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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by University of California, San Francisco
Sponsor:
Collaborators:
Susan G. Komen Breast Cancer Foundation
Plexxikon
Eisai Inc.
Information provided by (Responsible Party):
Hope Rugo, MD, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01596751
First received: May 7, 2012
Last updated: August 15, 2014
Last verified: August 2014
  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.


Condition Intervention Phase
Metastatic Breast Cancer
Drug: PLX3397
Drug: Eribulin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Maximum tolerated dose of PLX3397 given in combination with with standard dose eribulin in patients with metastatic breast cancer (Phase 1b) [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]
  • 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) [ Time Frame: Evaluated at week 12 tumor assessment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Serum concentrations for the combination of PLX3397 and eribulin (Phase 1b) [ Time Frame: Up to 42 days. ] [ Designated as safety issue: No ]
  • Safety of treatment (Phase 1b & 2) [ Time Frame: Approximately 24 months ] [ Designated as safety issue: Yes ]
    AE and toxicity assessments (laboratory tests, physical exams & history) on Days 1 and Day 8 of each cycle during treatment

  • Immune response (Phase 1b & 2) [ Time Frame: Up to 42 days. ] [ Designated as safety issue: No ]
  • Efficacy of drug combination including response rate and duration of response (Phase 2) [ Time Frame: Participants will be assessed every 3 weeks and have CT scans every 6 weeks during treatment. Average participation is approximately 24 months. ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: July 2012
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Eribulin in combination with PLX3397

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
Drug: PLX3397
Dosage Form: 100 mg or 200 mg capsules, Dosage: 400 - 1000 mg, oral administration
Drug: Eribulin
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
Other Names:
  • Halaven
  • E7389

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01596751

Contacts
Contact: Hope S. Rugo, MD 415-353-7428 hrugo@medicine.ucsf.edu

Locations
United States, California
UCSF Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94115
Contact: Paula Fiermonte    415-885-7605    fiermontep@cc.ucsf.edu   
Contact: Lauren Metzroth    415-885-7213    Lauren.Metzroth@ucsfmedctr.org   
Principal Investigator: Hope S. Rugo, MD         
United States, North Carolina
Duke University Cancer Center Not yet recruiting
Durham, North Carolina, United States, 27710
Contact: Kimberly Blackwell, MD    919-668-1748    black034@mc.duke.edu   
Principal Investigator: Kimberly Blackwell, MD         
United States, Tennessee
Vanderbilt-Ingram Cancer Center Not yet recruiting
Nashville, Tennessee, United States, 37232
Contact: Ingrid Mayer, MD    615-322-4967    Ingrid.mayer@vanderbilt.edu   
Principal Investigator: Ingrid Mayer, MD         
Sponsors and Collaborators
Hope Rugo, MD
Susan G. Komen Breast Cancer Foundation
Plexxikon
Eisai Inc.
Investigators
Study Chair: Hope S. Rugo, MD University of California, San Francisco
  More Information

No publications provided

Responsible Party: Hope Rugo, MD, Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01596751     History of Changes
Other Study ID Numbers: UCSF Protocol No. 12751
Study First Received: May 7, 2012
Last Updated: August 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
metastatic
breast
cancer
triple
negative
PLX
Eribulin

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases

ClinicalTrials.gov processed this record on August 27, 2014