Phase II, Multicentre Clinical Trial to Evaluate the Activity of Encorafenib and Binimetinib Administered Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain

Phase II clinical trial, with two cohorts of patients included in parallel, all with melanoma BRAF mutated and brain metastases without previous local treatment in the brain. Cohort 1 will include patients with asymptomatic brain metastases and cohort 2 will include patients with symptomatic brain metastasis.

Start Date18 Jul 2019

Sponsor / Collaborator

Mfar Constructions Pvt Ltd.

[+1]

NCT03430947 / TerminatedPhase 2IIT

An Open-label Phase II Multicenter Study of Vemurafenib (Zelboraf®) Plus Cobimetinib (Cotellic®) After Radiosurgery in Patients With Active BRAF-V600-mutant Melanoma Brain Metastases

This is a phase II, open label, non-randomised study of vemurafenib and cobimetinib after radiosurgery in adult patients with BRAFV600-mutant melanoma brain metastases. All patients will receive vemurafenib 960 mg twice a day on days 1 - 28 combined with cobimetinib 60 mg once a day on days 1 - 21 of each 28-day treatment cycle until disease progression, drug toxicity or death.
The primary objective of this study is to determine the best overall response rate (BORR) in the brain. The extracranial BORR, intra- and extracranial duration of response, progression-free survival and overall survival, adverse events, quality of life and radiomics features predicting long-term local control of brain metastases and treatment-related toxicity will also be examined.

Start Date01 Jul 2018

Sponsor / Collaborator

Dresden University of Technology

NCT01721603 / TerminatedPhase 2IIT

A Phase 2 Prospective Trial of Dabrafenib and Trametinib With Stereotactic Radiosurgery in BRAF Mutant Melanoma Brain Metastases

The purpose of this study is to test the safety and find out what effects, good and/or bad, dabrafenib (a BRAF inhibitor) alone or dabrafenib when given in combination with gamma knife radiosurgery has on participants with a certain type of skin cancer (BRAFV600E melanoma) and brain metastases (tumors that have spread to the brain).

Start Date01 Apr 2013

Sponsor / Collaborator

The University of California, San Francisco

[+1]

100 Clinical Results associated with BRAF-mutation brain cancer

100 Translational Medicine associated with BRAF-mutation brain cancer

0 Patents (Medical) associated with BRAF-mutation brain cancer

Literatures (Medical) associated with BRAF-mutation brain cancer

01 Nov 2024·Critical Reviews in Oncology/Hematology

Role of mitochondria and potential of mitochondria-targeted therapy in BRAF mutant cancer: A review

Review

Author: Zheng, Hua ; Gao, Yanyan

The classical mitogen-activated protein kinase (MAPK) signaling pathway, the Ras/Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK protein kinase cascade, is a conserved cascade that regulates cell growth, differentiation, and proliferation. The significance of BRAF in cancer was established with the discovery of cancer-activating mutations in BRAF in several human tumors in 2002. Currently, BRAF is recognized as a driver mutation that affects cancer phenotypes in different ways, making it an important therapeutic target for cancer. BRAF-selective inhibitors have shown promise in clinical trials involving patients with metastatic melanoma. However, resistance mechanisms to BRAF inhibitors therapy have resulted in short-lived therapeutic responses. Further in-depth research is imperative to explore resistance mechanisms that oppose the effectiveness of BRAF inhibitors. Metabolic reprogramming has emerging role in BRAF-mutant cancers. In particular, mitochondrial metabolism and its closely related signaling pathways mediated by mitochondria have become recognized as potential new targets for treating BRAF-mutant cancers. This review, examines the progress in understanding BRAF mutations in cancer, the clinicopathological correlation of BRAF inhibitors, and recent advances in mitochondrial metabolism, mitochondrial dynamics and mitochondrial mediated death in BRAF-mutant cancer. This review will inform future cancer research and lay the foundation for novel treatment combinations of BRAF-mutant cancers.

04 Sep 2024·Cancer Discovery

A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation

Article

Author: Gadgeel, Shirish M. ; Taylor, Matthew H. ; Rothenberg, S. Michael ; Mou, Tung-Chung ; McKean, Meredith A. ; Brown, Suzy A. ; Gaudino, John J. ; Lee, Patrice A. ; Maity, Arnab K. ; Kahn, Dean R. ; Wu, Wen-I ; Wong, Jim ; Bowles, Daniel W. ; Drescher, Stefanie K. ; Hartley, Dylan P. ; Reddy, Micaela B. ; Sturtz, Keren B. ; Singh, Anurag ; Sengupta, Bhaswati ; Mihalcioiu, Catalin ; Papadopoulos, Kyriakos P. ; Brown, Eric N. ; Feng, Gang ; Diamond, Eli L. ; Haq, Rizwan ; Rosen, Neal ; Gadal, Sunyana ; Beck, J. Thaddeus ; Baer, Brian R. ; Yaeger, Rona ; Cohen, Jonathan E.

AbstractRAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors.Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.

15 May 2024·Cancer

A phase 1 study of triple‐targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF‐mutated cancers

Article

Author: Chmielowski, Bartosz ; Lao, Christopher D ; Moon, James ; Gufford, Brandon T ; Lewis, Karl D ; Lomeli, Shirley H ; Gonzalez, Rene ; Lo, Roger S ; Othus, Megan ; Kendra, Kari L ; Ribas, Antoni ; Kim, Kevin ; Latkovic-Taber, Michaella ; Scumpia, Philip O ; Curti, Brendan D ; Godwin, John E ; Algazi, Alain P

AbstractBackgroundAberrant PI3K/AKT signaling in BRAF‐mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF‐mutated solid tumors (ClinicalTrials.gov identifier NCT01902173).MethodsPatients with BRAF V600E/V600K–mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose‐limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8‐week intervals.ResultsTwenty‐seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor‐resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib.ConclusionsConcomitant inhibition of both the MAPK and PI3K‐AKT pathways for the treatment of BRAF‐mutated cancers was well tolerated, leading to objective responses, but higher level drug‐drug interactions affected exposure to dabrafenib and its metabolites.

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