Overview
The purpose of this study is to evaluate the safety, tolerability, and antitumor activity of BGB-3245 in participants with advanced or refractory tumors harboring specific v-RAF murine sarcoma viral oncogene homolog B (B-RAF) genetic mutations.
Description
This is a first-in-human, Phase 1a/1b (dose escalation and expansion) study of BGB-3245 in participants with tumors harboring B-RAF mutations that are likely to respond to a RAF dimer inhibitor. BGB-3245 is a second-generation B-RAF inhibitor that has demonstrated potent inhibitory activity against the RAF family of serine/threonine kinases preclinically. In preclinical studies, BGB-3245 showed it inhibited tumor cell lines harboring non-V600 B-RAF mutations; it was also active towards B-RAF/MAP-ERK Kinase (MEK) inhibitor-resistant tumors.
Phase 1a will consist of a dose-escalation and dose-finding component to establish the MTD and/or RP2D and to evaluate the pharmacokinetics of BGB-3245 3245 in participants with MAPK pathway aberrations. Phase 1b will consist of an expansion component to further evaluate the pharmacokinetics, safety, and tolerability of BGB-3245 at the RP2D and to assess the preliminary antitumor activity of the compound in participants with select tumor types and B-RAF mutational status.
Eligibility
Key Inclusion Criteria:
- Participants with histologically or cytologically confirmed advanced or metastatic solid tumor who have experienced disease progression during or after at least 1 line of prior systemic anticancer therapy, or for whom treatment is not available or not tolerated/acceptable to the participants. In addition, participants must meet the following eligibility criteria for the corresponding phase of the study:
- Phase 1a: Participants with a known mutation status and tumor harboring an oncogenic B-RAF or K-RAS/N-RAS mutation, or any other MAPK pathway aberrations. In Phase 1a, the study recruitment will be limited to approximately one third (1/3) participants with K-RAS/N-RAS mutation, and among these participants the study recruitment will be limited to approximately one third (1/3) colorectal cancer (CRC) or pancreatic participants.
- Phase 1b: participants must have a known mutation status and meet one of the following criteria according to the group they are enrolled into:
- Group 1: participants with solid tumors with non-V600 B-RAF mutations including RAF fusions,; or
- Group 2: participants with B-RAF V600 mutated melanoma or non-small cell lung cancer (NSCLC), and have progressed on a B-RAF-inhibitor and/or MEK-inhibitor resistant tumors (i.e., mitogen-activated protein kinase/extracellular signal regulated kinase) inhibitor resistant tumors.
- Participants must provide tumor tissue sample (archival tumor tissue or agree to a fresh tumor biopsy) for mutation and biomarkers analysis 3. Participants must have measurable disease as defined per RECIST v1.1. 4. Eastern Cooperative Oncology Group performance status of 1 at Screening. 5. Adequate hematologic and organ function, as indicated by the following laboratory values, prior to Cycle 1 Day 1
Key Exclusion Criteria:
- Participants receiving cancer therapy (chemotherapy or other systemic anticancer therapies, immunotherapy, radiation therapy, or surgery) at the time of Cycle 1 Day 1.
- All participants who have received prior systemic anticancer treatment within the following time frames will be excluded:
- Cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (i.e., 6 weeks for nitrosourea, mitomycin C) prior to Cycle 1 Day 1; and
- Biologic therapy (i.e., antibodies), continuous or intermittent small-molecule therapies, or any other investigational agents within a period of 5 times the half-life of the agent or 4 weeks (whichever is shorter) prior to Cycle 1 Day 1.
- History or presence of gastrointestinal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
- Leptomeningeal disease or untreated/unstable brain metastasis except participants with previously treated brain metastasis who are radiologically stable (imaging evidence required), asymptomatic and have been off steroids and antiseizure medications for longer than 28 days prior to Cycle 1 Day 1 are permitted.
- Any unstable, preexisting major medical condition that in the opinion of the investigator contraindicates the use of an IMP, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Participants who are hepatitis B surface antigen (HBsAg) positive or HCV antibody positive at Screening may be enrolled only if HBV DNA titers <500 IU/mL or negative HCV RNA polymerase chain reaction test, respectively.
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.