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A Phase 1b Study to Assess the Safety of PLX3397 and Paclitaxel in Patients With Advanced Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Advanced, Incurable Solid Tumors

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Trial Information

A Phase 1b Study to Assess the Safety of PLX3397 and Paclitaxel in Patients With Advanced Solid Tumors

This is a nonrandomized, open label phase 1b study employing a standard 3+3 sequential dose
escalation design to determine the maximum tolerated dose (MTD) of PLX3397, a novel
inhibitor of the CSF-1 receptor (Fms), when administered in combination with paclitaxel in
patients with advanced, incurable solid tumors. Treatment with PLX3397 will consist of oral
administration with the starting dose of 600 mg/day for 28 days. Paclitaxel will be
administered once weekly over approximately 60 minutes in each 28-day treatment cycle. The
planned cohorts are Cohort 1: 600 mg/day; Cohort 2: 800 mg/day; and Cohort 3: 1000 mg/day.

Each dose level cohort will enroll 3-6 patients. Enrollment into the next higher dose level
will begin only if the first 3 patients enrolled into the cohort complete the 28-day
observation period without the occurrence of a Dose-Limiting Toxicity (DLT). If one of the
3 initial patients at a given dose level experiences a DLT, the cohort at this dose level
will be expanded to include an additional 3 patients (6 patients total).

If ≥ 2/6 patients experience a DLT, then dose escalation will be stopped and the preceding
dose level will be considered the MTD.

Enrollment is planned to include approximately 30 patients recruited from approximately 3-4
sites. The total number of patients to be enrolled will depend on the number of cohorts and
whether a cohort requires 3 or 6 patients. During the first cycle, a patient that does not
receive at least 21 days of PLX3397 or does not receive at least 3 of 4 doses of paclitaxel
for reasons other than a DLT, the patient may be replaced.

Study treatment will be provided until disease progression, unacceptable or dose-limiting
toxicity, death, withdrawal of consent, study termination by Sponsor, or if the Investigator
and patient agree that it is in the patient's best interests to discontinue.

The primary objective of this phase 1b study is to establish the DLT and MTD of PLX3397 when
given in combination with weekly standard dose Paclitaxel.

The secondary objectives include (1) evaluation of overall safety and tolerability of
PLX3397 in combination with paclitaxel, (2) explore the efficacy of PLX3397 in combination
with paclitaxel in patients with advance solid tumors, and (3) determine the PK of PLX3307
when administered in combination with paclitaxel.

Inclusion Criteria:

- Advanced, incurable solid tumor.

- Patients with stable brain metastases are eligible. However, patients must not have
required steroid treatment for their brain metastases within 30 days of Screening.

- Bone-directed therapy (e.g., bisphosphonates or denosumab) is permitted. However,
patients should not have started bone-directed therapy within 2 weeks of C1D1, and
new bone-directed therapy should not be initiated during the first 4 weeks of study
(i.e., cycle 1).

- Washout from any prior investigational therapy of at least 28 days prior to Cycle 1,
Day 1 (i.e.,C1D1).

- Washout from prior chemotherapy of at least 2 weeks or 1 elimination half-life,
whichever is longer, prior to C1D1.

- Washout from prior hormonal therapy of at least 2 weeks prior to C1D1.

- Washout of at least 2 weeks from the most recent radiation treatment prior to C1D1.

- Resolution of all prior treatment-related toxicities to Grade 1 or less, except for
Grade 2 fatigue or alopecia prior to C1D1.

- Age 18 years or older.

- ECOG performance status 0-2, inclusive.

- Anticipated life expectancy of at least 12 weeks.

- Adequate bone marrow reserve: ANC ≥ 1000/mm3, platelets ≥ 100,000/mm3.

- Adequate renal function: serum creatinine < 1.5X ULN or calculated CrCl > 60 mL/min
using Cockcroft-Gault formula. GFR = [(140-age)*(weight in kg)*(0.85 if

- Adequate hepatic function: AST and ALT < 2.5X ULN, Total and Direct Bilirubin < 1.5X
ULN. However, in the presence of liver metastases, AST and ALT must be < 5X ULN and
Total and Direct Bilirubin < 3X ULN.

- Cardiac ejection fraction ≥ 50%, and QTcF < 450 ms on ECG at Baseline. Fridericia's
Formula: QTcF = (QT)/RR0.33

- Able to swallow capsules and maintain adequate hydration.

- Ability to give written informed consent and willing 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 three months after receiving their last dose of
study drug. Fertile men must also agree to use an acceptable method of birth control
while on study drug and for at least 3 months after last dose.

Exclusion Criteria:

- Presence of an active secondary malignancy.

- Patients with a non-melanomatous, in situ malignancy or disease that is
completely resectable with surgery may be considered after discussion with the
Medical Monitor.

- Patients with a completely treated prior malignancy with no evidence of disease
for ≥ 3 years are eligible.

- Refractory nausea and vomiting, malabsorption, external biliary shunt or significant
small bowel resection that would preclude adequate absorption of PLX3397.

- Ongoing treatment with any other investigational therapy.

- Prior anaphylactic or severe hypersensitivity reaction to paclitaxel or
Cremophor-containing agent.

- Persistent grade 2 fatigue at Baseline.

- 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.

- Active untreated infection.

- Known chronic Hepatitis B or C, or HIV infection.

- The presence of a medical or psychiatric condition that, in the opinion of the
Principal Investigator, makes the patient inappropriate for inclusion in this study.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety--Subject incidence of adverse events

Outcome Description:

Subjects will take oral doses of PLX3397 twice a day using a continuous dosing regimen. Paclitaxel IV will be administered weekly in each 28-day treatment cycle. Physical exminations, vital signs, 12-lead electrocardiograms (ECG), adverse events, hematology, and serum chemistry will be used to assess safety throughout the study. Adverse events will be monitored and reviewed for safety issues/abnormal changes in the above mentioned tests.

Outcome Time Frame:

1 year

Safety Issue:



United States: Food and Drug Administration

Study ID:




Start Date:

May 2012

Completion Date:

September 2013

Related Keywords:

  • Advanced, Incurable Solid Tumors
  • Neoplasms



UCSF San Francisco, California  941430324
University Hospitals of Cleveland Cleveland, Ohio  44106
Ohio State University Columbus, Ohio  43210