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PARP Inhibitor BMN-673, Carboplatin, and Paclitaxel in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Adult Solid Neoplasm

Intervention: Carboplatin (Drug); Laboratory Biomarker Analysis (Other); Paclitaxel (Drug); Pharmacological Study (Other); Talazoparib (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Kari Wisinski, Principal Investigator, Affiliation: Rutgers Cancer Institute of New Jersey

Summary

This phase I trial studies the side effects and best dose of poly (ADP-ribose) polymerase 1 (PARP) inhibitor BMN-673 when given together with carboplatin and paclitaxel in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery. PARP inhibitor BMN-673 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 PARP inhibitor BMN-673 with carboplatin and paclitaxel may kill more tumor cells.

Clinical Details

Official title: A Phase 1 Study of BMN 673 in Combination With Carboplatin and Paclitaxel in Patients With Advanced Solid Tumors

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

MTD and RP2D of BMN 673 seven day schedule, defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a dose-limiting toxicity (DLT) and two or more patients have experienced a DLT at the next higher dose level

MTD and RP2D of BMN 673 three day schedule, defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a DLT and two or more patients have experienced a DLT at the next higher dose level

Secondary outcome:

Anti-tumor response (as determined by RECIST criteria)

Incidence of toxicity, graded according to NCI CTCAE

Pharmacokinetic (PK) parameters (area under the curve and concentration) in plasma samples

Detailed description: PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BMN 673 (PARP inhibitor BMN-673) three day schedule in combination with carboplatin and paclitaxel. II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BMN 673 seven day schedule in combination with carboplatin and paclitaxel. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity of BMN 673 in combination with carboplatin and paclitaxel. II. To determine whether the pharmacokinetic parameters of BMN 673 when given in combination with carboplatin and paclitaxel correlate with thrombocytopenia. TERTIARY 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 BMN 673, carboplatin, and paclitaxel therapy. II. To explore mechanisms of resistance to the combination of BMN 673 with carboplatin and paclitaxel. OUTLINE: This is a dose-escalation study of PARP inhibitor BMN-673. Patients are assigned to 1 of 2 dosing schedules. SCHEDULE A: Patients receive paclitaxel intravenously (IV) over 3 hours on days 1, 8, and 15, carboplatin IV over 30 minutes on day 1, and PARP inhibitor BMN-673 orally (PO) once daily (QD) on days 1-3. Treatment repeats every 21 days for 4-6 courses in the absence of disease progression or unacceptable toxicity. SCHEDULE B: Patients receive paclitaxel IV over 3 hours on days 1, 8, and 15, carboplatin IV over 30 minutes on day 1, and PARP inhibitor BMN-673 PO QD on days 1-7. Treatment repeats every 21 days for 4-6 courses in the absence of disease progression or unacceptable toxicity. After 4-6 courses of treatment, patients may continue combination study therapy with PARP inhibitor BMN-673, carboplatin and paclitaxel, PARP inhibitor BMN-673 and carboplatin, or enter an observation period with no treatment (neither study treatment nor an alternative standard of care) at the discretion of the treating physician. After completion of study treatment, patients are followed up for 4 weeks.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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 either a) there is reasonable expectation of response to the combination of carboplatin/paclitaxel or b) breast cancer 1 (BRCA) germline mutation is present

- 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

- Ability to take oral medications

- Patients with central nervous system (CNS) metastases must be stable after therapy

for CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for at least 3 months and must be off steroid treatment for 2 weeks prior to study enrollment

- Women of child-bearing potential and men must agree to use adequate contraception

(hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of BMN 673 administration

- Ability to understand and the willingness to sign a written informed consent document

- Archived primary or metastatic tissue blocks or unstained slides available at

baseline and willingness to undergo a biopsy at the time of cancer progression 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 from adverse events due to agents administered

- No prior carboplatin unless given in neoadjuvant/adjuvant setting for curative intent

and 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 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

- 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

- CYP3A4 inducers

- CYP3A4 sensitive substrates

- Exclusions: the following supportive care medications will be allowed:

dexamethasone, aprepitant, fosaprepitant, and ondansetron

- Other contraindicated medications (per above) are not allowed unless close

monitoring with labs or drug levels with dose adjustments is feasible; patients taking these concurrent medications are ineligible unless they can discontinue or switched to alternative medications prior to initiation of the study drug (at least 5 half-lives)

- Use with caution:

- CYP2C8 sensitive substrates

- CYP2C8 weak inhibitors

- CYP3A4 non-sensitive substrates

- CYP3A4 weak inhibitors

- These agents may be permitted if discontinuation is not feasible and no

acceptable alternatives are available as determined by the treating physician; however, caution should be used; consider monitoring with labs or drug levels and dose adjustments of the medication

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active

infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

- Breastfeeding should be discontinued if the mother is treated with BMN 673

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral

therapy are ineligible

- No clinically significant bleeding (i. e. gastrointestinal [GI] bleed, intracranial

bleeding) within 6 months or major surgery within 4 weeks; minor surgeries (i. e. port placement, cataract surgery) are allowed within 2 weeks

- Anticoagulation and anti-platelet therapies are not permitted (this includes

Coumadin, low molecular weight heparins, factor Xa inhibitors, aspirin and non-steroidal anti-inflammatory drug [NSAIDS] or other medicines with similar effects)

Locations and Contacts

Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, United States; Not yet recruiting
Kari B. Wisinski, Phone: 608-263-6222, Email: kbwisinski@medicine.wisc.edu
Kari B. Wisinski, Principal Investigator
Additional Information

Starting date: May 2015
Last updated: May 11, 2015

Page last updated: August 23, 2015

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