation or prevention of the progression in a human patient of solid colorectal cancer tumors, wherein said human patient has been found by genotype testing to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive, which comprises performing and repeating steps a) to e) according to the first or second aspect of the present invention, over a total treatment period of at least 16 weeks.
  • a method for retardation or prevention of the progression in a human of solid colorectal cancer tumors wherein said human patient has been found by genotype testing to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive, which method comprises performing and repeating steps a) to e) according to the first or second aspect of the present invention, over a total treatment period of at least 16 weeks.
  • DESCRIPTION OF FIGURES Figure 1 (adapted from Huang 2018): Table showing a subgroup analysis for the association between KRAS, BRAF and p53 mutations and CRC distant metastasis
  • Figure 2 is a table of all the 31 participating patients in the follow-up study including a status for each patient as regards KRAS and BRAF genotype results.
  • Arfolitixorin has been in development for a number of years and has been studied in several clinical studies. During one of these studies (the Phase l/lla study ISO-CC-005) it was surprisingly discovered in December 2017 that administration of [6R]-MTHF and 5-FU according to a particular treatment regimen over a treatment period of at least 8 weeks lead to a prevention or retarding of the progression in a human of solid tumors. No statistically significant progression of said solid tumors was observed between 8 and 16 weeks after initiating treatment. These results are discussed i.a. in applicant's international patent application WO 2019/037899 published 28 February 2019. The completion of the study was announced in January 2020. In total, 105 patients were included in the study.
  • Applicant completed the dose definition part of ISO-CC-005 in March 2018, which evaluated the safety and efficacy of arfolitixorin in patients with mCRC. Shortly after, applicant started two additional treatment groups in 2018 to generate more safety and efficacy data, i.e. the safety extension Cohort #18 (Treatment Arm #4) and Cohort #19 (Treatment Arm #6). The aim was to evaluate as many patients as possible from the additional treatment groups after a treatment period of 16 weeks+.
  • This "mutation group” would be expected to have an overall best ORR reflecting the proportion of BRAF mutation-positive CRC patients + the proportion of KRAS mutation-positive CRC patients, which can be calculated as follows:
  • the ARFIRI/ARFOX treatment protocols have proven surprisingly effective in the treatment of CRC patients having tested BRAF- or KRAS mutation-positive, and much more effective than the FOLFIRI/FOLFOX treatment protocols which employ leucovorin.
  • [6R]-5,10-methylenetetrahydrofolate for use in a human patient in the treatment of solid colorectal cancer tumors, which treatment comprises the following steps: a) administering a continuous IV infusion containing 85 mg/m 2 (of BSA) oxaliplatin, followed by b) administering an IV bolus containing 400 mg/m 2 (of BSA) 5-fluorouracil, followed by c) administering an IV bolus containing 60 mg/m 2 [6R]-5,10-methylenetetrahydrofolate, followed by d) administering a continuous IV infusion containing 2400 mg/m 2 5-fluorouracil over 46 hours ⁇ 1 hour by e) administering an IV bolus containing 60 mg/m 2 (of BSA) [6R]-5,10-methylenetetrahy- drofolate, wherein said human patient has been found by genotype testing to be either BRAF mutationpositive
  • [6R]-5,10-methylenetetrahydrofolate for use in a human patient in the treatment of solid colorectal cancer tumors, which treatment comprises the following steps: a) administering a continuous IV infusion containing 180 mg/m 2 (of BSA) irinotecan, followed by b) administering an IV bolus containing 400 mg/m 2 (of BSA) 5-fluorouracil, followed by c) administering an IV bolus containing 60 mg/m 2 [6R]-5,10-methylenetetrahydro- folate, followed by d) administering a continuous IV infusion containing 2400 mg/m 2 5-fluorouracil over 46 hours ⁇ 1 hour followed by e) administering an IV bolus containing 60 mg/m 2 (of BSA) [6R]-5,10-methylenetetra- hydrofolate, wherein said human patient has been found by genotype testing to be either BRAF mutationpositive or KRAS mutation
  • the treatment regimen according to the first aspect is referred to as the "ARFOX” protocol
  • the treatment regimen according to the second aspect is referred to as the "ARFIRI” protocol.
  • the treatment based on the ARFOX or ARFIRI protocol may in principle be terminated "for any reason", such as e.g. by a patient decision or a decision taken by the responsible medical person, i.a. due to disease progression or adverse events. Furthermore, the ARFOX or ARFIRI protocol may be interrupted by treatment holidays and the like. Finally, the responsible medical person may decide on a fixed number of treatment cycles.
  • ctDNA cell-free tumor DNA
  • the method is also referred to as "Liquid Biopsy" analysis.
  • Cell-free DNA (cfDNA) is fragmented DNA that is found in the non-cellular blood components.
  • ctDNA is 150-200 base pair fragments that are released by tumor cells into the bloodstream and represents a small fraction of the total cfDNA.
  • ctDNA retains epigenetic characteristics and carries tumor-specific mutations that can be detected in peripheral blood (Bi 2020). Analysis of ctDNA in plasma is based on sequencing assays, see eg Finkle 2021.
  • [6R]-5,10-methylene-tetrahydrofolate is provided for use in a human patient in the treatment of solid colorectal cancer tumors, which treatment comprises steps a) - e) according to the first or second aspect of the invention, wherein the human patient has been found either by traditional tumor tissue analysis or in preferred embodiments by ctDNA analysis to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive.
  • bevacizumab is administered to a human patient during the treatment period according to the first or second aspect.
  • bevacizumab is administered to a human patient at a dose of 5 mg/kg as an IV infusion every two weeks.
  • bevacizumab administration is initiated 8 weeks after initiating treatment.
  • [6R]-5,10-methylene-tetrahydrofolate is therefore provided for use in the retardation or prevention of the progression in a human patient of solid colorectal cancer tumors, wherein said human patient has been found by genotype testing to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive, which comprises performing and repeating steps a) to e) according to the first or second aspect of the present invention, over a total treatment period of at least 16 weeks.
  • [6R]-5,10-methylene- tetrahydrofolate for use in the retardation or prevention of the progression of the progression in a human of solid colorectal cancer tumors, wherein said human patient has been found by genotype testing to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive, whereby steps a) to e) according to the first or second aspect of the present invention are performed and repeated over a total treatment period of at least 16 weeks, and whereby no statistically significant progression of said solid tumors is observed between 8 and 16 weeks after initiating treatment.
  • a method for retardation or prevention of the progression in a human of solid colorectal cancer tumors wherein said human patient has been found by genotype testing to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive, which method comprises performing and repeating steps a) to e) according to the first or second aspect of the present invention, over a total treatment period of at least 16 weeks.
  • a method for retardation or prevention of the progression in a human of solid colorectal cancer tumors wherein said human patient has been found by genotype testing to be either BRAF mutation-positive or KRAS mutation-positive or both BRAF mutation-positive and KRAS mutation-positive, which method comprises performing and repeating steps a) to e) according to the first or second aspect of the present invention, over a total treatment period of at least 16 weeks, whereby no statistically significant progression of said solid tumors is observed between 8 and 16 weeks after initiating treatment.
  • 5-fluorouracil is replaced by a fluorinated pyrimidine base such as capecitabine (Xeloda), ie. N4-pentyloxycarbonyl-5'- deoxy-5-fluorocytidine, tegafur, 5-fluoro-pyrimidinone, UFT, doxifluridine, 2'-deoxy-5 fluorouridine, 5'-deoxy-5-fluorouridine, l-(2'-oxopropyl)-5-FU, and alkyl-carbonyl-5-FU, BOF- A2, ftorafur(TS-l), and S-l.
  • Xeloda capecitabine
  • [6R]-5,10-methylenetetra- hydrofolate ([6R]-MTHF) is employed as a solid form which is soluble in water, such as a lyophilizate or a salt, optionally stabilized by one or more suitable excipients and/or antioxidants such as citric acid or ascorbic acid or salt forms thereof.
  • the lyophilisate of 6R-MTHF is reconstituted in aqueous media.
  • the lyophilisate of 6R-MTHF is prepared from 6R-MTHF hemisulfate salt. In other preferred embodiments of any of the aspects of the invention the lyophilisate is prepared from 6R-MTHF hemisulfate salt and trisodium citrate dihydrate.
  • the intravenous bolus administration of steps (b), (c) and (e) occur over of a period of 10 minutes or less. In preferred embodiments of any of the aspects of the invention, the intravenous bolus administration of steps (b), (c) and (e) occur over of a period of 5 minutes or less.
  • the intravenous bolus administration of steps (b), (c) and (e) occur over of a period of 3 minutes or less.
  • step (c) follows step (b) after a period of 30 minutes ⁇ 5 minutes.
  • step (d) follows step (c) after a period of less than 60 minutes.
  • step (d) follows step (c) after a period of between 30 and 60 minutes.
  • Arfolitixorin (former Modufolin®) is a folate-based biomodulator developed by applicant to improve the outcome of a range of antimetabolite treatments used within oncology.
  • One of the therapeutic areas of specific interest included in the development program of Arfolitixorin is as biomodulator of 5-fluorouracil (5-FU) activity in standard treatment regime for advanced, metastatic CRC, such as Stage IV.
  • Arfolitixorin The drug substance in Arfolitixorin is [6R]-5,10-MTHF described hereinabove, which is a stable formulation of the naturally occurring diastereoisomer of MTHF.
  • Arfolitixorin (Modufolin®), [6R]-5,10- methylenetetrahydrofolate, abbreviated herein as [6R]-5,10-MTHF, needs to be metabolically formed when using the widely used folate-based drugs leucovorin and levoleucovorin.
  • Arfolitixorin (Modufolin®) does not require metabolic activation to exert its effect and may be directly involved in the formation of the FdUMP TS ternary complex discussed hereinabove.
  • Clinical Study ISO-CC-005 was an exploratory, Phase l/l I multiple-centre study to be carried out in Stadium IV CRC patients. The study was designed to show clinical relevance for patients by characterizing the tolerability of four Arfolitixorin dose levels (30, 60, 120, and 240 mg/m 2 ) in six different standard clinical settings in the presence of fixed doses of 5-FU alone or in combination with either Oxaliplatin, Irinotecan, or Oxaliplatin and Bevacizumab.
  • Clinical Study ISO-CC-005 was an exploratory, Phase l/ll multiple-centre study to be carried out in Stadium IV CRC patients.
  • the study was designed to show clinical relevance for patients by characterizing the tolerability of four arfolitixorin dose levels (30, 60, 120, and 240 mg/m 2 ) in six different standard clinical settings in the presence of fixed doses of 5-FU alone or in combination with either oxaliplatin, irinotecan, or oxaliplatin and bevacizumab.
  • the below Table shows the initial treatment protocol for the Chemotherapy Agents (Bevacizumab, Oxaliplatin, Irinotecan, and/or 5-FU) and of the Study Drug arfolitixorin (Modufolin®): Table 1
  • N/A not applicable
  • SP2D selected phase 2 dose
  • the time-point window for Irinotecan administration will be expanded to allow infusion times of up to 90 minutes, if necessary.
  • the administered bolus 5-FU dose should not surpass the maximum recommended daily dose of 1000 mg, regardless of the body surface area.
  • the tolerability of Arfolitixorin was to be determined by the presence of Dose Limiting Toxicity (DLT) in each of the treatment arms and for each investigated Arfolitixorin dose.
  • DLT Dose Limiting Toxicity
  • the study was divided in the Main Study and the Follow-up study.
  • In the Main Study patients received study treatment with Arfolitixorin during eight (8) weeks. Patients eligible for the Follow-up study could participate until reaching progress, but no longer than 18 months.
  • the Main Study was divided into a dose-finding and a proof-of-concept part.
  • the goal with the Dose-finding Part of the Main Study was to establish the Arfolitixorin dose level assessed as having the most favourable profile, i.e. the selected phase 2 dose (SP2D).
  • the goal with the Proof-of-concept Part of the Main Study was to acquire data on the safety and tolerability of Arfolitixorin at the SP2D dose level in settings equivalent to the two well-established combination therapies FOLFOX (i.e. Oxaliplatin/5-FU/LV) and FOLFIRI (i.e. lrinotecan/5- FU/LV).
  • tumour biomarker (TK1) To evaluate the change in tumour biomarker (TK1) levels in blood after every four (4) consecutive cycles of treatment with combination therapy in the subset of patients with available blood samples.
  • the patient is a 32-year-old white female randomized for treatment according to the ARFOX protocol (see above).
  • Genotype testing [2018-05-10] shows patient is KRAS mutant and BRAF wildtype, NRAS wildtype.
  • MSI microsatelite instability
  • Baseline CT [2018-04-30] showed 1 target lesion in the liver (right lobe).
  • the patient is a 64-year-old white female randomized for treatment according to the ARFOX protocol (see above).
  • the primary right sided tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2018-07-27] shows patient is KRAS, BRAF and NRAS wildtype.
  • Baseline CT [2018-07-02] showed 2 target lesions in the liver parenchyma.
  • the patient is a 69-year-old white female randomized for treatment according to the ARFOX protocol (see above).
  • the primary right sided tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2018-09-13] shows patient is KRAS wildtype, BRAF mutant, NRAS wildtype.
  • Genotype testing [2019-02-14] shows patient is MMR stable.
  • the primary right sided tumour has been removed and adjuvant therapy with CAPECITABINE has been given.
  • Genotype testing [2018-09-13] shows patient is KRAS mutant and BRAF and NRAS wildtype.
  • Baseline CT [2018-08-01] showed 1 target lesion in the left lower lobe of the lung.
  • the patient is a 69-year-old white female randomized for treatment according to the ARFOX protocol (see above).
  • the primary left sided tumour has been removed but no adjuvant therapy has been given.
  • Genotype testing [2018-09-13] shows patient is KRAS mutant and BRAF and NRAS wildtype.
  • the patient is a 71-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • the primary rectal tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2018-08-24] shows patient is KRAS mutant and MLH1, PMS2 and MSH2 stable.
  • Baseline CT [2018-09-14] showed 1 target lesion in the segment 6/7 of the liver.
  • the patient is a 75-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • Genotype testing [2018-11-06] shows patient is KRAS, BRAF and NRAS wildtype.
  • Baseline CT [2018-10-12] showed 3 target lesions; 2 in the lung (left and right lower lobe) and 1 in the liver (left lobe).
  • the patient is a 62-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • the only medical history finding at enrolment is right colectomy and no concomitant medication.
  • Genotype testing [2018-10-16] shows patient is KRAS wildtype, BRAF mutant, NRAS wildtype.
  • Genotype testing [2018-10-24] shows patient is MSI negative.
  • Baseline CT [2018-10-17] showed 5 target lesions in the liver, lung and tumour deposit.
  • Bevacizumab treatment was initiated during the follow-up study.
  • the patient is a 61-year-old white female randomized for treatment according to the ARFOX protocol (see above). Medical history findings at enrolment are hyperuricemia and hypertension that are both treated.
  • the primary left sided tumour has been removed but no adjuvant therapy has been given.
  • Genotype testing [2018-10-17] shows patient is KRAS wildtype, BRAF mutant, NRAS wildtype and MSI negative.
  • Baseline CT [2018-10-25] showed 3 target lesions in the liver (segment IV, VI and VII).
  • Bevacizumab treatment was initiated during the follow-up study in addition to the concomitant medication patient had at enrollment in the study.
  • the patient is a 48-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • the primary rectal tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2018-11-26] shows patient is KRAS, BRAF and NRAS wildtype.
  • Baseline CT+MRI [2018-11-12] showed 3 target lesions; in the liver lobe, in the horronic lymph nodes (lymph nodes) and in left pelvis.
  • the patient is a 67-year-old white female randomized for treatment according to the ARFOX protocol (see above). Medical history findings at enrolment are an ostomy surgery in the past and an ongoing Candida infection, but no concomitant medication.
  • Genotype testing [2018-12-12] shows patient is KRAS and BRAF wildtype, NRAS mutant.
  • Baseline CT [2018-12-16] showed 2 target lesions in the liver (right lobe dorsal lateral).
  • 8week CT [2019-02-26] the sum of diameter of the target lesion(s) decreased with 40% (partial response) and patient consented to participation in the follow-up study.
  • AEs dry skin grade 1, treated with Canoderm, ileostomy infection grade 2, treated with antibiotics, insomnia grade 1 and loss of appetite grade 2.
  • Patient also had a number of AEs related to bone marrow toxicity (neutropenia, leukopenia) with grade ranging from 1-3 - treated accordingly with Zarzio, and a couple of occasions of nausea grade 1 despite a number of prophylactic drugs given.
  • neuropathy grade 1 a number of AEs related to bone marrow toxicity (neutropenia, leukopenia) with grade ranging from 1-3 - treated accordingly with Zarzio, and a couple of occasions of nausea grade 1 despite a number of prophylactic drugs given.
  • the patient is a 69-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • Genotype testing [2018-12-28] shows patient is KRAS and NRAS wildtype.
  • Baseline CT [2018-12-03] showed 3 target lesions; in the part IV of the liver, in left adrenal gland and in lung nodules.
  • the patient is a 34-year-old white female randomized for treatment according to the ARFOX protocol (see above).
  • Genotype testing [2019-01-31] shows patient is KRAS, BRAF and NRAS wildtype.
  • panitimumab was added to the ARFOX treatment during the follow-up study.
  • the patient is a 53-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • Medical history finding at enrolment is depression, which is treated with Sobril.
  • Other concomitant medication at enrolment is treatment of pain, heartburn, rhinit as well as constipation and thrombosis prophylaxes.
  • the primary right sided tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2019-01-09] shows patient is KRAS wildtype, BRAF mutant, NRAS wildtype and MSS negative.
  • Baseline CT [2019-01-02] showed 3 target lesions in the liver (segment IV and VII) and lymph node.
  • 8week CT [2019-03-27] the sum of diameter of the target lesion(s) increased with 29% and additional lesions were discovered (progressive disease).
  • the patient is a 68-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • Genotype testing [2019-01-31] shows patient is KRAS mutant and MSS negative.
  • Baseline CT [2019-02-21] showed 2 target lesions; in segment 6/7 and segment 8 of the liver.
  • 8week CT [2019-04-15] the sum of diameter of the target lesion(s) decreased with 53% (partial responses) and patient was thereby eligible for participation in the follow-up study.
  • the patient is a 70-year-old white male randomized for treatment according to the ARFOX protocol (see above).
  • Genotype testing [2018-09-26] shows patient is MSI stable (microsatellite instability absent).
  • Genotype testing [2020-02-04] shows patient is KRAS, BRAF and NRAS wildtype.
  • the patient is a 66-year-old white female randomized for treatment according to the ARFOX protocol (see above).
  • the primary rectal tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2019-01-08] shows patient is KRAS mutant and BRAF and NRAS wildtype.
  • Baseline CT [2019-03-07] showed 2 target lesions; in the left lower lung lobe and in the right upper lung lobe.
  • the patient is a 68-year-old white male randomized for treatment according to the ARFIRI protocol (see above).
  • Medical history findings at enrolment are depression, gastroesophageal reflux and insomnia which are treated accordingly. Other medical history findings are untreated atrial fibrillation grade 2 and back pain. Patient also has liver surgery and hemicolectomy reported as medical history.
  • the primary left sided tumour has been removed and adjuvant therapy with FOLFOX [EOT 2017-01-05] has been given.
  • Genotype testing shows patient is KRAS wildtype, BRAF mutant, NRAS wildtype.
  • Baseline MRI [2018-03-06] showed 1 target lesion in the liver (right dorsal).
  • the patient had severe problems with Gl related toxicity such as nausea and vomiting.
  • Patient was allowed to try the following 5-FU bolus regimen (irinotecan 180 mg/m2 on day 1, bolus 5-FU 500 mg/m2 and arfolitixorin 60 mg/m2 on day 1 and 2) during the followup study without any significant change of toxicity.
  • Patient also reported a number of occasions of fatigue grade 1-2 during study participation and initially one episode of paroxysmal atrial fibrillation grade 3 and a month later atrial fibrillation grade 3 - both reported to be related to the study drug by the investigator.
  • the patient is a 65-year-old white female randomized for treatment according to the ARFIRI protocol (see above).
  • Genotype testing [2018-03-22] shows patient is KRAS, BRAF and NRAS wildtype.
  • Baseline CT [2018-03-27] showed 1 target lesion in the pelvis (cervix, near rectal stump).
  • the patient is a 74-year-old white male randomized for treatment according to the ARFIRI protocol (see above). Medical history findings at enrolment are hypertension that is treated accordingly, hyperlipidemia and a right hemicolectomy. Patient is treated with Salospir and Placol as cardiovascular prevention.
  • the primary right sided tumour has been removed and adjuvant therapy with CAPECITABINE- OXALIPLATIN [EOT 2017-UNK-UNK] has been given.
  • Genotype testing [2018-05-04] shows patient is KRAS, BRAF and NRAS wildtype.
  • Baseline CT [2018-05-14] showed 5 target lesions in the lung (right and left lobe), abdomen and abdominal aorta.
  • the patient is a 67-year-old white male randomized for treatment according to the ARFIRI protocol (see above).
  • the primary left sided tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2018-05-22] shows patient is KRAS mutant, BRAF wildtype and MLH1, PMS2, MSH2 and MSH6 stable.
  • Baseline CT [2018-04-16] showed 3 target lesions in the liver; 1 in left lobe apical and 2 in right lobe.
  • the patient is a 58-year-old white male randomized for treatment according to the ARFIRI protocol (see above).
  • the primary left sided tumour has been removed but no adjuvant therapy has been given.
  • Genotype testing [2017-11-28] shows patient is KRAS mutant and BRAF and NRAS wildtype.
  • Baseline CT [2018-07-23] showed 2 target lesions in the lung; right lower lobe and lymphnode.
  • the patient is a 68-year-old white male randomized for treatment according to the ARFIRI protocol (see above).
  • the primary left sided tumour has been removed but no adjuvant therapy has been given.
  • Genotype testing [2018-08-10] shows patient is KRAS wildtype, BRAF wildtype and MLH1, PMS2, MSH2 and MSH6 stable.
  • Baseline MRI [2018-07-06] showed 2 target lesions in the liver (segment 1 and 7).
  • hypotension grade 2 hypotension grade 2
  • insomnia grade 1 worsening of restless legs (grade 1) that was reported as medical history.
  • the patient is a 58-year-old white female randomized for treatment according to the ARFIRI protocol (see above).
  • Medical history findings at enrolment are depression and pain that are treated accordingly.
  • Other medical history findings are twisted ovarian cyst, struma [goitre], anorexia, rash, fatigue and dry mouth. Medication for rash is prescribed at enrolment.
  • Genotype testing [2018-07-31] shows patient is KRAS mutant and BRAF wildtype, NRAS wildtype.
  • Baseline CT [2018-08-22] showed 2 target lesions in retroperitoneal lymph node.
  • Dizziness grade 1 and nausea grade 1 are reported at almost every treatment cycle, and nausea is treated with both oral an i.v. nausea prophylaxis.
  • Patient also reports several episodes of epistaxis grade 1. Dry skin grade 1 is reported a couple of times and so is pain grade 1, lasting for several weeks at a time. During follow-up study oral mucositis lasting for more than a month is reported, treated with chamomile flower tea.
  • the patient is a 65-year-old white male randomized for treatment according to the ARFIRI protocol (see above).
  • the primary left sided tumour has been removed but no adjuvant therapy has been given.
  • Genotype testing [2017-10-12] shows patient is KRAS mutant and BRAF wildtype.
  • Genotype testing [2017-10-13] shows patient is MSI negative.
  • Baseline CT [2018-08-23] showed 1 target lesion in segment VI of the liver.
  • the patient is a 63-year-old white male randomized for treatment according to the ARFIRI protocol (see above).
  • the primary right sided tumour has been removed but no adjuvant therapy has been given. No genotype testing performed.
  • Baseline CT [2018-10-29] showed 2 target lesions; left ventral (gland) and left aorta (gland).
  • the patient is a 45-year-old white male randomized for treatment according to the ARFIRI protocol (see above).
  • the primary right sided tumour has been removed and adjuvant therapy with FLOX [EOT 2017-06-29] has been given.
  • Genotype testing [2018-08-06] shows patient is KRAS mutant and MLH1, PMS2, MSH2 and MSH6 stable.
  • Baseline CT [2018-12-07] showed 1 target lesion the right lower lobe of the lung, ventral.
  • CT the sum of diameter of the target lesion(s) increased with 50% (progressive disease).
  • the patient is a 46-year-old Asian female randomized for treatment according to the ARFIRI protocol (see above).
  • the primary rectal tumour is still in place and no adjuvant therapy has been given.
  • Genotype testing [2018-11-16] shows patient is KRAS and BRAF wildtype and NRAS mutant.
  • Baseline CT [2018-12-27] showed 2 target lesions in the liver.
  • the patient is a 72-year-old white female randomized for treatment according to the ARFIRI protocol (see above).
  • Medical history finding at enrolment is (mild) hypertension treated with hydrochlorothiazide. No other medical history finding nor concomitant medication.
  • the primary left sided tumour has been removed but no adjuvant therapy has been given.
  • Genotype testing [2019-03-01] shows patient is KRAS and BRAF mutant, NRAS mutant.
  • Genotype testing [2019-12-12] shows patient is MSI stable (microsatellite instability absent).
  • Baseline CT [2019-03-19] showed 1 target lesion in the lung (left upper lobe).
  • the patient is a 68-year-old white female randomized for treatment according to the ARFIRI protocol (see above).
  • the primary left sided tumour has been removed but no adjuvant therapy has been given.
  • Genotype testing [2019-04-11] shows patient is BRAF mutant and MSI stable (microsatellite instability absent).
  • Genotype testing [2019-04-16] shows patient is KRAS wildtype.
  • Genotype testing [2019-04-19] shows patient is NRAS wildtype.
  • Baseline CT [2019-04-03] showed 3 target lesions in the liver (right lobe) and lung (right lobe).
  • 8week CT [2019-06-04] the sum of diameter of the target lesion(s) decreased with 54% (partial response) and patient consented to participation in the follow-up study.
  • the patient is a 52-year-old white female randomized for treatment according to the ARFIRI protocol (see above).
  • Genotype testing [2019-04-25] shows patient is KRAS and BRAF mutant, NRAS wildtype.
  • Genotype testing [2019-04-19] shows patient is MSI stable (microsatellite instability absent).
  • Baseline CT [2019-03-13] showed 2 target lesions in the lung (left and right lower lobe).

Abstract

La présente invention concerne le traitement du cancer colorectal chez les populations humaines ayant une haute fréquence de mutations de BRAF- ou KRAS-, qui consiste à administrer de multiples bolus de [6R]-5,10-méthylènetétrahydrofolate ([6R]-MTHF) en liaison avec la chimiothérapie à base de 5-fluorouracile (5-FU).
PCT/EP2021/076512 2021-09-27 2021-09-27 [6r]-mthf dans une chimiothérapie à base de 5-fu de cancer colorectal à mutation de kras ou braf WO2023046304A1 (fr)

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PCT/EP2022/076606 WO2023046940A1 (fr) 2021-09-27 2022-09-26 [6r]-mthf utilisé dans la chimiothérapie basée sur 5-fu du cancer colorectal à mutation braf ou kras

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PCT/EP2022/076606 WO2023046940A1 (fr) 2021-09-27 2022-09-26 [6r]-mthf utilisé dans la chimiothérapie basée sur 5-fu du cancer colorectal à mutation braf ou kras

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EP3446703A1 (fr) * 2017-08-24 2019-02-27 Isofol Medical AB Administration de bolus multiples 6r]-mthf dans une chimiothérapie à base de 5-fluorouracile
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EP3446703A1 (fr) * 2017-08-24 2019-02-27 Isofol Medical AB Administration de bolus multiples 6r]-mthf dans une chimiothérapie à base de 5-fluorouracile
WO2019037899A1 (fr) 2017-08-24 2019-02-28 Isofol Medical Ab Administration de multiples bolus de [6r]-mthf au cours d'une chimiothérapie à base de 5-fluoro-uracile
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