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

Daiichi Sankyo

Status and phase: Completed; Phase 1

Conditions: Solid Tumors

Treatments: Drug: PLX3397; Drug: Paclitaxel

Study type: Interventional

Funder types: Industry

Identifiers

NCT01525602

PLX108-07

Details and patient eligibility

About

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.

Enrollment: 74 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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74 participants in 3 patient groups

Part 1

Experimental group

Description:

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)

Treatment:

Drug: Paclitaxel

Drug: PLX3397

Part 2

Experimental group

Description:

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)

Treatment:

Drug: Paclitaxel

Drug: PLX3397

Part 3

Experimental group

Description:

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)

Treatment:

Drug: Paclitaxel

Drug: PLX3397