Clinical Trials /

Phase Ib/II Study of PLX 3397 and Eribulin in Patients With Metastatic Breast Cancer

NCT01596751

Description:

The purpose of the Phase 1b portion of the study is to determine the best dose of PLX3397 when given in combination with standard dose eribulin (Halaven™). The purpose of the Phase 2 portion of the study is to find out what effects, good and/or bad, these drugs have on patients and their metastatic breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Phase Ib/II Study of PLX 3397 and <span class="go-doc-concept go-doc-intervention">Eribulin</span> in Patients With Metastatic <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Phase Ib/II Study of PLX 3397 and Eribulin in Patients With Metastatic Breast Cancer
  • Official Title: Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting Macrophages: A Multicenter Phase Ib/II Study of PLX 3397 and Eribulin in Patients With Metastatic Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT01596751

    ORG ID: UCSF Protocol No. 12751

    Trial Conditions

    Metastatic Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    PLX3397 Eribulin in combination with PLX3397
    Eribulin Halaven, E7389 Eribulin in combination with PLX3397

    Trial Purpose

    The purpose of the Phase 1b portion of the study is to determine the best dose of PLX3397
    when given in combination with standard dose eribulin (Halaven). The purpose of the Phase
    2 portion of the study is to find out what effects, good and/or bad, these drugs have on
    patients and their metastatic breast cancer.

    Detailed Description

    This is a nonrandomized, open label phase Ib/II study evaluating the safety and efficacy of
    eribulin in combination with PLX3397, a novel CSF1 inhibitor, in patients with metastatic
    breast cancer. The phase II portion of this trial will be limited to patients with triple
    negative disease.

    The phase I portion of this trial is a dose escalation of PLX3397 to determine the maximum
    tolerated dose (MTD) of PLX3397 when given in combination with standard dose eribulin.
    Patients will be enrolled in cohorts of three, using the dose levels and plan outlined in
    the statistical section, with 6 patients enrolled at the MTD. All patients with accessible
    tumor will be required to have a tumor biopsy at study start before starting therapy.
    Pharmacokinetics of PLX3397 and eribulin, and blood levels of CSF1 will be obtained as
    outlined in section 14. To allow rapid accrual to phase Ib, and an earlier start to the
    phase II trial, patients will be enrolled in phase I with both hormone receptor positive and
    negative disease, and at any line of therapy assuming eligibility criteria are otherwise
    met.

    Dose limiting toxicity (DLT) will be defined as any treatment-related toxicity meeting the
    criteria below and occurring within the first 21 days of combination therapy. Patients must
    receive at least 14 days of PLX3397 and 2 doses of eribulin during the first cycle in order
    to be considered evaluable for DLT (unless the missed doses are due to a DLT).

    Patients in each cohort will be followed for at least 3 weeks (one full cycle) before
    opening accrual to the next dose level. If one patient in any cohort develops a DLT, an
    additional 3 patients will be enrolled at that level. If no additional toxicities occur in
    the six patients, then this particular dose would be used for the phase II trial, and the
    next higher dose would be considered the MTD. A minimum of 12 and maximum of 24 patients
    will be enrolled in the phase I study. The phase II trial will not open until the last
    patient in the phase I study has been followed for at least 3 weeks.

    The phase II portion of this trial will evaluate PFS in patients with TNBC treated with
    PLX3397 and eribulin, using the dose of PLX3397 determined in the phase Ib study in a
    two-step design. Please see the statistical section for details regarding enrollment and
    statistical design. Treatment is preceded by a 5 to 7 day lead-in phase, in which patients
    will take PLX3397 alone daily. Patients with accessible tumor will undergo a core biopsy of
    tumor before the start of PLX3397 treatment, and then a fine needle aspiration or core
    biopsy will be performed on the day of or the day before the start of eribulin (day -1 to
    day 0).

    Trial Arms

    Name Type Description Interventions
    Eribulin in combination with PLX3397 Experimental Phase Ib: 21 day treatment cycle: PLX3397 100-200 mg gelcaps, po daily & Eribulin 1.4 mg/m2 IV day 1 and 8 Cohort 1: 600 mg/day Cohort 2: 800 mg/day Cohort 3: 1000 mg/day Phase II: Lead in period of 5-7 d with PLX3397 at MTD po qd (day -7/5 to day 0) 21 day cycles; Day 1: Add eribulin 1.4 mg/m2 IV day 1 and 8 Continue PLX3397 at MTD po qd PLX3397, Eribulin

    Eligibility Criteria

    Inclusion Criteria:

    - Pathologically confirmed diagnosis of breast cancer with documented progressive
    disease.

    - Patients with stable brain metastases are eligible for this trial.

    - At least one prior chemotherapy regimen for metastatic breast cancer. Prior
    treatment must be discontinued at least 2 weeks before treatment start.

    - Concomitant therapy with bisphosphonates is allowed.

    - Stable dose coumadin anticoagulation is allowed, providing that anticoagulation can
    be safely held to an INR within normal range for the purpose of tumor biopsy. LMWH is
    the preferred method of anticoagulation.

    - PT/INR and PTT within institutional normal limits within two weeks before initial
    biopsy.

    - Measurable disease, as defined by RECIST guidelines or evaluable disease. Bone
    metastases must be evaluable.

    - Disease amenable to core biopsy. Patients with pulmonary metastases as their only
    site of disease may enroll on this trial and will not undergo biopsy.

    - For Phase I: patients with HER2 overexpressing disease must have been previously
    treated with trastuzumab. Patients with HER2 overexpressing disease are not
    eligible for the Phase II trial.

    - Age eighteen years or older.

    - ECOG performance status </= 2.

    - Life expectancy of >/= 12 weeks.

    - Patients with < grade 1 peripheral neuropathy are eligible for this trial.

    - Adequate bone marrow reserve: ANC >/= 1000, platelets >/= 100,000.

    - Adequate renal function: serum creatinine </= 1.5x upper limit of normal OR
    calculated creatinine clearance 50 ml/min.

    - Sodium, potassium, and chloride levels within institutional normal limits.

    - Adequate hepatic function: AST and ALT </= 2.5 x ULN, and total bilirubin </= 1.5x
    upper limit of normal. In patients with liver dysfunction due to hepatic metastases,
    AST and ALT are permitted to be </= 5 times the ULN.

    - At baseline: EF 50%, no evidence of QT prolongation, no history of congenital long
    QT syndrome, and no use of drugs known to increase the risk of Torsades de Point -
    patients may be eligible for study if the drug can be changed to another agent with
    less risk (such as changing from citalopram to an alternate antidepressant).

    - Able to take oral medications and maintain hydration.

    - Ability to give written informed consent and willingness to comply with the
    requirements of the protocol

    - Women of child-bearing potential must agree to use an effective method of birth
    control during treatment and for six months after receiving their last dose of study
    drug

    Specific inclusion criteria for Phase II

    Patients enrolling on the phase II portion of this trial must have ER, PR and HER2
    negative disease defined as less than 10% staining for ER and PR, and HER2 not amplified
    by FISH, 0-1% by IHC, or 2+ by IHC and no evidence of amplification by FISH.

    Exclusion Criteria:

    - Treatment with another chemotherapy or hormonal therapy within the past 2 weeks.

    - Treatment with trastuzumab, bevacizumab or other targeted therapies within the past 2
    weeks.

    - Concurrent treatment with radiotherapy.

    - Ongoing treatment with any other investigational therapy.

    - Prior treatment with eribulin

    - Severe, concurrent illness including congestive heart failure, significant cardiac
    disease and uncontrolled hypertension, that would likely prevent the patient from
    being able to comply with the study protocol.

    - Inadequate bone marrow, renal, or hepatic function as defined above, or an active
    coagulopathy that precludes tissue biopsy.

    - Pregnant or lactating women and women of child-bearing potential who are not using an
    effective method of birth control. Women of childbearing potential must undergo a
    serum pregnancy test within seven days of starting the study drug.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose of PLX3397 given in combination with with standard dose eribulin in patients with metastatic breast cancer (Phase 1b)

    Percentage of patients with chemotherapy pre-treated triple negative metastatic breast cancer treated with PLX3397 in combination with eribulin who are progression free at 12 weeks (Phase 2)

    Secondary Outcome Measures

    Serum concentrations for the combination of PLX3397 and eribulin (Phase 1b)

    Safety of treatment (Phase 1b & 2)

    Immune response (Phase 1b & 2)

    Efficacy of drug combination including response rate and duration of response (Phase 2)

    Trial Keywords

    metastatic

    breast

    cancer

    triple

    negative

    PLX

    Eribulin