Phase I/IIa Study to Evaluate the Safety, PK, PD, and Preliminary Efficacy of PLX8394 in Patients With Advanced 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.

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