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.
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
- ORG STUDY ID:
12751
- SECONDARY ID:
NCI-2015-01321
- NCT ID:
NCT01596751
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| PLX3397 | | Phase II: 800 mg/Day PLX3397 Lead in +Combined with Eribulin |
| Eribulin | Halaven, E7389 | Phase II: 800 mg/Day PLX3397 Lead in +Combined with Eribulin |
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 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).
Trial Arms
| Name | Type | Description | Interventions |
|---|
| 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. | |
| 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 | |
| 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 | |
| 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 | |
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 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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Maximum Tolerated Dose (MTD) of PLX3397 Given in Combination With Standard Dose Eribulin in Participants With Metastatic Breast Cancer (Phase 1b) |
| Time Frame: | Up to Day 21 |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Objective Response Rate (ORR) (Phase II) |
| Time Frame: | From baseline until study completion, an average of 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Median Duration of Response (Phase II) |
| Time Frame: | From date of first confirmed disease response to confirmed disease progression or death due to any cause, an average of 2 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Median Time to Disease Progression (Phase II) |
| Time Frame: | From Day 1 to date of disease progression, an average of 4 months |
| Safety Issue: | |
| Description: | 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 |
Details
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Hope Rugo, MD |
Trial Keywords
- metastatic
- breast
- cancer
- triple
- negative
- PLX
- Eribulin
Last Updated
July 17, 2020
