A Phase 1 Study of Talazoparib (BMN 673) in Combination With Carboplatin and Paclitaxel in Patients With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Carboplatin
- Conditions
- Advanced Malignant Solid Neoplasm
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 43
- Locations
- 3
- Primary Endpoint
- Maximum tolerated dose and recommended phase 2 dose of talazoparib three day schedule
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of talazoparib when given together with carboplatin and paclitaxel in treating patients with solid tumors that have spread to other places in the body (advanced) or cannot be removed by surgery. Talazoparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving talazoparib with carboplatin and paclitaxel may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of talazoparib (BMN 673) seven day schedule in combination with carboplatin and paclitaxel. II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of talazoparib (BMN 673) three day schedule in combination with carboplatin and paclitaxel. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity of talazoparib (BMN 673) in combination with carboplatin and paclitaxel. II. To determine whether the pharmacokinetic parameters of talazoparib (BMN 673) when given in combination with carboplatin and paclitaxel correlate with thrombocytopenia. III. To observe and record anti-tumor activity of talazoparib (BMN 673) alone after the combination with carboplatin, paclitaxel and talazoparib (BMN 673). IV. To observe the safety and tolerability of talazoparib (BMN 673) in combination with paclitaxel and carboplatin and talazoparib (BMN 673) alone after the combination therapy. EXPLORATORY OBJECTIVES: I. To serially evaluate pharmacokinetic and pharmacodynamics parameters and use indirect pharmacokinetic/pharmacodynamics models to correlate with tumor response and resistance to the combination talazoparib (BMN 673), carboplatin, and paclitaxel therapy. II. To explore mechanisms of resistance to the combination of talazoparib (BMN 673) with carboplatin and paclitaxel. OUTLINE: This is a dose-escalation study of talazoparib. Patients are assigned to 1 of 2 dosing schedules. SCHEDULE A: Patients receive talazoparib orally (PO) once daily (QD) on days 1-7, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. SCHEDULE B: Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician. After completion of study treatment, patients are followed up for 4 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed solid malignancy (excluding lymphoma) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective, and for which: a) there is reasonable expectation of response to the combination of carboplatin/paclitaxel OR b) BRCA 1/2 germline mutation is present; due to the longstanding acceptance of BRCA 1 and 2 mutation testing through Myriad, results from Myriad will be acceptable; if testing for BRCA 1 and 2 germline mutations is done through another organization, a report from a genetics consult with a qualified medical professional confirming that the laboratory results show a recognized germline deleterious BRCA 1 or 2 mutation or rearrangement is required; if the latter cannot be obtained, principal investigator (PI) or study chair review of the lab results and confirmation of BRCA mutation or rearrangement will be required OR c) BRCA 1/2 somatic mutation previously identified using a Clinical Laboratory Improvement Amendments (CLIA) certified assay
- •Patients must have measurable or evaluable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Life expectancy of greater than 12 weeks
- •Absolute neutrophil count \>= 1,500/mcL
- •Hemoglobin \>= 9 g/dL
- •Platelets \>= 150,000/mcL
- •Total bilirubin =\< 1.25 x institutional upper limit of normal (ULN), with the exception of \< 2.9 mg/dL for patients with Gilbert's disease
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN; =\< 5 x ULN in setting of metastatic liver disease
- •Creatinine =\< 1.5 x upper limit of normal OR creatinine clearance \>= 50 mL/min
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or targeted therapies within 2 weeks prior to entering the study or those who have not recovered (=\< grade 1) from adverse events due to agents administered with the exception of any grade of alopecia
- •No prior carboplatin unless given in neoadjuvant/adjuvant setting for curative intent and more than 6 months have elapsed since last carboplatin dose; in the case of relapsed ovarian cancer, patients are eligible if more than 6 months have elapsed since last carboplatin dose
- •Patients who are receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to talazoparib (BMN 673) or other agents used in study
- •Peripheral neuropathy of severity greater than grade 1
- •The following medications are contraindicated or must be used with caution; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference
- •Contraindicated:
- •Cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) strong and moderate inhibitors
- •CYP2C8 inducers
- •Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) strong and moderate inhibitors
Arms & Interventions
Schedule A (7-day talazoparib, paclitaxel, carboplatin)
Patients receive talazoparib PO QD on days 1-7, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.
Intervention: Carboplatin
Schedule A (7-day talazoparib, paclitaxel, carboplatin)
Patients receive talazoparib PO QD on days 1-7, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.
Intervention: Paclitaxel
Schedule A (7-day talazoparib, paclitaxel, carboplatin)
Patients receive talazoparib PO QD on days 1-7, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.
Intervention: Talazoparib
Schedule B (3-day talazoparib, paclitaxel, carboplatin)
Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.
Intervention: Carboplatin
Schedule B (3-day talazoparib, paclitaxel, carboplatin)
Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.
Intervention: Paclitaxel
Schedule B (3-day talazoparib, paclitaxel, carboplatin)
Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.
Intervention: Talazoparib
Outcomes
Primary Outcomes
Maximum tolerated dose and recommended phase 2 dose of talazoparib three day schedule
Time Frame: 21 days
Defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a dose-limiting toxicity and two or more patients have experienced a dose-limiting toxicity at the next higher dose level. Adverse events will be evaluated by type and severity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 until March 31, 2018. CTCAE version 5.0 will be utilized beginning April 1, 2018. Adverse events data collection include adverse event diagnosis, date of onset and resolution, whether the event is ongoing, CTCAE grade, whether the event is serious, frequency, and outcome status, and action taken.
Maximum tolerated dose and recommended phase 2 dose of talazoparib seven day schedule
Time Frame: 21 days
Defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a dose-limiting toxicity and two or more patients have experienced a dose-limiting toxicity at the next higher dose level. Adverse events will be evaluated by type and severity using the National Cancer Institute CTCAE version 4.0 until March 31, 2018. CTCAE version 5.0 will be utilized beginning April 1, 2018. Adverse events data collection include adverse event diagnosis, date of onset and resolution, whether the event is ongoing, CTCAE grade, whether the event is serious, frequency, and outcome status, and action taken.
Secondary Outcomes
- Incidence of toxicity(Up to 4 weeks after last dose of treatment)
- Anti-tumor response(Up to 4 weeks after last dose of treatment)
- Pharmacokinetic parameters (area under the curve and concentration) in plasma samples(Pre-dose and 4 hours after talazoparib administration on days 1 and 3 or 7 (depending on assigned schedule) of cycle 1 and 0 and 4 hours on day 1 of all subsequent cycles)