Phase I/IIa Study to Evaluate the Safety, PK, PD, and Preliminary Efficacy of PLX8394 in Patients With Advanced Cancers.
Phase I/IIa Study to Evaluate the Safety, PK, PD, and Preliminary Efficacy of PLX8394 in Patients With Advanced Cancers.
The study objective is to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics
 (PD) of orally administered PLX8394 in patients with advanced solid tumors. An additional
 objective is to identify a Recommended Phase 2 (RP2D) for further evaluation in the Extension
 Cohorts (Phase IIa portion).

 The study objective of the Extension Cohorts (PART 2 portion) is to assess the objective
 tumor response and the PK, PD, and safety of PLX8394 when the RP2D is used in patients with
 advanced BRAF-mutated cancers.
This is an open-label, multi-center Phase I/IIa two-part study with a sequential dose
 escalation part, followed by three parallel Extension cohorts (BRAF-mutated melanoma,
 BRAF-mutated non-melanoma solid tumors, and BRAF-mutated classical hairy cell leukemia). Up
 to approximately 42 patients may be enrolled in the dose escalation phase of the study,
 depending on the number of cohorts required, number of patients per cohort needed, and the
 need for replacement patients. Approximately 130 patients are planned to be enrolled in the
 BRAF-mutated tumor Extension cohorts, with the goal of enrolling approximately 50 patients
 with BRAF/MEK/ERK inhibitor-naïve melanoma, approximately 10-15 patients with BRAF/MEK/ERK
 inhibitor-pretreated melanoma, approximately 50 patients with non-melanoma solid tumors, and
 approximately 10-15 patients with hairy cell leukemia. The trial was intended to be a Phase
 1/2 trial, but the trial never moved forward to Phase 2.
Inclusion Criteria:

 -  Age ≥ 18 years

 -  Measurable disease by RECIST 1.1 criteria (solid tumors)

 -  ECOG performance status of 0-2

 -  Life expectancy ≥ 3 months

 -  Adequate hematologic, hepatic, and renal function:

 1. Solid Tumors - Absolute neutrophil count ≥ 1.5 × 109/L, Hgb > 9 g/dL, platelet
 count ≥ 100 × 109/L, AST/ALT ≤ 2.5 × ULN, bilirubin ≤ 2, creatinine ≤ 1.5 × ULN
 or calculated CrCl >50 mL/min (Cockcroft-Gault formula)

 2. Hairy Cell Leukemia - Absolute neutrophil count ≤ 1.0 × 109/L, Hgb ≤ 10.0 g/dL or
 platelet count ≤ 100 × 109/L; AST/ALT ≤ 2.5 × ULN, bilirubin ≤ 2, creatinine ≤
 1.5 × ULN or calculated CrCl >50 mL/min (Cockcroft-Gault formula)

 -  Women of child-bearing potential must have a negative serum pregnancy test within 14
 days of initiating study drug and must agree to use an acceptable method of birth
 control from the time of the negative pregnancy test up to 6 months after the last
 dose of study drug. Urine pregnancy testing during the study and in follow-up per
 country specific requirements. Fertile men must also agree to use an acceptable method
 of birth control while on study drug and up to 6 months after the last dose of study
 drug.

 -  Completion of previous chemotherapy, immunotherapy, or radiation therapy at least 2
 weeks before study drug initiation, with resolution of all associated toxicity (to ≤
 Grade 1 or Baseline)

 -  Willingness and ability to provide written informed consent prior to any study-related
 procedures and to comply with all study requirements

 -  Eligibility for medical insurance coverage

 1. DOSE-ESCALATION COHORTS

 -  advanced solid tumors that are refractory to standard therapy, have no standard
 therapy, or are considered by the investigator to be inappropriate for standard
 therapy

 2. EXTENSION COHORTS

 -  Cancers with a BRAF-activating mutation as assessed by a CLIA-certified method

 a. Melanoma

 -  unresectable Stage IIIC or Stage IV disease (sub-cohort 1a: BRAF/MEK/ERK inhibitor
 naïve, sub-cohort 1b: BRAF/MEK/ERK inhibitor pre-treated) b. Non-melanoma Solid Tumors

 -  advanced anaplastic thyroid cancer, advanced papillary thyroid cancer, and advanced
 solid tumors (e.g., colorectal cancer, non-small cell lung cancer, cholangiocarcinoma,
 etc) that are refractory to standard therapy, relapsed after standard therapy, have no
 standard therapy, or are considered by the investigator to be inappropriate for
 standard therapy c. Hairy Cell Leukemia

 -  histologically confirmed classical hairy cell leukemia that failed to achieve CR or PR
 to initial purine analog-based therapy, relapsed ≤ 2 years after purine analog-based
 therapy, or a history of intolerance to purine analogs

 Exclusion Criteria:

 -  Extension Cohorts (except 1b) - Previous treatment with a selective BRAF/MEK/EKR
 inhibitor

 -  Symptomatic brain metastases. Patients with untreated brain metastasis ≤ 1 cm can be
 considered eligible if deemed asymptomatic by the investigator upon consultation with
 the medical monitor and do not require immediate radiation or steroids. Patients with
 brain metastasis that is treated and stable for 1 month may be considered eligible if
 they are asymptomatic and on stable dose of steroids or if they do not require
 steroids following successful local therapy.

 -  Investigational drug use within 28 days (or < 5 half-lives, whichever is shorter) of
 the first dose of PLX8394

 -  Major surgical procedure, open biopsy (excluding skin cancer resection), or
 significant traumatic injury within 14 days of initiating study drug (unless the wound
 has healed) or anticipation of the need for major surgery during the study

 -  Uncontrolled intercurrent illness

 -  Active secondary malignancy unless the malignancy is not expected to interfere with
 the evaluation of safety and is approved by the Medical Monitor. Examples of the
 latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the
 cervix, and isolated elevation of prostate-specific antigen. Patients with a
 completely treated prior malignancy and no evidence of disease for ≥ 2 years are
 eligible.

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

 -  Baseline mean QTcF ≥ 450 ms (males) or ≥ 470 ms (females)

 -  Women who are breast-feeding or pregnant

 -  Known chronic HIV, HCV, or HBV infection