Safety Study of PLX3397 and Paclitaxel in Patients With Advanced Solid Tumors

Phase 1

Completed

Conditions: Solid Tumors

Interventions: Drug: PLX3397
Drug: Paclitaxel

Registration Number: NCT01525602

Lead Sponsor: Daiichi Sankyo

Brief Summary: This was a 3-part study designed to explore the safety and tolerability of escalating doses of PLX3397 with weekly paclitaxel to establish a recommended Phase 2 dose (RP2D), to confirm RP2D in participants with advanced non-resectable solid tumors, and to determine the efficacy of PLX3397 600 mg twice daily (BID) administered in combination with weekly paclitaxel in participants with advanced, metastatic or non-resectable, platinum-resistant or -refractory epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 74

Inclusion Criteria

Patients with:
- Part 1 (enrollment closed): an advanced, incurable solid tumor
- Part 2 (enrollment closed): an advanced, incurable solid tumor for whom a taxane would be considered a reasonable chemotherapy option
- Part 3 (enrollment closed): advanced, metastatic or non-resectable epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer with
  - platinum-resistant cancer, defined as disease that responded to a platinum-containing chemotherapy regimen, but demonstrated recurrence within six months following the completion of that platinum-containing regimen, OR
  - platinum-refractory cancer, defined as disease failed to achieve at least a partial response to a platinum-containing regimen (i.e., stable disease or actual disease progression), AND
  - have not been treated with a taxane within six months of Cycle 1 Day 1 (C1D1), AND
  - have not been treated with weekly paclitaxel after first-line treatment in which weekly paclitaxel plus a platinum is permitted
Part 3: Patients must have target (≥2 cm diameter) or non-target lesion cancer that is accessible for core biopsies before starting on study and after one cycle of treatment.
Patients with stable brain metastases are eligible for this trial. 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.
Washout from any prior investigational therapy of at least five times the T1/2 prior to C1D1
Washout from any prior biologic or targeted therapy at least 4 weeks or five times the plasma half-life (T1/2) (whichever is shorter) prior to 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 eighteen years or older
Eastern Cooperative Oncology Group (ECOG) performance status 0-2, inclusive
Anticipated life expectancy of at least 12 weeks
Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥1500/mm3, platelets ≥100,000/mm3
Adequate renal function: serum creatinine <1.5 x ULN or calculated creatinine clearance (CrCl) >60 mL/min using Cockcroft-Gault formula
Adequate hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x upper limit of normal (ULN), Total and Direct Bilirubin <1.5 x ULN. However, in the presence of liver metastases, AST and ALT must be <5 x ULN
Cardiac ejection fraction ≥50%, and QT interval corrected by Fridericia's formula (QTcF) <450 ms (males) or <470 ms (females) on electrocardiogram (ECG) at Baseline.
Able to swallow capsules and maintain adequate hydration
Ability to give written informed consent and willing to comply with the requirements of the protocol; and for Part 3, to give written informed consent for 2 cancer biopsy procedures
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 active 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Part 2	Paclitaxel	Extension cohort at the RP2D of single-agent PLX3397 in combination with paclitaxel in approximately 30 patients in advanced solid tumors. Enrollment completed. (Closed to recruitment)
Part 1	PLX3397	Open-label, sequential PLX3397 single-agent dose escalation in combination with paclitaxel in approximately 30 patients with advanced solid tumors. Enrollment completed. (Closed to recruitment)
Part 3	PLX3397	Extension cohort at the RP2D of single-agent PLX3397 in combination with paclitaxel in approximately 30 patients with advanced, metastatic, or non-resectable, platinum-resistant or -refractory epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. (Closed to recruitment)
Part 2	PLX3397	Extension cohort at the RP2D of single-agent PLX3397 in combination with paclitaxel in approximately 30 patients in advanced solid tumors. Enrollment completed. (Closed to recruitment)
Part 1	Paclitaxel	Open-label, sequential PLX3397 single-agent dose escalation in combination with paclitaxel in approximately 30 patients with advanced solid tumors. Enrollment completed. (Closed to recruitment)
Part 3	Paclitaxel	Extension cohort at the RP2D of single-agent PLX3397 in combination with paclitaxel in approximately 30 patients with advanced, metastatic, or non-resectable, platinum-resistant or -refractory epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. (Closed to recruitment)

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With TEAEs (>10%) Classified by Preferred Term Following PLX3397 Administered in Combination With Paclitaxel (Part 3) (Safety Population)	From post first dose up to 28 days after the last dose, up to 5 years 9 months	Treatment-emergent adverse events (TEAEs) reported by \>10% of all participants in Part 3 are reported.
Best Overall Tumor Response Based on RECIST V1.1 Following PLX3397 Administered in Combination With Paclitaxel (Parts 1 and 2) (Efficacy Evaluable Population)	From post first dose up to 5 years 9 months post dose	Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Best Overall Tumor Response Based on RECIST V1.1 Following PLX3397 Administered in Combination With Paclitaxel (Part 3) (Efficacy Evaluable Population)	From 26 days (CR and PR) and 54 days (SD) up to 5 years 9 months post dose	Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Percentage of Participants With Treatment-emergent Adverse Events (>10%) Classified by Preferred Term Following PLX3397 Administered in Combination With Paclitaxel (Parts 1 and 2) (Safety Population)	From post first dose up to 28 days after the last dose, up to 5 years 9 months	Treatment-emergent adverse events (TEAEs) reported by \>10% of all participants in Parts 1 and 2 are reported.

Secondary Outcome Measures

Name	Time	Method
Duration of Response Following PLX3397 Administered in Combination With Paclitaxel (Parts 1 and 2) (Efficacy Evaluable Population)	From the date of initial response until disease progression or death, whichever occurs first, up to 5 years 9 months post dose
Duration of Response Following PLX3397 Administered in Combination With Paclitaxel (Part 3) (Efficacy Evaluable Population)	From the date of initial response until disease progression or death, whichever occurs first, up to 5 years 9 months post dose
Progression-free Survival Following PLX3397 Administered in Combination With Paclitaxel (Part 3) (Efficacy Evaluable Population)	From the first day of treatment to the first documented disease progression or date of death, whichever occurred first, up to 5 years 9 months post dose	Progression-free survival (PFS) is defined as the number of days from the start of therapy (i.e. Cycle 1 Day 1) to the date of first documented disease progression/relapse or death, whichever occurs first. If the disease progression/relapse does not occur, PFS will be censored as of the date of their last evaluable tumor assessments.
A Summary of Pharmacokinetic Parameter (Tmax) Following Exposure to PLX3397 (Parts 1 and 3)	Cycle 1, Day 15
A Summary of Pharmacokinetic Parameter (Cmax) Following Exposure to PLX3397 (Parts 1 and 3)	Cycle 1, Day 15
A Summary of Pharmacokinetic Parameters (AUC[0-4h], AUC[0-6h], and AUC[0-12h]) Following Exposure to PLX3397 (Parts 1 and 3)	Cycle 1, Day 15
Percentage of Participants With PLX3397-Related Treatment-emergent Adverse Events (>10%) by Preferred Term (Parts 1 and 2) (Safety Analysis Set)	From post first dose up to 28 days after the last dose, up to 5 years 9 months
Percentage of Participants With Paclitaxel-Related Treatment-emergent Adverse Events (>10%) by Preferred Term (Parts 1 and 2) (Safety Analysis Set)	From post first dose up to 28 days after the last dose, up to 5 years 9 months
Percentage of Participants With PLX3397- and/or Paclitaxel-Related TEAEs (>10%) by Preferred Term (Part 3) (Safety Analysis Set)	From post first dose up to 28 days after the last dose, up to 5 years 9 months

Trial Locations

Locations (8): Ohio State University
🇺🇸
Columbus, Ohio, United States
Univeristy of California, San Francisco
🇺🇸
San Francisco, California, United States
Sylvester Comprehensive Cancer Center/UMHC
🇺🇸
Miami, Florida, United States
University Hospitals of Cleveland
🇺🇸
Cleveland, Ohio, United States
University of Utah, Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
University of Colorado, Anschutz Cancer Pavilion
🇺🇸
Aurora, Colorado, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States