Talazoparib and Temozolomide in Treating Patients with Metastatic Castration Resistant Prostate Cancer with No Mutations in DNA Damage Repair
- Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information or have their legally authorized representative provide written informed consent. A signed informed consent must be obtained prior to performing screening procedures. * NOTE: HIPAA authorization may be either included in the informed consent or obtained separately.
- Histologically or cytologically confirmed adenocarcinoma of the prostate.
- Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotrophin releasing hormone (GnRH) agonist/antagonist (surgical or medical castration).
- Progression of mCRPC on treatment with at least 1 second generation hormonal agent (e.g., enzalutamide and/or abiraterone acetate/prednisone).
- Documented progressive mCRPC based on at least one of the following criteria: * Prostate specific antigen (PSA) progression defined as at least 2 rises in PSA with a minimum of a 1-week interval. ** 1.0 ng/mL is the minimal starting value if confirmed rise is only indication of progression. * Soft-tissue progression per RECIST v1.1. * Progression of bone disease (evaluable disease) or two or more new bone lesions by bone scan.
- Metastatic disease documented by bone lesions on whole-body radionuclide bone scan or soft tissue disease by computed tomography/magnetic resonance imaging (computed tomography [CT]/magnetic resonance imaging [MRI]).
- Consent to a fresh tumor biopsy during screening or have sufficient archival tumor tissue available for molecular profile and biomarker analyses.
- Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
- Serum testosterone =< 50 ng/dL at screening.
- Subjects who receive palliative radiotherapy must complete radiation 3 weeks prior to treatment start (wash out period)
- Absolute neutrophil count (ANC) >= 1,500/uL (within 14 days of treatment start).
- Hemoglobin >= 9 g/dL (within 14 days of treatment start).
- Platelet count >= 100,000/uL (within 14 days of treatment start).
- Creatinine clearance >= 60 mL/min estimated using the Cockcroft-Gault equation (within 14 days of treatment start).
- Potassium >= 3.5 mmol/L (within institutional normal range) (within 14 days of treatment start).
- Bilirubin =< 1.5 upper limit of normal (ULN) (Note: In subjects with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is =< 1.5 x ULN, subject may be eligible)
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 14 days of treatment start).
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN (within 14 days of treatment start).
- Subjects must agree to use a highly effective method of contraception (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence during treatment, and for at least 7 months after completing therapy. Furthermore, male patients with female partners of reproductive potential and pregnant partners must use a condom (even after vasectomy), during treatment and for at least 4 months after the final dose. Sperm donation is prohibited during the study and for 30 days after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.
- Prior treatment with a taxane-based chemotherapy for mCRPC (prior treatment with a taxane-based chemotherapy for metastatic non-castrate prostate cancer is permitted).
- Prior treatment with a PARP inhibitor, platinum, cyclophosphamide, mitoxantrone chemotherapy, or temozolomide.
- Subject has received radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) of treatment start.
- Documented carrier of a pathogenic or likely pathogenic germline or somatic mutation in BRCA 1, BRCA 2 or ATM or known carrier (pathogenic or likely pathogenic) of one of the following DNA damage repair genes considered as sensitizing tumors to PARP inhibitors: FANCA, CHECK2, PALB2, MRE11A, NBN, RAD51C, ATR, MLH1, and CDK12. Testing is required for BRCA 1, BRCA 2, or ATM. If a subject has had next generation sequencing that did not include FANCA, CHECK2, PALB2, MRE11A, NBN, RAD51C, ATR, MLH1, or CDK12 he will not be excluded from the study if status is unknown. * Note, if testing is germline negative, somatic testing is still required. If the subject is germline positive, the subject is ineligible.
- Use of systemic hormonal (except for GnRH analog), biologic, radium-223, or any investigational therapy for treatment of metastatic prostate cancer within 4 weeks prior to treatment start. Exceptions include abiraterone, which may not have been administered within 2 weeks of treatment start.
- Medical conditions such as uncontrolled hypertension, uncontrolled diabetes mellitus, or cardiac disease that would, in the opinion of the investigator, make this protocol unreasonably hazardous to the subject.
- Known or suspected brain metastasis or active leptomeningeal disease.
- Symptomatic or impending spinal cord compression or cauda equine syndrome.
- Diagnosis of myelodysplastic syndrome (MDS).
- History of another cancer within 2 years of treatment start with the exception of nonmelanoma skin cancers or American Joint Committee on Cancer stage 0 or stage 1 cancer that has a remote probability of recurrence in the opinion of the investigator and the sponsor.
- Use of any prohibited concomitant medications within 14 days prior to the first dose of talazoparib. * (Note, use of P-gp inhibitors that may be taken with caution at the investigator’s discretion will not exclude subjects from the trial).
- Grade > 2 treatment-related toxicity unresolved from prior therapy.
- Known allergy to any of the compounds under investigation.
- Any other condition which, in the opinion of the investigator, would preclude participation in this trial.
I. To determine the safety, maximum tolerated dose (MTD), recommended phase II dose, of intermittent talazoparib tosylate (talazoparib) plus temozolomide in subjects with metastatic castration resistant prostate cancer (mCRPC) whose tumors do not harbor mutations in deoxyribonucleic acid (DNA) damage repair. (Phase Ib)
II. To determine the efficacy of intermittent talazoparib plus temozolomide in subjects with mCRPC whose tumors do not harbor mutations in DNA Damage Repair. (Phase II)
I. To evaluate radiographic progression free survival (rPFS) in bone by Prostate Cancer Working Group 3 (PCWG3) and soft tissue by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. (Phase II)
II. To evaluate overall survival (OS). (Phase II)
III. To evaluate the safety of intermittent talazoparib plus temozolomide at the MTD/recommended phase 2 dose (RP2D) in subjects with mCRPC. (Phase II)
I. To evaluate pharmacokinetics (PK) of talazoparib and temozolomide. (Phase Ib/II)
II. To evaluate National Cancer Institute Select Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). (Phase Ib/II)
III. To evaluate circulating tumor cells (CTC) enumeration, morphology, subtype, and heterogeneity using the Epic Sciences platform at baseline and on treatment to assess changes with treatment and interrogation of surviving CTCs to better understand resistance. (Phase Ib/II)
IV. To evaluate molecular profiling from archival and/or fresh tumor tissue. (Phase Ib/II)
V. To evaluate SLFN11 expression from archival and/or fresh tumor tissue and its association with response. (Phase Ib/II)
VI. To evaluate circulating tumor (ct)DNA at baseline and on treatment. (Phase Ib/II)
OUTLINE: This is a phase Ib, dose-escalation study of talazoparib and temozolomide followed by a phase II dose expansion study.
Patients receive talazoparib orally (PO) once daily (QD) on days 1-6 and temozolomide PO QD on days 2-8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and then every 3 months for 1 year.
Trial Phase Phase I/II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
- Primary ID 19-041
- Secondary IDs NCI-2019-05121
- Clinicaltrials.gov ID NCT04019327