On February 27, 2020 MapKure, LLC, a clinical-stage company developing precision medicines for patients with life-threatening diseases, together with BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160) and SpringWorks Therapeutics, Inc. (NASDAQ: SWTX), who are joint owners of MapKure, reported that the first patient has been dosed in Australia in a Phase 1 clinical trial to evaluate BGB-3245, an investigational, next-generation B-RAF inhibitor, in patients with advanced or refractory solid tumors (Press release, MapKure, FEB 27, 2020, View Source [SID1234554894]). The companies also announced that the U.S. Food and Drug Administration (FDA) has allowed the Investigational New Drug (IND) application submitted for BGB-3245 to proceed, which will enable study expansion to U.S. sites.
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B-RAF gene mutations and fusions have been shown to play a key role in the development of certain cancers. BGB-3245 is designed to inhibit both monomeric and dimeric forms of activating B-RAF mutations including V600 and non-V600 mutations, and RAF fusions, and has shown potent preclinical activity against a range of B-RAF gene alterations, including those for which there are no approved targeted therapies and those associated with resistance to currently approved therapies.
"Preclinical data suggest that BGB-3245 could potentially address a range of B-RAF driven tumors, which represent a significant need for patients who currently lack targeted therapeutic options, as well as patients who have developed resistance to first generation B-RAF inhibitors," said Neal Rosen, M.D., Ph.D., the Enid A. Haupt Chair in Medical Oncology at Memorial Sloan-Kettering Cancer Center and Chair of the MapKure Scientific Advisory Board. "If our hypothesis is correct, we believe that BGB-3245 could have meaningful, single agent antitumor activity in B-RAF-altered cancers through its ability to address key primary and resistance gene alterations that are currently unaddressed by approved therapies."
The Phase 1 clinical trial is a first-in-human, open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics (PK) and antitumor activity of BGB-3245 in adult patients with solid tumors, including those harboring specific B-RAF driver mutations and fusions that are likely to respond to a RAF dimer inhibitor, as well as in certain adult patients who have developed resistance to first-generation B-RAF V600 inhibitors. The trial is designed to define the dose and assess the tolerability of BGB-3245 and will capture early antitumor activity signals to allow for potential cohort expansion.
In addition, MapKure has completed the formation of its Scientific Advisory Board (SAB), comprised of renowned leaders in MAPK pathway biology and targeted oncology clinical development. The SAB will continue to collaborate with MapKure’s joint steering committee, consisting of representatives from BeiGene and SpringWorks, to support the advancement of BGB-3245. The composition of the SAB is as follows:
Neal Rosen, M.D., Ph.D., the Enid A. Haupt Chair in Medical Oncology at Memorial Sloan-Kettering Cancer Center. Dr. Rosen is the founding member and Chair of the MapKure SAB.
Antoni Ribas, M.D., Professor of Medicine, Professor of Surgery, and Professor of Molecular and Medical Pharmacology at the University of California Los Angeles.
Kevin Koch, Ph.D., President and CEO of Edgewise Therapeutics; formerly Founder, President, and Chief Scientific Officer of Array BioPharma.
Zhan Yao, Ph.D., Assistant Research Professor, Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center.
Dejan Juric, M.D., Program Director, Investigational Cancer Therapeutics Program and Attending Physician in Medical Oncology, Massachusetts General Hospital.
About the Phase 1 Trial
The Phase 1 trial (NCT04249843) of BGB-3245 is an open-label, dose-escalation trial of BGB-3245 in adult patients with advanced or refractory solid tumors, including those with B-RAF driver mutations and fusions that are likely to respond to a RAF dimer inhibitor. The study will enroll patients who have experienced disease progression during or after at least one prior line of systemic anticancer therapy or for which treatment is not tolerated or acceptable to the participants.
The trial is designed in two parts: the Phase 1a portion will consist of a dose-escalation and dose-finding component to establish the maximum tolerated dose and/or the recommended Phase 2 dose and to evaluate the pharmacokinetics of BGB-3245 in patients with MAPK pathway aberrations. The Phase 1b portion will consist of one or more expansion cohorts to further evaluate the pharmacokinetics, safety, and tolerability of BGB-3245 at the recommended Phase 2 dose and to assess the preliminary antitumor activity of the compound in patients with select tumor types and B-RAF status (B-RAF point mutations and gene fusions).
About BGB-3245
BGB-3245 is an investigational, oral, selective small molecule inhibitor of monomer and dimer forms of activating B-RAF mutations including V600 B-RAF mutations, non-V600 B-RAF mutations, and RAF fusions. These mutations and fusions have been identified in a number of solid tumors to be drivers of cancer growth, including in non-small cell lung cancer, colorectal cancer, thyroid cancer, and brain tumors. Preclinical data have demonstrated that BGB-3245 has activity in patient-derived xenografts driven by B-RAF fusions and non-V600 mutations for which approved B-RAF inhibitors are ineffective. In addition, BGB-3245’s preclinical activity in cancer models driven by V600 B-RAF mutations has suggested that it could provide an additional therapeutic option for patients with the potential to reduce dimer-driven resistance.
In addition to its intended use as a monotherapy in several genetically defined solid tumor types, BGB-3245 also has the potential to be used in rational combination therapies in the future.