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

Study Overview
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Brief Summary
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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
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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 progression free survival (PFS) in patients with Triple negative breast cancer (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).

Official Title
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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

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: PLX3397
* Drug: Eribulin


Participation Criteria
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Eligibility Criteria
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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 International Normalized Ratio (INR) within normal range for the purpose of tumor biopsy. Low molecular weight heparin (LMWH is the preferred method of anticoagulation. Prothrombin time (PT)/International Normalized Ratio (INR) and partial thromboplastin time (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 human epidermal growth factor receptor 2 (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. Eastern Cooperative Oncology Group (ECOG) performance status </= 2. Life expectancy of >/= 12 weeks. Patients with < grade 1 peripheral neuropathy are eligible for this trial. Adequate bone marrow reserve: Absolute Neutrophil Count (ANC) >/= 1000, platelets >/= 100,000. Adequate renal function: serum creatinine </= 1.5x upper limit of normal (ULN) OR calculated creatinine clearance ≥ 50 ml/min. Sodium, potassium, and chloride levels within institutional normal limits. Adequate hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (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: Ejection fraction (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, progesterone receptors (PR) and HER2 negative disease defined as less than 10% staining for ER and PR, and HER2 not amplified byFluorescent in situ hybridization (FISH), 0-1% by Immunohistochemistry (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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib: 600 mg/Day PLX3397 Combined with Eribulin<br>Treatments are given in 21 day cycles. For each cycle, treatment includes: PLX3397 at a dose of 600 mg/day taken by mouth in the form of 100-200 mg gelcaps Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8. | Drug: PLX3397<br>* Dosage Form: 100 mg or 200 mg capsules, Dosage: 400 - 1000 mg, oral administration<br>Drug: Eribulin<br>* Dosage Form: 1 mg per 2 mL (0.5 mg per mL); Solution (clear, colorless, sterile, packaged in glass vial) Dosage: 1.4 mg/m2, 2-5 min IV, Day 1, 8 q21 days<br>* Other names: E7389;|
| Experimental: Phase Ib: 800 mg/Day PLX3397 Combined with Eribulin<br>Treatments are given in 21 day cycles. For each cycle, treatment includes: PLX3397 at a dose of 800 mg/day taken by mouth in the form of 100-200 mg gelcaps Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8 | Drug: PLX3397<br>* Dosage Form: 100 mg or 200 mg capsules, Dosage: 400 - 1000 mg, oral administration<br>Drug: Eribulin<br>* Dosage Form: 1 mg per 2 mL (0.5 mg per mL); Solution (clear, colorless, sterile, packaged in glass vial) Dosage: 1.4 mg/m2, 2-5 min IV, Day 1, 8 q21 days<br>* Other names: E7389;|
| Experimental: Phase Ib: 1000 mg/Day PLX3397 Combined with Eribulin<br>Treatments are given in 21 day cycles. For each cycle, treatment includes: PLX3397 at a dose of 1000 mg/day taken by mouth in the form of 100-200 mg gelcaps Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8 | Drug: PLX3397<br>* Dosage Form: 100 mg or 200 mg capsules, Dosage: 400 - 1000 mg, oral administration<br>Drug: Eribulin<br>* Dosage Form: 1 mg per 2 mL (0.5 mg per mL); Solution (clear, colorless, sterile, packaged in glass vial) Dosage: 1.4 mg/m2, 2-5 min IV, Day 1, 8 q21 days<br>* Other names: E7389;|
| Experimental: Phase II: 800 mg/Day PLX3397 Lead in +Combined with Eribulin<br>Treatment begins with a 7 day Lead-in phase of PLX3397 alone, followed by 21 day cycles of PLX3397 in combination with eribulin. Lead-in phase treatment: PLX3397 at a dose of 800 mg/day given by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest. Treatment given in each 21 day cycle: PLX3397 at a dose of 800 mg/day given by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest, repeated weekly Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8 | Drug: PLX3397<br>* Dosage Form: 100 mg or 200 mg capsules, Dosage: 400 - 1000 mg, oral administration<br>Drug: Eribulin<br>* Dosage Form: 1 mg per 2 mL (0.5 mg per mL); Solution (clear, colorless, sterile, packaged in glass vial) Dosage: 1.4 mg/m2, 2-5 min IV, Day 1, 8 q21 days<br>* Other names: E7389;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of PLX3397 Given in Combination With Standard Dose Eribulin in Participants With Metastatic Breast Cancer (Phase 1b) | The MTD was determined using a standard dose-escalation schema with 3 to 6 participants per cohort (3+3 design) for participants enrolled in Phase 1b. The starting dose level of PLX3397 was 600 mg/day and was raised in successive cohorts up to a dose of 1000 mg/day. Participants in each Phase Ib cohort were followed for dose limiting toxicities (DLTs) within the first 21 days of combination therapy and had to 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 were due to a DLT). A toxicity was considered a DLT if it was treatment related and met specific requirements for type of toxicity and severity assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 4. The MTD was defined as the lowest dose level at which 2 or more participants in a cohort experienced a DLT. The dose level just below the MTD was selected for Phase 2. | Up to Day 21 | 
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) (Phase Ib) | DLTs are select treatment related toxicities described in the protocol that were Grade 3 or 4 in severity per CTCAE v4, occurring within the first 21 days of combination therapy for patients enrolled in Phase Ib (for example, Grade 3 thrombocytopenia with significant bleeding, Grade 4 neutropenia lasting more than 5 days, or any Grade 3 or higher non-hematologic toxicity other than alopecia unless clearly unrelated to treatment). Grade 3 and 4 toxicities are considered severe and may be life threatening. Participants had to 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 were due to a DLT). A treatment delay of greater than 7 days for PLX3397 or inability to get two doses of eribulin in the first cycle due to toxicity that was unrelated to cancer worsening or other illness was considered a DLT. | Up to Day 21 | 
| Percentage of Total Phase II Participants With Chemotherapy Pre-Treated Triple Negative Metastatic Breast Cancer Who Are Progression Free at 3 Months | Progression-free survival (PFS) at 3 months is defined as the proportion of participants in the combined Phase II cohorts that are alive and progression-free 90 days after Study Day 1, from the first administration of PLX3397 with eribulin. Duration of PFS is defined as the time from Study Day 1 to the earlier of disease progression or death due to any cause. These analyses are designed to include only objective progression events per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. PFS will be estimated as a simple percentage based upon the results of the 3 month tumor assessment. Participants for whom this assessment is not performed will be included as failures, even if known to be alive at this time point. Confidence intervals will be provided. | Up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) (Phase II) | The objective response rate (ORR) is defined as the proportion of patients for whom the best overall response at the time of data cutoff is confirmed complete response (CR) or confirmed partial response (PR) as assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 criteria. The analysis of ORR employed the Per Protocol population. Patients who did not have any post-baseline tumor assessments were counted as non-responders. | From baseline until study completion, an average of 24 months | 
| Median Duration of Response (Phase II) | Duration of response is defined as the time from first documentation of objective response that is subsequently confirmed to progressive disease (PD) by the criteria or death due to any cause. Responders who have not been documented to have progressed or died at time of data cutoff will be right censored at the last available adequate tumor assessment. Median duration of response and its associated confidence interval will be estimated using the Kaplan-Meier method. | From date of first confirmed disease response to confirmed disease progression or death due to any cause, an average of 2 months | 
| Median Time to Disease Progression (Phase II) | Time to progression will be estimated using the Kaplan-Meier method. Efficacy responses, disease progression and relapse classified based on RECIST v1.1 criteria will be used to determine progression. Time to progression will be calculated from the first administration of PLX3397 with eribulin. Participants who do not have disease progression will be censored at the date of the last evaluation for study disease or at the time of initiation of the new therapy, whichever is earlier. Patients lacking any response assessment after randomization will be censored at Day 1 | From Day 1 to date of disease progression, an average of 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic, breast, cancer, triple, negative, PLX, Eribulin