WO2020239478A1 - Trabectédine pour le traitement de sarcomes basé sur des marqueurs génomiques - Google Patents

Trabectédine pour le traitement de sarcomes basé sur des marqueurs génomiques Download PDF

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WO2020239478A1
WO2020239478A1 PCT/EP2020/063663 EP2020063663W WO2020239478A1 WO 2020239478 A1 WO2020239478 A1 WO 2020239478A1 EP 2020063663 W EP2020063663 W EP 2020063663W WO 2020239478 A1 WO2020239478 A1 WO 2020239478A1
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gene
subject
trabectedin
mutation
lce3b
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PCT/EP2020/063663
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English (en)
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Shibu THOMAS
Joshi SHILPY
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Pharma Mar, S.A.
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Publication of WO2020239478A1 publication Critical patent/WO2020239478A1/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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Treatment is palliative in nature, and the goal is delay of the progression and severe morbidity that can arise when tumor growth compromises organ function (Schoffski P, Cornillie J,
  • the present invention provides methods of treating a subject having sarcoma, comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • the present invention provides methods of treating a subject having sarcoma, comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, EB2ATR4, and combinations thereof; and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • trabectedin for use in the treatment of scarcoma, wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • trabectedin for use in the treatment of scarcoma, wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • trabectedin in the manufacture of a medicament for the treatment of sarcoma, wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • trabectedin in the manufacture of a medicament for the treatment of sarcoma, wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • the homozygous mutation is in LCE3B, LCE3C or both LCE3B and LCE3C.
  • the overall survival of the subject is improved relative to a subject with sarcoma who is determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the progression- free survival is improved relative to a subject with sarcoma who is determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the tumor sample is a sarcoma tumor biopsy sample
  • the tumor sample is a surgical sarcoma tumor sample.
  • the tumor sample comprises one or more cell.
  • the tumor sample is a blood sample.
  • the administering is by intravenous administration.
  • the mutation is a deletion of all of the coding sequence of the gene.
  • the mutation is a deletion of a portion of the coding sequence of the gene.
  • the mutation leads to a loss-of-function mutation.
  • a loss of function mutation can be determined using routine methods in the art.
  • the mutation is the deletion of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5 wherein the mutation leads to a loss of function.
  • the mutation is a substitution and/or addition of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the mutation leads to a loss of function.
  • the present invention provides methods of treating a subject having soft tissue sarcoma (STS), comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • STS soft tissue sarcoma
  • the present invention provides methods of treating a subject having STS, comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof; and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • trabectedin for use in the treatment of soft tissue sarcoma (STS), wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • trabectedin for use in the treatment of soft tissue sarcoma (STS), wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • STS soft tissue sarcoma
  • trabectedin in the manufacture of a medicament for the treatment of soft tissue sarcoma (STS), wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • trabectedin in the manufacture of a medicament for the treatment of soft tissue sarcoma (STS), wherein trabectedin is administered to a subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • the homozygous mutation is in LCE3B, LCE3C or both LCE3B and LCE3C.
  • the overall survival is improved relative to subjects with STS having a tumor sample determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the progression- free survival is improved relative to subjects with STS having a tumor sample determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the tumor sample is a tumor biopsy sample.
  • the tumor sample is a surgical tumor sample.
  • the tumor sample comprises one or more cell.
  • the tumor sample is a blood sample.
  • the administering is by intravenous administration.
  • the mutation is a deletion of all of the coding sequence of the gene.
  • the mutation is a deletion of a portion of the coding sequence of the gene.
  • the mutation leads to a loss-of-function mutation.
  • a loss of function mutation can be determined using routine methods in the art.
  • the mutation is the deletion of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the mutation leads to a loss of function.
  • the mutation is a substitution and/or addition of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the mutation lead to a loss of function.
  • the STS is liposarcoma.
  • the STS is leiomyosarcoma.
  • the patient was previously treated with at least one of anthracycline and ifosfamide.
  • the present invention provides methods of identifying a patient suffering with sarcoma that is responsive to treatment (e.g., realizes a long term benefit, such as, e.g., overall survival) with trabectedin comprising evaluating a biological sample from the patient for the presence of a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof; and determining whether the homozygous mutation is present in the sample, wherein the presence of the homozygous mutation indicates that the patient is responsive to treatment with trabectedin.
  • the method comprises determining the presence of a homozygous mutation in LCE3B, LCE3C or both LCE3B and LCE3C.
  • the biological sample comprises a tumor sample (e.g., a sarcoma sample).
  • a tumor sample e.g., a sarcoma sample.
  • the tumor sample is a cancer cell.
  • the sarcoma is resectable.
  • the sarcoma is metastatic.
  • the homozygous mutation is a homozygous deletion.
  • the subject is determined to have a homozygous mutation in at least two genes selected from the group consisting of DDX12P, LCE3B, LCE3C, and HEATR4. In a specific embodiment of the methods provided, the subject is determined to have a homozygous mutation in at least three genes selected from the group consisting of DDX12P, LCE3B, LCE3C, and HEATR4. In a specific embodiment of the methods provided, the subject is determined to have a homozygous mutation in all four genes of the group consisting of DDX12P, LCE3B, LCE3C, and HEATR4.
  • kits comprising trabectedin, wherein the kit further comprises instructions to obtain a tumor sample from the subject and determine whether said sample has a homozygous mutation in a gene selected from the group consisting of DDX12P, FCE3B, FCE3C, HEATR4, and combinations thereof.
  • kits comprising trabectedin, wherein the kit further comprises instructions to obtain a tumor sample from the subject and determine whether said sample has a homozygous mutation in a gene selected from the group consisting of DDX12P, FCE3B, FCE3C, HEATR4, and combinations thereof and whether the tumor sample has a normal copy number of the MDM2 gene.
  • FIGs. 1A, IB and 1C provide background and results of a Phase III Study of
  • FIG. 1 A provides background of the study (Demetri GD, et al. J Clin Oncol 34:786-93, 2016). Key eligibility criteria were: patients with histologically proven LPS or LMS; previously treated with an anthracycline and ifosamide/anthracycline containing regimen and one additional cytotoxic chemotherapy regimen. Stratified by prior lines chemotherapy (lvs > 20; ECOG PS (0 vs 1); sarcoma subtype (LPS vs LMS).
  • FIGs. IB and 1C show final progression free survival (PFS) and overall survival (OS) curves of patients in the clinical study. Dashed line is dacarbazine. Solid line is Trabectedin.
  • FIG. 2 illustrates the population, sample distribution and methodology for biomarker analysis of samples from the SAR3007/NCT01343277 Phase III study.
  • the SAR3007 first Phase IP trial was to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen.
  • Population 70% LMS; 30% LPS. 454 total sarcoma specimens (all archival) from this population.
  • FIGs. 3A and 3B illustrate copy number variations and genetic alteration frequencies and defined biomarker subsets observed in leiomyosarcoma and liposarcoma patients from the SAR3007 clinical study data.
  • FIG. 3B shows a higher-resolution image of the“Copy Number Variations” panel in FIG. 3A.
  • FIGs. 4A, 4B and 4C show graphs illustrating improved OS with trabectedin treatment in LMS and LPS patients from the SAR3007 study having a four (4)-gene molecular signature (Homozygous deletion in at least one of the 4 genes: DDX12P, LCE3B, LCE3C, HEATR4); Fig 4A: Final OS between T and D (dashed line is D); FIG: 4B: dacarbazine - multivariate; FIG. 4C: Trabectedin - Multivariate.
  • FIGs. 5A, 5B, 5C and 5D show poor PFS (5A and 5B) and OS (5C and 5D) when patients from the SAR-3007 study were treated with trabectedin when MDM2 is amplified (MDM2 amplifications > 5 fold). No significant improvement in PFS was observed in this biomarker-defined sub-group.
  • FIGs.6A, 6B, 6C and 6D show improved PFS (6A and 6B) and OS (6C and 6D) when patients from the SAR-3007 study were treated with trabectedin (6B and 6D) versus dacarbazine (6A and 6C) when MDM2 has a normal copy number (no significant improvement in PFS was observed in this biomarker-defined sub-group.
  • FIGs.7A and 7B show improved OS in subjects from the SAR-3007 study with a homozygous deletion in LCE3B or LCE3C and treated with trabectedin (7B) versus dacarbazine (7A). Homozygous deletion in LCE3B or LCE3C.
  • FIG. 8 shows the nucleotide sequence of the human MDM2 proto-oncogene (SEQ ID NO: 1).
  • FIG. 9 shows the nucleotide sequence of the human DDX12P DEAD/H-box helicase 12 gene (SEQ ID NO: 2).
  • FIG. 10 shows the nucleotide sequence of the human LCE3B late cornified envelope 3B gene (SEQ ID NO: 3).
  • FIG. 11 shows the nucleotide sequence of the human LCE3C late cornified envelope 3C gene (SEQ ID NO: 4).
  • FIG. 12 shows the nucleotide sequence of the human HEATR4 HEAT repeat containing 4 gene (SEQ ID NO: 5).
  • cancer refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to remote organs in the body.
  • soft tissue sarcoma or“STS” as used herein refers to histologically or cytologically confirmed sarcoma that develops in connective tissue.
  • Leiomyosarcoma is a type of soft tissue sarcoma that develops from smooth muscle tissue.
  • Liposarcoma is another type of soft tissue sarcoma that develops from fat tissue.
  • composition means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • continuous daily dosing schedule refers to the administration of a particular therapeutic agent without any drug holidays from the particular therapeutic agent.
  • a continuous daily dosing schedule of a particular therapeutic agent comprises administration of a particular therapeutic agent every day at roughly the same time each day.
  • treat and treatment refer to the treatment of a patient afflicted with a pathological condition and refers to an effect that alleviates the condition by killing the cancerous cells, but also to an effect that results in the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis is also included.
  • PFS progression-free survival
  • progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Furthermore, the appearance of one or more new lesions is also considered progression. For subjects with only non-measurable disease observed on CT or MRI scans, unequivocal progression (representative of overall disease status change) or the appearance of one or more new lesions was considered progression. For new lesions detected on scans, a second imaging modality (e.g., CT or MRI) was required to confirm progression.
  • CT or MRI a second imaging modality
  • administration of a safe and effective amount of trabectedin provides improved anti-tumor activity as measured by progression-free survival rate.
  • the term“overall survival” or“OS” is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive. In addition, for subjects with no postbaseline information survival, data was to be censored on the date of randomization; for subjects who are lost to follow-up or who withdraw consent, data is censored on the last known date that they were alive. In some embodiments,
  • trabectedin provides improved anti-tumor activity as measured by overall survival.
  • time to progression refers to the time interval in months between the date of randomization and the date of disease progression or death due to progression, whichever occurred first.
  • objective response rate is defined as the percentage of participants who achieved a complete response (CR) or partial response (PR) as best responses according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST).
  • CR defined as
  • survival benefit means an increase in survival of the patient from time of randomization on the trial of administered drug to death.
  • the survival benefit is about 1 month, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 80, about 100 months or greater than 100 months.
  • delay in symptoms related to disease progression means an increase in time in the development of symptoms such as pain and quality of life considerations from the time of randomization on the trial of administered drug.
  • the term 'randomization' as it refers to a clinical trial refers to the time when the patient is confirmed eligible for the clinical trial and gets assigned to a treatment arm.
  • the term“duration of response” refers to the time from the date of initial documentation of a response (CR or PR) to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death.
  • drug product or“approved drug product” is product that contains an active pharmaceutical ingredient that has been approved for marketing for at least one indication by a governmental authority, e.g., the Food and Drug Administration or the similar authority in other countries.
  • a governmental authority e.g., the Food and Drug Administration or the similar authority in other countries.
  • The“normal copy number” is two.
  • a normal copy number may also be referred to as “no amplification” of MDM2 herein. Accordingly, in embodiments of the present invention, an increase in the copy number of MDM2 is associated with a reduction in PFS and/or OS.
  • the increase in the metastasis-free survival is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, or greater than 20 months.
  • administration of a safe and effective amount of trabectedin provides an increase in the metastasis-free survival of a human, said population having been treated with a placebo.
  • metastasis- free survival refers to the time from randomization to the time of first evidence of blinded independent central review (BICR)-confirmed bone or soft tissue distant metastasis or death due to any cause, whichever occurs first.
  • BICR blinded independent central review
  • NCT01343277 (also coded as ET743-SAR-3007 and SAR-3007) Phase III clinical trial was carried out to show the efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy.
  • Trabectedin demonstrated improved disease control versus conventional dacarbazine in patients who had advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end-point, this study supported the activity of trabectedin for patients with these malignancies.
  • FIG. 2 illustrates the population, sample distribution and methodology for biomarker analysis of samples from the SAR-3007 Phase III study.
  • SAR-3007 study 1% of the solid tumors were STS. There were 454 total sarcoma specimens (all archival) from the population of LMS and LPS patients. Of the 1%, 70% were LMS and 30% were LPS.
  • the sample distribution included LMS comprising uterine LMS (uLMS) and non-uterine LMS (non-uLMS), and LPS comprising dedifferentiated LPS (ddLPS), myxoid LPS (mLPS), and pleiomorphic LPS (pLPS).
  • uLMS uterine LMS
  • non-uLMS non-uterine LMS
  • ddLPS dedifferentiated LPS
  • mLPS myxoid LPS
  • pLPS pleiomorphic LPS
  • FIG. 3 illustrates copy number variations and genetic alteration frequencies and defined biomarker subsets observed in leiomyosarcoma and liposarcoma patients from the SAR- 3007 clinical study data.
  • the defined biomarker (BM) subsets included a four (4) gene signature (homozygous deletion (HD) in at least one of four genes: DDX12P, LCE3B, LCE3C and HEATR4) and a five (5) gene signature (HD in at least one of four (4) genes: DDX12P, LCE3B, LCE3C and HEATR4, and without DM2 amplification).
  • MDM2 comprises the sequence of SEQ ID NO: 1.
  • DDX12P comprises the sequence of SEQ ID NO: 2.
  • LCE3B comprises the sequence of SEQ ID NO: 3.
  • LCE3C comprises the sequence of SEQ ID NO: 4.
  • HE1ATR4 comprises the sequence of SEQ ID NO: 5.
  • FIGs. 4A, 4B and 4C show graphs illustrating improved OS with trabectedin treatment versus dacarbazine treatment in LPS and LMS patients from the SAR-3007 study having the aforementioned four (4) gene molecular signature.
  • FIGs. 5A, 5B, 5C and 5D show poor PFS (5A and 5B) and OS (5C and 5D) when patients from the SAR-3007 study were treated with trabectedin when MDM2 is amplified (approximately 5-fold) .
  • FIGs. 6A, 6B, 6C and 6D show improved PFS (6A and 6B) and OS (6C and 6D) when patients from the SAR-3007 study were treated with trabectedin (6B and 6D) versus dacarbazine (6A and 6C) when MDM2 has a normal copy number (the aforementioned five gene signature).
  • FIGs. 7 A and 7B show improved OS in ddLPS patients from the SAR-3007 study with a homozygous deletion in LCE3B or LCE3C and treated with trabectedin (7B) versus dacarbazine (7A).
  • the present invention discloses a novel molecular subset of LPS and LMS subjects with HD in at least one of the 4 genes ( DDX12P , LCE3B, LCE3C, HEATR4 ) that show improved OS with trabectedin treatment. Further, worse clinical outcomes in MDM2 - amplified patients suggest a TP53-dependent effect of trabectedin in LPS and LMS.
  • the present invention provides methods of treating a subject having sarcoma, comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • the present invention provides methods of treating a subject having sarcoma, comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HE1ATR4, and combinations thereof; and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • the invention provides a method of treating a subject having sarcoma comprising determining whether a tumor sample from the subject has a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof, and if such a homozygous mutation is present, administering trabectidin to the subject.
  • the invention provides a method of treating a subject having sarcoma comprising determining whether a tumor sample from the subject has a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof, and the tumor sample is also determined to have a normal copy number of the MDM2 gene, and if such a homozygous mutation is present, administering trabectidin to the subject.
  • the overall survival of the subject is improved relative to a subject with sarcoma who is determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the progression- free survival is improved relative to a subject with sarcoma who is determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the tumor sample comprises one or more cell.
  • the tumor sample is a sarcoma tumor biopsy sample
  • the tumor sample is a surgical sarcoma tumor sample.
  • the tumor sample is a blood sample.
  • the administering is by intravenous administration.
  • the mutation is a deletion of all of the coding sequence of the gene.
  • the mutation is a deletion of a portion of the coding sequence of the gene.
  • the mutation leads to a loss-of-function mutation.
  • a loss of function mutation can be determined using routine methods in the art.
  • the mutation is the deletion of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the mutation leads to a loss of function.
  • the mutation is a substitution or addition of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the bases lead to a loss of function mutation.
  • the present invention provides methods of treating a subject having soft tissue sarcoma (STS), comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof.
  • STS soft tissue sarcoma
  • the present invention provides methods of treating a subject having STS, comprising administering trabectedin to the subject if a tumor sample from the subject is determined to have a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof; and the tumor sample is determined to have a normal copy number of the MDM2 gene.
  • the overall survival is improved relative to subjects with STS having a tumor sample determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the progression- free survival is improved relative to subjects with STS having a tumor sample determined to have no homozygous mutation in any one of the DDX12P gene, LCE3B gene, LCE3C gene, or HEATR4 gene.
  • the tumor sample is a tumor biopsy sample.
  • the tumor sample is a surgery tumor sample.
  • the tumor sample is a blood sample.
  • the administering is by intravenous administration.
  • the mutation is a deletion of all of the coding sequence of the gene.
  • the mutation is a deletion of a portion of the coding sequence of the gene.
  • the mutation leads to a loss-of-function mutation.
  • a loss of function mutation can be determined using routine methods in the art.
  • the mutation is the deletion of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the mutation leads to a loss of function.
  • the mutation is a substitution or addition of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the bases lead to a loss of function mutation.
  • the STS is liposarcoma.
  • the STS is leiomyosarcoma.
  • the patient was previously treated with at least one of anthracycline and ifosfamide.
  • the present invention provides methods of identifying a patient suffering with sarcoma that is responsive to treatment (e.g., realize a long term benefit, such as, e.g., overall survival) with trabectedin comprising evaluating a biological sample from the patient for the presence of a homozygous mutation in a gene selected from the group consisting of DDX12P, LCE3B, LCE3C, HEATR4, and combinations thereof; and determining whether the homozygous mutation is present in the sample, wherein the presence of the homozygous mutation indicates that the patient is responsive to treatment with trabectedin.
  • the subject is determined to have a homozygous mutation in at least one gene selected from the group consisting of DDX12P, LCE3B, LCE3C, and HEATR4.
  • the subject is determined to have a homozygous mutation in at least two genes selected from the group consisting of DDX12P, LCE3B, LCE3C, and HEATR4.
  • the patient can be treated with trabectedin, including, when chemically possible, any tautomeric or stereochemically isomeric form thereof, N-oxide thereof, pharmaceutically acceptable salt thereof, or solvate thereof, if one or more homozygous mutations in at least one of DDX12P, LCE3B, LCE3C, and HEATR4 are present in the sample.
  • the biological sample comprises a tumor sample (e.g., a sarcoma sample).
  • a tumor sample e.g., a sarcoma sample.
  • the tumor sample is a cancer cell.
  • the sarcoma is resectable.
  • the sarcoma is metastatic.
  • the homozygous mutation is a homozygous deletion.
  • the mutation leads to a loss-of-function mutation.
  • a loss of function mutation can be determined using routine methods in the art.
  • the mutation is the deletion of one or more bases in SEQ ID NO: 2, , 4 and/or 5, wherein the mutation leads to a loss of function.
  • the mutation is a substitution or addition of one or more bases in SEQ ID NO: 2, 3, 4 and/or 5, wherein the bases lead to a loss of function mutation.
  • the tumor sample is a tumor biopsy sample.
  • the tumor sample is a surgical tumor sample.
  • a biopsy is a procedure to remove tissue (e.g., suspicious tissue) or a sample of cells from a living body of a subject, e.g., from a subject’s soft tissue.
  • Tumor biopsy samples can be collected in different ways. The tumor biopsy may involve passing a needle through the skin surface transdermally. An MRI or CT scan is generally used to guide this procedure. A physician may target a suspicious area to biopsy or may take samples from several places in the area. Generally, 10 to 12 tissue samples are taken. As such, in embodiments of the invention, the biopsy sample may include normal soft tissue and cancerous tissue, or only cancerous tissue.
  • a surgical tumor sample can include a tumor sample that is collected during a surgery.
  • a surgical tumor sample can include metastatic lesions that are remote to the primary tumor.
  • a surgical tumor sample can include the whole tumor, or a portion of the tumor, that is excised from the subject, e.g., patient.
  • a surgical tumor sample comprises a tumor.
  • the determination of whether the soft tissue sarcoma tumor sample comprises cells of a LPS or LMS subtype is made based on genomic analysis, e.g., mRNA expression analysis. In some embodiments, the determination of whether the soft tissue sarcoma tumor sample comprises cells of a LPS or LMS subtype is made based on a microscopic analysis of the histological features of the cells (e.g., based on Hematoxylin and eosin (H&E) staining, immunohistochemistry, or standard light microscopy).
  • genomic analysis e.g., mRNA expression analysis.
  • the determination of whether the soft tissue sarcoma tumor sample comprises cells of a LPS or LMS subtype is made based on a microscopic analysis of the histological features of the cells (e.g., based on Hematoxylin and eosin (H&E) staining, immunohistochemistry, or standard light microscopy).
  • H&E Hematoxylin and
  • the determination of whether the soft tissue sarcoma tumor sample comprises cells of a LPS or LMS subtype is made based on a gross analysis of the surgical tumor sample or tumor biopsy sample. In some embodiments, the determination of whether the tumor sample comprises cells of a LPS or LMS subtype is made based on a microscopic analysis of the histological features of the cells via a software analysis. In some embodiments, the determination of whether the tumor sample comprises cells of a LPS or LMS subtype is made based on molecular analysis of genetic markers for each of the LPS or LMS subtypes (e.g., Northern blot analysis, Southern blot analysis, Western blot analysis, microarray, etc.).
  • genetic markers for each of the LPS or LMS subtypes e.g., Northern blot analysis, Southern blot analysis, Western blot analysis, microarray, etc.
  • compositions described herein may be carried out in any manner, e.g., by parenteral or nonparenteral administration, including by aerosol inhalation, injection, infusions, ingestion, implantation or transplantation.
  • parenteral or nonparenteral administration including by aerosol inhalation, injection, infusions, ingestion, implantation or transplantation.
  • the compositions described herein may be administered to a patient trans-arterially, intradermally, subcutaneously, intratumorally, intramedullary, intranodally, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally.
  • the compositions of the present disclosure are administered by i.v. injection (e.g., through a central venous line).
  • the compositions of the present disclosure are administered to a subject by intradermal or subcutaneous injection.
  • the compositions may be injected, for instance, directly into a tumor, lymph node, tissue, or organ.
  • the administering is by oral administration.
  • the compositions e.g., trabectedin
  • the composition is formulated as a tablet.
  • Solid oral dosage forms containing trabectedin may be provided as soft gel capsules, as disclosed in WO2014113260 and
  • the active pharmaceutical ingredient can be admixed with a pharmaceutical carrier according to
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • suitable carriers and additives include but are not limited to diluents, granulating agents, lubricants, binders, glidants, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent an advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques.
  • compositions utilized by the methods described are in unit dosage forms from such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered aerosol or liquid sprays, drops, or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, rectal, dry powder inhaler or other inhalation or insufflation means.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, anti-adherents, and glidants.
  • diluents include, but are not limited to, starch (i.e.
  • corn, wheat, or potato starch which may be hydrolized), lactose (granulated, spray dried or anhydrous), sucrose, sucrose- based diluents (confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e.
  • AVICEL microcrystalline cellulose available from FMC Corp.
  • dicalcium phosphate calcium sulfate dihydrate
  • calcium lactate trihydrate and the like.
  • Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,
  • hydroxypropylmethylcellulose hydroxypropylcellulose, and the like
  • water soluble or dispersible binders i.e. alginic acid and salts thereof, magnesium aluminum silicate,
  • hydroxyethylcellulose i.e. TYLOSE available from Hoechst Celanese
  • polyethylene glycol polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch
  • Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e.
  • Suitable lubricants and anti-adherents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like.
  • Suitable gildants include, but are not limited to, talc, cornstarch, silica (i.e. CAB-O-SIL silica available from Cabot, SYLOID silica available from W.R. Grace/Davison, and AEROSIL silica available from Degussa) and the like.
  • silica i.e. CAB-O-SIL silica available from Cabot, SYLOID silica available from W.R. Grace/Davison, and AEROSIL silica available from Degussa
  • Sweeteners and flavorants may be added to chewable solid dosage forms to improve the palatabibty of the oral dosage form. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drug or for aesthetic purposes.
  • These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.
  • Binders suitable for use in the pharmaceutical compositions utilized herein include, but are not limited to, starches, cellulose, and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose), polyviny pyrrolidone, and mixtures thereof.
  • fillers suitable for use in the pharmaceutical compositions utilized herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants can be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical
  • compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in the pharmaceutical compositions utilized herein include, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in the pharmaceutical compositions utilized herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • Compressed tablet formulations may optionally be film-coated to provide color, light protection, and/or taste-masking. Tablets may also be coated so as to modulate the onset, and/or rate of release in the gastrointestinal tract, so as to optimize or maximize the biological exposure of the patient to the API.
  • Hard capsule formulations may be produced by filling a blend or granulation of e.g., apalutamide into shells consisting of, for example, gelatin, or hypromellose.
  • Soft gel capsule formulations may be produced.
  • compositions intended for oral use may be prepared from the solid dispersion formulations, and blended materials described above in accordance with the methods described herein, and other methods known to the art for the manufacture of pharmaceutical compositions.
  • Such compositions may further contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic
  • excipients that are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, granulating, and disintegrating agents, binding agents, glidants, lubricating agents, and antioxidants, for example, propyl gallate, butylated hydroxyanisole, and butylated hydroxy toluene.
  • the tablets may be uncoated or they may be film coated to modify their appearance or may be coated with a functional coat to delay disintegration, and absorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period.
  • compositions for oral use may also be presented as capsules (e.g., hard gelatin) wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or starch, or as soft gelatin capsules wherein the active ingredient is mixed with liquids or semisolids, for example, peanut oil, liquid paraffin, fractionated glycerides, surfactants or olive oil.
  • Aqueous suspensions contain the active materials in mixture with excipients suitable for the manufacture of aqueous suspensions.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • the pharmaceutical compositions of the invention include a diluent system, disintegrant, salt, lubricant, glidant, and filmcoat, at concentrations of from about 3%w/w to about 58%w/w, from about 4%w/w to about 20%w/w, from about 4%w/w to about 20%w/w, from about 0.5%w/w to about 4%w/w, from about 0%w/w to about 2%w/w, and from about l%w/w to about 5%w/w respectively, or at from about 18%w/w to about 40%w/w, from about 7%w/w to about 15%w/w, from about 7%w/w to about 18%w/w, from about 1.0% w/w to about 3.0%, from about 0.1 %w/w to about 1.0%w/w, and from about 2.0% w/w to about 4.0% w/w, respectively.
  • the solid dispersion formulations are blended with a dil
  • microcrystalbne cellulose croscarmellose sodium, sodium chloride, colloidal silica, sodium stearyl fumarate, and magnesium stearate.
  • the disintegrant may be present in a concentration from about 4%w/w to about 20%w/w or from about 7%w/w to about 15%w/w.
  • a salt may be also present, which may be sodium chloride, potassium chloride or a combination thereof.
  • the combination of salts and disintegrant is present at a concentration from about 5%w/w to about 35%w/w of the final pharmaceutical composition.
  • Salts can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002, which is incorporated herein by reference.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • the compounds for use in the disclosed methods may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • Examples of acid addition salts include salts formed with an acid including, but not limited to, acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(ES')-camphor- 10-sulphonic, capri c, caproic, caprylic, cinnamic, citric, cyclamic,
  • dodecylsulphuric ethane- 1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g.
  • One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic, naphthalenesulphonic, valeric, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • Another group of acid addition salts includes salts formed from acetic, adipic, ascorbic, aspartic, citric, DL-Lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic, methanesulphonic, sebacic, stearic, succinic and tartaric acids. [00170] If the compound is anionic, or has a functional group which may be anionic
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth metal cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., N]3 ⁇ 4R + , N hR2 + , NHR3 + , NR4 + ).
  • ethylamine diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH3)4 + .
  • the compounds may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of the disclosed compounds.
  • Compounds containing an amine function may also form N-oxides.
  • a reference herein to a compound that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen- containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady ( Syn . Comm. (1977), 7, 509-514) in which the amine compound is reacted with / «-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA chloroperoxybenzoic acid
  • the term“solvate” means a physical association of the compound with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the term“solvate” is intended to encompass both solution- phase and isolatable solvates.
  • suitable solvates include the disclosed compounds in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine and the like. The compound may exert its biological effects while in solution.
  • Solvates are well known in pharmaceutical chemistry. They can be important to the processes for the preparation of a substance (e.g. in relation to their purification), the storage of the substance (e.g. its stability) and the ease of handling of the substance, and are often formed as part of the isolation or purification stages of a chemical synthesis.
  • a person skilled in the art can determine by means of standard and long used techniques whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g.
  • the compound may have one or more polymorph (crystalline) or amorphous forms.
  • the compounds include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element.
  • a reference to hydrogen includes within its scope 'H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 0 and 18 0.
  • the isotopes may be radioactive or non-radioactive. In one embodiment, the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use.
  • the compound may contain one or more radioisotopes.
  • inactive ingredients of the core tablet are: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose.
  • the tablets are finished with a film-coating consisting of the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
  • the evaluating step comprises: isolating RNA from the biological sample; synthesizing cDNA from the isolated RNA; pre-amplifying the cDNA; and amplifying the pre-amplified cDNA with a pair of primers that bind to and amplify one or more of DDXI2P, LCE3B, LCE3C, HEATR4 and MDM2.
  • RNA from the biological sample can be performed by a number of procedures known to one skilled in the art.
  • RNA can be isolated from the biological sample using an AllPrep DNA/RNA FFPE Kit from Qiagen (product # 80234)
  • cDNA can be synthesized from isolated RNA using a High Capacity cDNA Reverse Transcriptase Kit with RNase Inhibitor from ABI (product # 4374966).
  • Pre-amplification of cDNA can be performed by a number of procedures known to one skilled in the art. Amplification procedures are well known in the art.
  • cDNA can be pre-amplified using a TaqMan® PreAmp Master Mix (Life Technologies/ Applied Biosystems® product # 4391128).
  • the amplifying step can comprise performing real-time PCR (qRT-PCR).
  • qRT-PCR can be a Taqman® Real-Time PCR assay.
  • qRT-PCR procedures can involve the use of probes to increase the specificity of the assay.
  • trabectedin is administered intravenously. In some embodiments, the trabectedin is administered daily.
  • the trabectedin is administered twice-a-day. In some embodiments, the trabectedin is administered three times a day. In some embodiments, the trabectedin is administered four times a day. In some embodiments, the trabectedin is administered every other day. In some embodiments, the trabectedin is administered weekly. In some embodiments, the trabectedin is administered twice a week. In some embodiments, the trabectedin is administered every other week or every third week. In some embodiments, the trabectedin is administered on a continuous daily dosage schedule.
  • the trabectedin is administered at 1.5 mg/m 2 body surface area. In another particular embodiment, the trabectedin is administered as a 24-hour continuous intravenous infusion. In another particular embodiment, the trabectedin is administered as a 24- hour continuous intravenous infusion once about every 3 weeks. In a particular embodiment, dexamethasone is administered prior to the trabectedin infusion, e.g., 20 mg dexamethasone is administered intravenously, 30 minutes before each infusion.
  • the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the trabectedin is conveniently presented in divided doses that are administered simultaneously (or over a short period of time) once a day.
  • the trabectedin is conveniently presented in divided doses that are administered in equal portions twice-a-day.
  • the trabectedin is conveniently presented in divided doses that are administered in equal portions three times a day.
  • the trabectedin is conveniently presented in divided doses that are administered in equal portions four times a day.
  • trabectedin employed for treatment of the diseases or conditions described herein in humans are typically in the range of 1 mg to 1000 mg per day.
  • trabectedin is administered intravenously to the human at a dose of about 0.1 mg/m 2 to about 5 mg/m 2 per day, such as about 0.25 mg/m 2 to about 2 mg/m 2 per day, such as about 1.5 mg/m 2 per day.
  • trabectedin is administered orally to the human at a dose of about 30 mg per day to about 1200 mg per day.
  • trabectedin is administered orally to the human at a dose of about 30 mg per day to about 600 mg per day.
  • trabectedin is administered orally to the human at a dose of about 30 mg per day, about 60 mg per day, about 90 mg per day, about 120 mg per day, about 160 mg per day, about 180 mg per day, about 240 mg per day, about 300 mg per day, about 390 mg per day, about 480 mg per day, about 600 mg per day, about 780 mg per day, about 960 mg per day, or about 1200 mg per day.
  • the daily dose of trabectedin is increased.
  • a once-a-day dosing schedule is changed to a twice-a-day dosing schedule.
  • a three times a day dosing schedule is employed to increase the amount of trabectedin that is administered.
  • the amount of trabectedin that is given to the human varies depending upon factors such as, but not limited to, condition and severity of the disease or condition, and the identity (e.g., weight) of the human, and the particular additional therapeutic agents that are administered (if applicable).
  • the trabectedin is co-administered with dexamethasone.
  • the dexamethasone is administered before the administration of trabectedin.
  • Dexamethasone may be administered by i.v. infusion.
  • 20mg of dexamethasone is administered by i.v. infusion about 30 min before the administration of trabectedin.
  • the trabectedin is co-administered with dacarbazine.
  • dacarbazine may be administered once every 3 weeks.
  • the dacarbazine may be administered at a dosage of 1,000 mg/m 2 intravenously.
  • the dacarbazine may be administered once every 3 weeks at a dosage of 1,000 mg/m 2 intravenously.
  • the dacarbazine may be administered as a 24-hour continuous intravenous infusion once every 3 weeks at a dosage of 1,000 mg/m 2 .
  • a subject with STS has received at least one prior therapy for the treatment of cancer, optionally wherein the prior therapy for the treatment of cancer is an anthracy cline.
  • a subject with STS has received at least one prior therapy for the treatment of cancer, optionally wherein the prior therapy for the treatment of cancer is an anthracycline and at least one additional systemic regimen.
  • a subject having STS is treatment naive.
  • a single unit dosage of a composition comprises, consists of, or consists essentially of about 0.25 mg to about 5mg, such as about 0.5 mg to about 2 mg, such as about 1 mg of a sterile lyophibzed powder of trabectedin (e.g., stored in a vial).
  • the total daily dose of trabectedin may be from about 0.1 mg/m 2 to about 2 mg/m 2 , such as about 1.5 mg/m 2 .
  • the trabectedin formulation is provided as a lyophibzed powder comprising a disaccharide, such as sucrose, lactose or combinations thereof, for example, a buffer and a surface active agent, for example as described in U.S. Patent No. 8,895,557 which is incorporated by reference in its entirety.
  • the lyophibzed powder may be reconstituted and administered by intravenous infusion.
  • the quantity and frequency of administration will be determined by such factors as the condition of the subject, and the type and severity of the subject’s disease, although appropriate dosages may be determined by clinical trials.
  • administration may be repeated after one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months or longer.
  • Repeated courses of treatment are also possible, as is chronic administration.
  • the repeated administration may be at the same dose or at a different dose.
  • the desired dose is presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the composition is presented in divided doses that are administered simultaneously (or over a short period of time) once a day.
  • the composition is presented in divided doses that are administered in equal portions twice a day.
  • the composition is presented in divided doses that are administered in equal portions three times a day.
  • the composition is presented in divided doses that are administered in equal portions four times a day.
  • the therapeutics may be administered in the methods of the invention by maintenance therapy, such as, e.g., every three weeks for a period of 6 months or more.
  • trabectedin is administered every three weeks until disease progression or unacceptable toxicity.
  • doses of trabectedin employed for treatment of STS described herein in humans are typically in the range of about 1 mg to about 3 mg per day when administered intravenously. .
  • trabectedin is administered at a dose of 1.5 mg/m 2 administered as an intravenous infusion, preferably over 24 hrs, through a central venous line every 21 days (3 weeks)k until disease progression or unacceptable toxicity.
  • Corticosteroids e.g.
  • dexamethasone at a dose of 20 mg intravenously may be administered 20-30 minutes prior to each dose of trabectadin.
  • General methods of administering trabectedin with dexamethasone are described in U.S. Patent No. 8,119, 638 which is incorporated herein by reference in its entirety.
  • trabectedin is administered orally to the human at a dose of about 30 mg per day to about 1200 mg per day. In some embodiments, trabectedin is
  • trabectedin is administered orally to the human at a dose of about 30 mg per day to about 600 mg per day.
  • trabectedin is administered orally to the human at a dose of about 30 mg per day, about 60 mg per day, about 90 mg per day, about 120 mg per day, about 160 mg per day, about 180 mg per day, about 240 mg per day, about 300 mg per day, about 390 mg per day, about 480 mg per day, about 600 mg per day, about 780 mg per day, about 960 mg per day, or about 1200 mg per day.
  • trabectedin is administered orally to the human at a dose of about 5 mg per day. In some embodiments, greater than 1 mg per day of trabectedin is administered to the human. In some embodiments, the trabectedin is administered orally to the human at a dose of about 60 mg four times per day. In some embodiments, trabectedin is administered orally to the human on a continuous daily dosing schedule.
  • Trabectedin has the chemical name
  • YONDELIS® for injection is supplied as a sterile lyophilized white to off-white powder/cake in a single-dose vial.
  • Each single-dose vial contains 1 mg of trabectedin, 27.2 mg potassium dihydrogen phosphate, 400 mg sucrose, and phosphoric acid and potassium hydroxide (for pH adjustment to 3.6 - 4.2).
  • the subject is also administered an anthracy cline concurrently. In some embodiments the subject has had (or will have) tumor resection.
  • the patient has received a prior anthracycline-containing regimen.
  • the dose is in 1 mg lyophilized powder in a single-dose vial for reconstitution.
  • the route of administration is IV infusion using an infusion set with a 0.2 micron PES in-line filter.
  • the dose is 1.5 mg/m 2 administered as an intravenous infusion of 24 hours through a central venous line every 21 days.
  • the trabectedin and the anthracycline can be administered simultaneously (e.g., in the same composition, or in separate compositions) or at different times, e.g., sequentially.
  • the trabectedin can be administered before administration of the anthracycline.
  • the anthracycline can be administered before administration of the trabectedin.
  • the subject is also administered one or more additional therapeutic agents, e.g., a composition or compound described herein.
  • An additional therapeutic agent can be administered with the anthracycline or the trabectedin simultaneously (e.g., in the same composition, or in separate compositions) or can be administered before or after administration of the anthracycline or trabectedin, or both before and after administration of the anthracycline or trabectedin.
  • the subject is also administered dacarbazine concurrently. In some embodiments the subject has had (or will have) tumor resection.
  • dacarbazine is a colorless to an ivory colored solid which is light sensitive.
  • dacarbazine for injection is reconstituted and administered intravenously (pH 3 to 4).
  • dacarbazine is an anticancer agent designated chemically as 5-(3,3-dimethyl-l-triazeno)- imidazole-4-carboxamide with the following structural formula:
  • the trabectedin and the dacarbazine can be administered simultaneously (e.g., in the same composition, or in separate compositions) or at different times, e.g., sequentially.
  • the trabectedin can be administered before administration of the dacarbazine.
  • the dacarbazine can be administered before administration of the trabectedin.
  • the subject is also administered one or more additional therapeutic agents, e.g., a composition or compound described herein.
  • An additional therapeutic agent can be administered with the anthracycline or dacarbazine or the trabectedin
  • anthracycline or dacarbazine or trabectedin can be administered before or after administration of the anthracycline or dacarbazine or trabectedin, or any combination before and after administration of the anthracycline or dacarbazine or trabectedin.
  • the therapeutics described herein may be used in a treatment regimen in combination with other treatments or agents (e.g., therapeutic agents), including one or more of surgery, radiation, chemotherapy, immunosuppressive agents, such as methotrexate, cyclosporin, azathioprine, mycophenolate, and FK506, antibodies, or other immunoablative agents such as anti-CD3 antibodies or other antibody therapies, cytoxin, fludarabine, cyclosporin, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation.
  • treatments or agents including one or more of surgery, radiation, chemotherapy, immunosuppressive agents, such as methotrexate, cyclosporin, azathioprine, mycophenolate, and FK506, antibodies, or other immunoablative agents such as anti-CD3 antibodies or other antibody therapies, cytoxin, fludarabine, cyclosporin, rapamycin, mycophenolic acid, steroids, FR901228,
  • the therapeutics can be used in combination with other chemotherapeutic agents in the methods described herein.
  • Example chemotherapeutic agents include, but are not limited to, an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, tositumomab), an antimetabolite
  • an anthracycline e.g., doxorubicin (e.g., liposomal doxorubicin)
  • a vinca alkaloid e.g.,
  • folic acid antagonists including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)
  • an mTOR inhibitor including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)
  • an mTOR inhibitor including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)
  • an mTOR inhibitor including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)
  • an mTOR inhibitor including, e.g., folic acid
  • a non-exhaustive list of chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), leucovorin calcium, melphalan (Alkeran®), 6- mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone,
  • hydrochloride for injection Hycamptin®
  • vinblastine Velban®
  • vincristine Oncovin®
  • vinorelbine® vinorelbine
  • Example alkylating agents include, without limitation, nitrogen mustards, ethyl enimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard
  • Temodar® Temodar®
  • thiotepa Thioplex®
  • busulfan Busulfan
  • Busulfan Busulfan
  • Busulfan Busulfan
  • carmustine BiCNU®
  • lomustine CeeNU®
  • streptozocin Zanosar®
  • dacarbazine DTIC-Dome®
  • alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexylen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®);
  • Lomustine also known as CCNU, CeeNU®
  • Cisplatin also known as CDDP, Platinol® and Platinol®-AQ
  • Chlorambucil Leukeran®
  • Cyclophosphamide Cytoxan® and Neosar®
  • dacarbazine also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®
  • Altretamine also known as hexamethylmelamine (HMM), Hexylen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HC1
  • immunomodulators useful herein include, but are not limited to, e.g., afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and IRX-2 (mixture of human cytokines including interleukin 1, interleukin 2, and interferon g, CAS 951209-71-5, available from IRX Therapeutics).
  • A“therapeutically effective amount” or“effective amount”, used interchangeably herein, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual.
  • Example indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well being of the patient, reduction of a tumor burden, arrested or slowed growth of a tumor, and/or absence of metastasis of cancer cells to other locations in the body.
  • a“subject” refers to an animal.
  • the terms “subject” and “patient” may be used interchangeably herein in reference to a subject.
  • a“subject” includes a human, e.g., a patient, such as a patient being treated for cancer, such as a patient that is being treated for STS.
  • Delivery systems useful in the context of embodiments of the invention may include time-released, delayed release, and sustained release delivery systems such that the delivery of the drugs occurs prior to, and with sufficient time to cause, sensitization of the site to be treated.
  • the composition can be used in conjunction with other therapeutic agents or therapies. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician, and may be particularly suitable for certain composition embodiments of the invention.
  • release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide),
  • Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109.
  • Delivery systems also include non-polymer systems that are lipids including sterols such as cholesterol, cholesterol esters, and fatty acids or neutral fats such as mono-di- and tri-glycerides; sylastic systems; peptide based systems; hydrogel release systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
  • Specific examples include, but are not limited to: (a) erosional systems in which the active composition is contained in a form within a matrix such as those described in U.S. Pat. Nos. 4,452,775; 4,667,014; 4,748,034; and 5,239,660 and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos. 3,854,480 and 3,832,253.
  • pump-based hardware delivery systems can be used, some of which are adapted for implantation.
  • the cancer is STS.
  • the progression-free survival is improved relative to administration of dacarbazine.
  • overall survival is improved relative to administration of dacarbazine.
  • the subject has undergone a tumor resection.
  • Genomic DNA samples were obtained retrospectively from patients participating in a Phase III, randomized, open-label, active-controlled, parallel-group, multicenter study conducted from May 2011 to September 2013.
  • the primary study protocol was approved by The Institutional Review Board or an Independent Ethics Committee at each site. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent with Good Clinical Practices, and applicable regulatory requirements. All patients provided written informed consent. Only those patients who signed a separate informed consent form indicating their willingness to participate in the optional pharmacogenomic and biomarker analyses were included in this retrospective analysis.
  • FFPE formalin-fixed paraffin embedded
  • WES whole exome sequencing
  • Genomic alterations were identified based on the altered coding sequence of the protein using small nucleotide variants (SNVs; point mutations, small insertion/deletions known as indels) and gene copy number variations (CNVs; gene deletions, amplifications). SNV and / or INDEF variants were filtered to include only somatic (matched tumors) or likely somatic variants (unmatched tumors) which were defined as having a population frequency >1% of any subpopulation of the 1000 Genomes Project (The Genomes Project C: A global reference for human genetic variation.
  • SNVs small nucleotide variants
  • CNVs gene copy number variations
  • Predictive biomarkers were identified and defined as genes which were significantly associated with clinical outcomes in one treatment arm (p ⁇ 0.05) and showed no association in other arm (p-value >0.2).
  • Prognostic biomarkers were identified and defined as genes which were associated with clinical outcomes independent of the treatment i.e., p ⁇ 0.05 for both treatment arms.
  • the clinical outcomes considered for this assessment were clinical parameters such as PFS, OS, maximum tumor volume reduction (MTVR) and number of treatment cycles.
  • Assessment for predictive and prognostic biomarkers were performed in matched tumors (somatic) or all tumors (somatic + germline).
  • Example 1 Exploration of tumor genetic alterations and associations with clinical outcomes: retrospective genomic analysis of archived liposarcoma (LPS) and
  • LMS leiomyosarcoma
  • Genomic alterations such as e.g., single nucleotide variants (SNVs) or gene copy number variations (CNVs), were identified using whole exome sequencing (WES) of archived tumor samples from Clinical Trial NCT01343277 (A Study of Trabectedin or
  • dacarbazine for the Treatment of Patients With Advanced Liposarcoma or Leiomyosarcoma Association of tumor-subtype or genetic alterations with clinical outcomes including maximum tumor volume reduction (MTVR), overall survival (OS), progression free survival (PFS) and treatment cycles received was assessed using multivariate Cox proportional hazard models.
  • MTVR maximum tumor volume reduction
  • OS overall survival
  • PFS progression free survival
  • results A total of 178 uterine LMS (uLMS), 121 non-uterine LMS (non-uLMS), 60 de-differentiated LPS (ddLPS), 40 myxoid LPS (mLPS) and 14 pleomorphic LPS (pLPS) tumors underwent WES and homozygous deletions (HD) were observed at relatively high frequency in 4 genes - DDX12P (36.4%), LCE3B (35.4%), LCE3C (32.1%), HEATR4 (24.4%) across all sarcoma subtypes. These genes are involved in cell proliferation, innate immune response and differentiation. HD in any of these genes was associated with improved OS in the T treatment arm. Tumors with MDM2 amplifications showed worse clinical outcome in the T treatment arm in terms of PFS and OS consistent with T-mediated induction of p-53 dependent apoptosis (Table 1).

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Abstract

L'invention concerne des méthodes de traitement d'un sujet atteint d'un sarcome, comprenant l'administration de trabectédine au sujet s'il est déterminé qu'un échantillon de tumeur provenant du sujet a une mutation homozygote dans un gène choisi dans le groupe constitué par DDX12P, LCE3B, LCE3C, HEATR4, et des combinaisons de ceux-ci. L'invention concerne également des méthodes de traitement d'un sujet atteint d'un sarcome, comprenant les étapes consistant à : administrer de la trabectédine au sujet s'il est déterminé qu'un échantillon de tumeur provenant du sujet a une mutation homozygote dans un gène choisi dans le groupe constitué par DDX12P, LCE3B, LCE3C, HEATR4, et des combinaisons de ceux-ci; et il est déterminé que l'échantillon de tumeur a un nombre de copies normal du gène MDM2.
PCT/EP2020/063663 2019-05-28 2020-05-15 Trabectédine pour le traitement de sarcomes basé sur des marqueurs génomiques WO2020239478A1 (fr)

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