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

NCT01596751 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 12751NCI-2015-01321
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Metastatic Breast Cancer

Keywords

metastatic; breast; cancer; triple; negative; PLX; Eribulin

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Objective Response Rate (ORR) (Phase II)

  From baseline until study completion, an average of 24 months

• Median Duration of Response (Phase II)

  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)

  From Day 1 to date of disease progression, an average of 4 months

Study Arms (4)

Phase Ib: 600 mg/Day PLX3397 Combined with Eribulin

EXPERIMENTAL

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; Drug: Eribulin

Phase Ib: 800 mg/Day PLX3397 Combined with Eribulin

EXPERIMENTAL

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; Drug: Eribulin

Phase Ib: 1000 mg/Day PLX3397 Combined with Eribulin

EXPERIMENTAL

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; Drug: Eribulin

Phase II: 800 mg/Day PLX3397 Lead in +Combined with Eribulin

EXPERIMENTAL

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; Drug: Eribulin

Interventions

PLX3397 DRUG

Dosage Form: 100 mg or 200 mg capsules, Dosage: 400 - 1000 mg, oral administration

Phase II: 800 mg/Day PLX3397 Lead in +Combined with Eribulin; Phase Ib: 1000 mg/Day PLX3397 Combined with Eribulin; Phase Ib: 600 mg/Day PLX3397 Combined with Eribulin; Phase Ib: 800 mg/Day PLX3397 Combined with Eribulin

Eribulin DRUG

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

Also known as: Halaven, E7389

Phase II: 800 mg/Day PLX3397 Lead in +Combined with Eribulin; Phase Ib: 1000 mg/Day PLX3397 Combined with Eribulin; Phase Ib: 600 mg/Day PLX3397 Combined with Eribulin; Phase Ib: 800 mg/Day PLX3397 Combined with Eribulin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hope Rugo, MD: lead
• Susan G. Komen Breast Cancer Foundation: collaborator
• Plexxikon: collaborator

Study Sites (3)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Duke University Cancer Center

Durham, North Carolina, 27710, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis; Neoplasms

Interventions

pexidartinib; eribulin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Hope Rugo, MD
• Organization: University of California, San Francisco

Hope.Rugo@ucsf.edu

(415) 353-7070

Study Officials

• Hope S. Rugo, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Professor

Study Record Dates

• First Submitted: May 7, 2012
• First Posted: May 11, 2012
• Study Start: July 12, 2012
• Primary Completion: July 5, 2017
• Study Completion: July 5, 2019
• Last Updated: July 17, 2020
• Results First Posted: May 14, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)