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

• Sponsor: Hope Rugo, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT01596751
• Collaborator: Susan G. Komen Breast Cancer Foundation (Other), Plexxikon (Industry)
• Enrollment: 67
• Locations: 3
• Arms: 4
• Actual Duration (Months): 83.7
• Patients Per Site: 22.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: PLX3397; Drug: Eribulin	Phase 1/Phase 2

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (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
• Actual Study Start Date: Jul 12, 2012
• Actual Primary Completion Date: Jul 5, 2017
• Actual Study Completion Date: Jul 5, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of PLX3397 Given in Combination With Standard Dose Eribulin in Participants With Metastatic Breast Cancer (Phase 1b) [Up to Day 21]

   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.

2. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) (Phase Ib) [Up to Day 21]

   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.

3. Percentage of Total Phase II Participants With Chemotherapy Pre-Treated Triple Negative Metastatic Breast Cancer Who Are Progression Free at 3 Months [Up to 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.

Secondary Outcome Measures

1. Objective Response Rate (ORR) (Phase II) [From baseline until study completion, an average of 24 months]

   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.

2. 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]

   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.

3. Median Time to Disease Progression (Phase II) [From Day 1 to date of disease progression, an average of 4 months]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	Duke University Cancer Center	Durham	North Carolina	United States	27710
3	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Hope S. Rugo, MD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 3, 2016
• Informed Consent Form - Nov 10, 2016

More Information

Publications

None provided.

• Responsible Party: Hope Rugo, MD, Clinical Professor, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01596751
• Other Study ID Numbers: 12751; NCI-2015-01321
• First Posted: May 11, 2012
• Last Update Posted: Jul 17, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Hope Rugo, MD, Clinical Professor, University of California, San Francisco: metastatic; breast; cancer; triple; negative; PLX; Eribulin
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Arm/Group Title	Phase Ib/1: 600 mg/Day PLX3397 Combined With Eribulin	Phase Ib/2: 400 mg/Day PLX3397 Combined With Eribulin	Phase Ib/3: 600 mg/Day PLX3397 Combined With Eribulin	Phase Ib/4: 800 mg/Day PLX3397 Combined With Eribulin	Phase Ib/5: 800 mg/Day PLX3397 Combined With Eribulin	Phase Ib/6: 1000 mg/Day PLX3397 Combined With Eribulin	Phase II/1: 1000 mg/Day PLX3397 Combined With Eribulin	Phase II/2: 800 mg/Day PLX3397 Lead In+Combined With Eribulin
Arm/Group Description	Treatments were given in 21 day Cycles. For each cycle, participants received 600 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 400 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.1 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 600 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 800 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 800 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 1000 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatment began with a 7 day Lead-in Phase, consisting of 1000 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 1000 mg/day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.	Treatment began with a 7 day Lead-in Phase, consisting of 800 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 800 mg/day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.
Period Title: Overall Study
STARTED	5	4	3	6	4	6	17	22
COMPLETED	5	4	3	6	4	6	17	22
NOT COMPLETED	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase Ib/1: 600 mg/Day PLX3397 Combined With Eribulin	Phase Ib/2: 400 mg/Day PLX3397 Combined With Eribulin	Phase Ib/3: 600 mg/Day PLX3397 Combined With Eribulin	Phase Ib/4: 800 mg/Day PLX3397 Combined With Eribulin	Phase Ib/5: 800 mg/Day PLX3397 Combined With Eribulin	Phase Ib/6: 1000 mg/Day PLX3397 Combined With Eribulin	Phase II/1: 1000 mg/Day PLX3397 Combined With Eribulin	Phase II/2: 800 mg/Day PLX3397 Combined With Eribulin	Total
Arm/Group Description	Treatments were given in 21 day Cycles. For each cycle, participants received 600 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 400 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.1 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 600 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 800 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 800 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 1000 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatment began with a 7 day Lead-in Phase, consisting of 1000 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 1000 mg/day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.	Treatment began with a 7 day Lead-in Phase, consisting of 800 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 800 mg/day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.	Total of all reporting groups
Overall Participants	5	4	3	6	4	6	17	22	67
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50.79	54.38	41.88	51.30	46.46	48.33	54.31	56.06	51.54
Sex: Female, Male (Count of Participants)
Female	5 100%	4 100%	3 100%	6 100%	4 100%	6 100%	17 100%	22 100%	67 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 20%	0 0%	0 0%	3 50%	0 0%	0 0%	1 5.9%	2 9.1%	7 10.4%
Not Hispanic or Latino	4 80%	3 75%	3 100%	3 50%	4 100%	6 100%	14 82.4%	18 81.8%	55 82.1%
Unknown or Not Reported	0 0%	1 25%	0 0%	0 0%	0 0%	0 0%	2 11.8%	2 9.1%	5 7.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 20%	1 25%	1 33.3%	1 16.7%	1 25%	0 0%	1 5.9%	2 9.1%	8 11.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	1 16.7%	0 0%	1 4.5%	2 3%
White	4 80%	3 75%	1 33.3%	4 66.7%	3 75%	4 66.7%	12 70.6%	14 63.6%	45 67.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 33.3%	1 16.7%	0 0%	1 16.7%	4 23.5%	5 22.7%	12 17.9%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of PLX3397 Given in Combination With Standard Dose Eribulin in Participants With Metastatic Breast Cancer (Phase 1b)
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.
Time Frame	Up to Day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase Ib: Eribulin in Combination With PLX3397
Arm/Group Description	Phase Ib: 21 day treatment cycle: PLX3397 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously, day 1 and 8 Cohort 1: 600 mg/day Cohort 2: 800 mg/day Cohort 3: 1000 mg/day
Measure Participants	28
Number [miligrams per day]	1,000

2. Primary Outcome

Title	Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) (Phase Ib)
Description	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.
Time Frame	Up to Day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase Ib/1: 600 mg/Day PLX3397 Combined With Eribulin	Phase Ib/2: 400 mg/Day PLX3397 Combined With Eribulin	Phase Ib/3: 600 mg/Day PLX3397 Combined With Eribulin	Phase Ib/4: 800 mg/Day PLX3397 Combined With Eribulin	Phase Ib/5: 800 mg/Day PLX3397 Combined With Eribulin	Phase Ib/6: 1000 mg/Day PLX3397 Combined With Eribulin
Arm/Group Description	Treatments were given in 21 day Cycles. For each cycle, participants received 600 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 400 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.1 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 600 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 800 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 800 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.	Treatments were given in 21 day Cycles. For each cycle, participants received 1000 mg/day of PLX3397 in 100-200 mg gelcaps, by mouth daily & Eribulin 1.4 mg/m2 intravenously on days 1 and 8.
Measure Participants	5	4	3	6	4	6
Count of Participants [Participants]	3 60%	0 0%	0 0%	1 16.7%	0 0%	1 16.7%

3. Primary Outcome

Title	Percentage of Total Phase II Participants With Chemotherapy Pre-Treated Triple Negative Metastatic Breast Cancer Who Are Progression Free at 3 Months
Description	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.
Time Frame	Up to 3 months

Outcome Measure Data

Analysis Population Description

Both Phase II Cohorts were combined for this planned analysis. Only 31 participants in Phase II obtained an objective progression event per RECIST v1.1 criteria at month 3

Arm/Group Title	Phase II: PLX3397 Combined With Eribulin
Arm/Group Description	Treatment began with a 7 day Lead-in Phase, consisting of 800 mg or 1000 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 800 mg or 1000mg /day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.
Measure Participants	31
Number (95% Confidence Interval) [Percentage of Participants]	35.7 714%

4. Secondary Outcome

Title	Objective Response Rate (ORR) (Phase II)
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.
Time Frame	From baseline until study completion, an average of 24 months

Outcome Measure Data

Analysis Population Description

Both Phase II Cohorts were combined for this planned analysis. Only 31 participants in Phase II obtained an objective event per RECIST v1.1

Arm/Group Title	Phase II: PLX3397 Combined With Eribulin
Arm/Group Description	Treatment began with a 7 day Lead-in Phase, consisting of 800 mg or 1000 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 800 mg or 1000mg /day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.
Measure Participants	31
Number [percentage of participants]	16 320%

5. Secondary Outcome

Title	Median Duration of Response (Phase II)
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.
Time Frame	From date of first confirmed disease response to confirmed disease progression or death due to any cause, an average of 2 months

Outcome Measure Data

Analysis Population Description

Both Phase II Cohorts were combined for this planned analysis. Only 5 participants in Phase II obtained an objective response

Arm/Group Title	Phase II: PLX3397 Combined With Eribulin
Arm/Group Description	Treatment began with a 7 day Lead-in Phase, consisting of 800 mg or 1000 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 800 mg or 1000mg /day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.
Measure Participants	5
Median (Full Range) [days]	94

6. Secondary Outcome

Title	Median Time to Disease Progression (Phase II)
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
Time Frame	From Day 1 to date of disease progression, an average of 4 months

Outcome Measure Data

Analysis Population Description

Both Phase II Cohorts were combined for this planned analysis. Only 31 participants in Phase II obtained an objective progression event per RECIST v1.1 criteria

Arm/Group Title	Phase II: PLX3397 Combined With Eribulin
Arm/Group Description	Treatment began with a 7 day Lead-in Phase, consisting of 800 mg or 1000 mg/day PLX3397 given by mouth for 5 days followed by 2 days of rest (no PLX3397). Then combination treatment was given in 21 day cycles. For each cycle, participants received 800 mg or 1000mg /day of PLX3397 by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest repeated weekly and Eribulin at 1.4 mg/m2 intravenously on days 1 and 8.
Measure Participants	31
Median (Full Range) [days]	50.2

Adverse Events

Time Frame	Up to 24 months
Arm/Group Title	Phase Ib/1: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/2: 400 mg/Day PLX3397 Combined With Eribulin		Phase Ib/3: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/4: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/5: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/6: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/1: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/2: 800 mg/Day PLX3397 Combined With Eribulin
Arm/Group Description	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. PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 600mg, oral administration 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		Treatments are given in 21 day cycles. For each cycle, treatment includes: PLX3397 at a dose of 400 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. PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 400mg, oral administration 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		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. PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 600 mg, oral administration 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		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 PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 800 mg, oral administration 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		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 PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 800 mg, oral administration 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		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 PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 1000 mg, oral administration 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		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 1000 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 1000 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 PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 1000 mg, oral administration 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		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 PLX3397: Dosage Form: 100 mg or 200 mg capsules, Dosage: 800 mg, oral administration 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
All Cause Mortality
	Phase Ib/1: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/2: 400 mg/Day PLX3397 Combined With Eribulin		Phase Ib/3: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/4: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/5: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/6: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/1: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/2: 800 mg/Day PLX3397 Combined With Eribulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/4 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		1/17 (5.9%)		0/22 (0%)
Serious Adverse Events
	Phase Ib/1: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/2: 400 mg/Day PLX3397 Combined With Eribulin		Phase Ib/3: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/4: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/5: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/6: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/1: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/2: 800 mg/Day PLX3397 Combined With Eribulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		3/4 (75%)		1/3 (33.3%)		2/6 (33.3%)		1/4 (25%)		3/6 (50%)		6/17 (35.3%)		14/22 (63.6%)
Blood and lymphatic system disorders
Febrile neutropenia	3/5 (60%)	3	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	5/22 (22.7%)	6
Cardiac disorders
Atrial fibrillation	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	0/22 (0%)	0
Myocardial Infarction	0/5 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Eye disorders
Blurred Vision	0/5 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Gastrointestinal disorders
Dysphagia	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
General disorders
Fever	0/5 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	2/17 (11.8%)	2	1/22 (4.5%)	1
General disorders and administration site conditions - Other	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	2/22 (9.1%)	2
Localized edema	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Non-cardiac chest pain	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Pain	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Infections and infestations
Sepsis	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Catheter related infection	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/17 (0%)	0	0/22 (0%)	0
Soft Tissue infection	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Infections and Infestations other	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/17 (0%)	0	0/22 (0%)	0
Investigations
Alanine aminotransferase increased	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Aspartate aminotransferase increased	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	1/22 (4.5%)	1
Blood bilirubin increased	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	0/22 (0%)	0
Neutrophil count decreased	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Metabolism and nutrition disorders
Hyponatremia	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	0/22 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	0/5 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Bone Pain	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Nervous system disorders
Paresthesia	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	0/22 (0%)	0
Transient Ischemia Attack	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Psychiatric disorders
Confusion	0/5 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/5 (0%)	0	1/4 (25%)	2	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	4/22 (18.2%)	4
Hoarseness	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Pleural effusion	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	1/17 (5.9%)	1	0/22 (0%)	0
Respiratory failure	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Hypoxia	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/17 (0%)	0	0/22 (0%)	0
Cough	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders - Other	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/17 (0%)	0	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Phase Ib/1: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/2: 400 mg/Day PLX3397 Combined With Eribulin		Phase Ib/3: 600 mg/Day PLX3397 Combined With Eribulin		Phase Ib/4: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/5: 800 mg/Day PLX3397 Combined With Eribulin		Phase Ib/6: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/1: 1000 mg/Day PLX3397 Combined With Eribulin		Phase II/2: 800 mg/Day PLX3397 Combined With Eribulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		4/4 (100%)		1/3 (33.3%)		4/6 (66.7%)		3/4 (75%)		6/6 (100%)		14/17 (82.4%)		22/22 (100%)
Gastrointestinal disorders
Diarrhea	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/4 (25%)	1	2/6 (33.3%)	2	4/17 (23.5%)	5	7/22 (31.8%)	7
Mucositis oral	2/5 (40%)	4	1/4 (25%)	2	0/3 (0%)	0	0/6 (0%)	0	2/4 (50%)	2	0/6 (0%)	0	3/17 (17.6%)	5	4/22 (18.2%)	4
Nausea	1/5 (20%)	1	1/4 (25%)	1	1/3 (33.3%)	1	0/6 (0%)	0	0/4 (0%)	0	4/6 (66.7%)	4	9/17 (52.9%)	11	8/22 (36.4%)	11
Vomiting	2/5 (40%)	2	0/4 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	1/17 (5.9%)	1	6/22 (27.3%)	13
Dyspepsia	1/5 (20%)	2	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	2/22 (9.1%)	2
Bloating	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/17 (0%)	0	3/22 (13.6%)	3
Constipation	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	1/6 (16.7%)	1	0/17 (0%)	0	3/22 (13.6%)	3
Abdominal Pain	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	1/17 (5.9%)	1	1/22 (4.5%)	1
General disorders
Fatigue	3/5 (60%)	4	2/4 (50%)	2	1/3 (33.3%)	1	2/6 (33.3%)	2	0/4 (0%)	0	2/6 (33.3%)	2	10/17 (58.8%)	13	14/22 (63.6%)	19
Fever	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	1/4 (25%)	1	2/6 (33.3%)	2	6/17 (35.3%)	7	5/22 (22.7%)	21
Pain	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	3/17 (17.6%)	3	6/22 (27.3%)	10
Hepatobiliary disorders
Hepatic Failure	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	0/22 (0%)	0
Infections and infestations
Upper respiratory infection	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	4	1/4 (25%)	1	1/6 (16.7%)	1	1/17 (5.9%)	2	0/22 (0%)	0
Investigations
Alanine aminotransferase increased	0/5 (0%)	0	1/4 (25%)	3	0/3 (0%)	0	0/6 (0%)	0	3/4 (75%)	6	2/6 (33.3%)	2	7/17 (41.2%)	18	8/22 (36.4%)	24
Alkaline phosphatase increased	0/5 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	1/6 (16.7%)	1	2/17 (11.8%)	7	4/22 (18.2%)	4
Aspartate aminotransferase increased	1/5 (20%)	1	1/4 (25%)	2	0/3 (0%)	0	2/6 (33.3%)	3	3/4 (75%)	7	2/6 (33.3%)	3	7/17 (41.2%)	20	10/22 (45.5%)	24
Blood bilirubin increased	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	2/22 (9.1%)	2
Neutrophil count decreased	2/5 (40%)	5	1/4 (25%)	2	1/3 (33.3%)	1	0/6 (0%)	0	2/4 (50%)	5	1/6 (16.7%)	1	9/17 (52.9%)	23	7/22 (31.8%)	18
Platelet count decreased	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	2	0/17 (0%)	0	2/22 (9.1%)	3
White blood cell decreased	3/5 (60%)	5	1/4 (25%)	2	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	8/17 (47.1%)	12	2/22 (9.1%)	5
Metabolism and nutrition disorders
Anorexia	3/5 (60%)	3	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	2/4 (50%)	2	4/6 (66.7%)	5	4/17 (23.5%)	5	3/22 (13.6%)	3
Hpyerglycemia	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	2/17 (11.8%)	3	2/22 (9.1%)	9
Hypokalemia	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	1/6 (16.7%)	1	3/17 (17.6%)	3	1/22 (4.5%)	1
Hypomagnesemia	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	4/22 (18.2%)	7
Musculoskeletal and connective tissue disorders
Back Pain	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	2/17 (11.8%)	3	1/22 (4.5%)	1
Generalized muscle weakness	2/5 (40%)	2	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	2/22 (9.1%)	3
Myalgia	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	2/22 (9.1%)	3
Nervous system disorders
Headache	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	6/22 (27.3%)	9
Peripheral sensory neuropathy	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	5/17 (29.4%)	5	5/22 (22.7%)	7
Dizziness	1/5 (20%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	2/17 (11.8%)	2	1/22 (4.5%)	1
Dysgeusia	0/5 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	2/22 (9.1%)	2
Psychiatric disorders
Anzxiety	1/5 (20%)	2	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	2/22 (9.1%)	3
Insomnia	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	1	4/22 (18.2%)	4
Respiratory, thoracic and mediastinal disorders
Cough	0/5 (0%)	0	3/4 (75%)	4	0/3 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	1/6 (16.7%)	1	6/17 (35.3%)	7	6/22 (27.3%)	6
Dyspnea	2/5 (40%)	2	2/4 (50%)	3	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	5/17 (29.4%)	6	3/22 (13.6%)	7
Sore Throat	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	5/17 (29.4%)	5	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	2/17 (11.8%)	4	2/22 (9.1%)	2
Rash maculo-papular	3/5 (60%)	4	1/4 (25%)	1	0/3 (0%)	0	3/6 (50%)	4	1/4 (25%)	3	1/6 (16.7%)	3	5/17 (29.4%)	12	7/22 (31.8%)	15
Alopecia	2/5 (40%)	2	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/17 (0%)	0	2/22 (9.1%)	2
Vascular disorders
Hypertension	0/5 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/17 (5.9%)	2	4/22 (18.2%)	6

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.