Clinical Trials /

Study of BMN-673 With Carboplatin and Paclitaxel in Patients With Advanced BRCA-mutated Solid Tumor or Triple Negative Metastatic Breast Cancer

NCT02358200

Description:

Open label, non-randomized, dose escalation and expansion Phase Ia/b trial to evaluate the safety of the combination of BMN 673 and carboplatin, and subsequently BMN 673 in combination with paclitaxel and carboplatin to determine the recommended Phase II dose of the combination.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of BMN-673 With Carboplatin and Paclitaxel in Patients With Advanced BRCA-mutated Solid Tumor or Triple Negative Metastatic Breast Cancer
  • Official Title: Phase I Study to Evaluate the Tolerability, Safety and Efficacy of BMN-673 in Combination With Carboplatin and Paclitaxel in Patients With Advanced Solid Tumor Malignancies That Have BRCA Mutations or Triple Negative Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 14955
  • NCT ID: NCT02358200

Conditions

  • Triple Negative Metastatic Breast Cancer
  • BRCA-mutated Solid Tumor

Interventions

DrugSynonymsArms
BMN-673Treatment
CarboplatinTreatment
PaclitaxelTreatment

Purpose

Open label, non-randomized, dose escalation and expansion Phase Ia/b trial to evaluate the safety of the combination of BMN 673 and carboplatin, and subsequently BMN 673 in combination with paclitaxel and carboplatin to determine the recommended Phase II dose of the combination.

Detailed Description

      PARP1/2 inhibitors are a novel class of anticancer agents that have shown activity in tumors
      with defects in DNA repair and may induce synthetic lethality in combination with agents that
      induce DNA damage by preventing DNA repair.

      The rationale of this study is to determine whether a DNA damaging agent can potentiate the
      cell death induced by PARP inhibitors in individuals with tumor that are more susceptible to
      chemotherapy.

      The study will evaluate the potential benefits of BMN 673 in combination with weekly
      carboplatin in patients with metastatic tumors associated with BRCA germ line mutations or
      patients with triple negative breast cancer with no known BRCA mutation, subsequently if
      tolerated, an additional cohort will examine the feasibility of adding paclitaxel to this
      combination for any solid tumor malignancies with potential benefit to this combination.

      This is the first study to evaluate the safety and efficacy of BMN 673 in combination with
      carboplatin in patients with either BRCA mutations or TNBC. If tolerable paclitaxel will be
      added to the combination in any solid tumor malignancies with potential benefit to this
      combination.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalBMN-673: Oral, every day, Days 1-21; Carboplatin: intravenous, every week, 750 μg/day; Paclitaxel: intravenous, every week, 0.75 x Maximum Tolerated Dose μg/day
  • BMN-673
  • Carboplatin
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Men and women, 18 years or older with advanced malignancies for which no standard
             therapy is available.

          -  Dose Escalation: Patients with any solid tumor malignancies

          -  Does Expansion:

          -  Patients with advanced malignancies that have germline and/or somatic BRCA mutations
             (cohort gBRCA) Or

          -  Triple negative (TN) metastatic breast cancer without known BRCA mutation (cohort
             TNBC). Tumors will be considered TN when:

          -  Estrogen receptor (ER) expression <1%

          -  Progesterone receptor (PR) expression <1%

          -  Her2 negative as per the ASCO guidelines

          -  Paclitaxel expansion: any solid tumor malignancy with potential benefit from this
             combination and paclitaxel (ASP).

          -  Dose expansion cohort only: Histological or cytological confirmation of advanced
             unresectable solid tumors for which no standard therapy is available in patients with
             a known BRCA germline mutation or those with metastatic triple negative breast cancer
             without known BRCA mutation (see inclusion criteria one for definition of triple
             negative breast cancer).. For the paclitaxel cohorts, any solid tumors with potential
             benefit from this combination and paclitaxel.

          -  Consent to screening tumor biopsy (for accessible tumors when appropriate) [optional
             in dose escalation, mandatory in dose expansion]

          -  Part 2 only: Measureable tumor (RECIST1.1)

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

          -  Adequate organ function:

          -  Absolute neutrophil count (ANC) ≥ 1.5 X 109/L

          -  Hemoglobin (Hgb) ≥9.5 g/dL(transfusion before treatment is allowable if more than 3
             days prior to study start)

          -  Platelets (plt) ≥ 100 x 109/L

          -  Potassium within normal range, or correctable with supplements;

          -  AST and ALT ≤2.5 x Upper Limit Normal (ULN)

          -  Serum total bilirubin ≤ 1.5 x ULN

          -  Serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance ≥ 60ml/min

          -  Females of child-bearing potential (FCBP) must have negative serum pregnancy test
             within 7 days before starting study treatment and willingness to adhere to acceptable
             forms of birth control (a physician-approved contraceptive method: oral, injectable,
             or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier
             contraceptive with spermicide; or vasectomized partner) for a minimum of 4 weeks
             following the discontinuation of study treatment.

        FCBP is defined as a sexually mature woman who:

          -  Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral
             oophorectomy (the surgical removal of both ovaries) or,

          -  Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
             had menses at any time during the preceding 12 consecutive months

          -  Male subjects with female partner of childbearing potential must agree to the use of a
             physician-approved contraceptive method throughout the course of the study and for a
             minimum of 4 weeks following the discontinuation of study treatment.

          -  Ability to take oral medications

        Exclusion Criteria:

          -  Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives
             or 4 weeks, whichever is shorter, prior to starting study treatment

          -  Patients must have recovered from side effects from prior cancer-directed therapy to
             grade 1 or less (unless deemed not clinically significant by study investigator).

          -  Major surgery ≤ 4 weeks prior to starting study regimen or who have not recovered from
             surgery.

          -  Any known unstable angina, significant cardiac arrhythmia, or New York Heart
             Association (NYHA) class 3 or 4 congestive heart failure.

          -  History of myocardial infraction (MI) within 6 month prior to starting study
             treatment.

          -  Any significant medical condition, laboratory abnormalities, which places the subject
             at unacceptable risk if he/she were to participate in the study.

          -  Any condition that confounds the ability to interpret data from the study.

          -  Symptomatic central nervous system metastases. Subjects with brain metastases that
             have been previously treated and are stable for 4 weeks are allowed.

          -  Malabsorption or uncontrolled peptic ulcer disease

          -  Grade 2 or higher peripheral neuropathy (paclitaxel arm only)

          -  Known allergic reaction or poor tolerability to PARP inhibitors, carboplatin, or
             paclitaxel

          -  Pregnant or breastfeeding

          -  Known active HIV, HCV or HBV
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:From date of randomization until the date of Initial response to the first documented tumor progression or date of death from any cause, up to 18 months.
Safety Issue:
Description:Response rate of combination (BMN 673 + carboplatin) in patients with BRCA germline mutations or triple negative cancer without known BRCA mutations, in solid tumor malignancies with paclitaxel with a 15 patient cohort expansion at the MTD. Response and progression in this study will be evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.

Secondary Outcome Measures

Measure:Intolerable Toxicity
Time Frame:From first dose to 30 day follow up.
Safety Issue:
Description:Analyses of adverse events will be performed for all patients having received at least one dose of study drug. The study will use the CTCAE v4.0 for reporting of non-hematologic adverse events.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

May 2, 2017