CFT1946 + Trametinib for Solid Tumors
Recruiting in Palo Alto (17 mi)
+26 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: C4 Therapeutics, Inc.
Must be taking: BRAF inhibitors
Must not be taking: CYP3A4/5 inhibitors
Disqualifiers: CNS involvement, Cardiac disease, Diabetes, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
The purpose of this study is to evaluate the safety and tolerability of CFT1946 as well as to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of CFT1946 as monotherapy (Arm A) and in combination with trametinib (CFT1946 + trametinib; Arm B) or Cetuximab (CFT1946 + cetuximab; Arm C).
Do I need to stop my current medications to join the trial?
The trial does not specify if you need to stop taking your current medications, but it does exclude those taking strong CYP3A4/5 inhibitors and inducers, including herbal medications. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug combination CFT1946 and Trametinib for solid tumors?
Research shows that trametinib, when combined with other drugs like dabrafenib, has been effective in treating various solid tumors with specific mutations, such as BRAF V600E. This combination has shown good response rates in different cancers, suggesting potential effectiveness for similar treatments.12345
What safety information is available for the combination of CFT1946 and Trametinib in treating solid tumors?
How is the drug CFT1946 + Trametinib different from other treatments for solid tumors?
CFT1946 + Trametinib is unique because it combines a novel drug, CFT1946, with trametinib, a MEK inhibitor, to target solid tumors. This combination may offer a new approach by potentially enhancing the effectiveness of trametinib, which is already used in various cancers with specific mutations.3451112
Eligibility Criteria
Adults with BRAF V600 mutant solid tumors who've had at least one prior treatment can join. They must be able to swallow pills, have good performance status and organ function, and agree to contraception rules. Excluded are those with certain other cancers, recent major surgery, CNS metastases unless stable, uncontrolled diabetes (for combination therapy), live vaccines recently, hepatitis B/C or HIV infections, recent serious cardiovascular events, eye disease risks (for combination therapy), lung conditions like pneumonitis or interstitial lung disease.Inclusion Criteria
I agree to follow the study's rules about using contraception and not donating sperm or blood.
My heart, liver, kidneys, and bone marrow are functioning well.
I can safely swallow pills.
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Exclusion Criteria
I am not taking strong CYP3A4/5 inhibitors or inducers, including herbal supplements.
I have side effects from cancer treatment, but not hair loss or treatable thyroid issues.
I have not had major surgery in the last 3 weeks.
See 13 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive CFT1946 as monotherapy or in combination with trametinib or cetuximab to determine the maximum tolerated dose and recommended Phase 2 dose
Up to 43 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 30 days after completion of study treatment
Pharmacokinetics Assessment
Plasma concentration of CFT1946 is measured to characterize pharmacokinetics parameters
Up to 20 weeks
Treatment Details
Interventions
- CFT1946 (CAR T-cell Therapy)
- Trametinib (MAPK/ERK Kinase (MEK) Inhibitor)
Trial OverviewThe trial is testing CFT1946 alone (Arm A) and combined with trametinib (Arm B) in patients with specific types of cancer including melanoma and lung cancer. It aims to find the safest maximum dose for future phases of research by monitoring participants' reactions.
Participant Groups
6Treatment groups
Experimental Treatment
Group I: Phase 2: Arm C1: CFT1946 + cetuximabExperimental Treatment2 Interventions
Approximately 40 subjects with CRC (post BRAF inhibitor)
Group II: Phase 2: Arm B1: CFT1946 + trametinibExperimental Treatment2 Interventions
Approximately 20 subjects with V600 melanoma or NSCLC (post BRAF Inhibitor)
Group III: Phase 2: Arm A1: CFT1946Experimental Treatment1 Intervention
Approximately 30 subjects with V600 melanoma or NSCLC (post BRAF inhibitor)
Group IV: Phase 1: Arm C: CFT1946 + cetuximabExperimental Treatment2 Interventions
Approximately 30 subjects with CRC (post BRAF inhibitor)
Group V: Phase 1: Arm B: CFT1946 + trametinibExperimental Treatment2 Interventions
Approximately 28 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma)
Group VI: Phase 1: Arm A: CFT1946Experimental Treatment1 Intervention
Approximately 40 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma, ATC)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Arizona - Cancer CenterTucson, AZ
Community Health NetworkIndianapolis, IN
Allina Health System DBA Virginia Piper Cancer InstituteMinneapolis, MN
Washington University School of MedicineSt. Louis, MO
More Trial Locations
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Who Is Running the Clinical Trial?
C4 Therapeutics, Inc.Lead Sponsor
References
Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131). [2023]Label="PURPOSE">Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with BRAF mutations outside the V600 locus, and in BRAF fusions. Thus, Subprotocol R of the NCI-MATCH study tested the MEK inhibitor trametinib in this population.
BRAF Inhibitors in Non-Small Cell Lung Cancer. [2022]RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.
Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. [2015]To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib.
Phase I Trial of Definitive Concurrent Chemoradiotherapy and Trametinib for KRAS-Mutated Non-Small Cell Lung Cancer. [2023]This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC).
Expanding the Benefit: Dabrafenib/Trametinib as Tissue-Agnostic Therapy for BRAF V600E-Positive Adult and Pediatric Solid Tumors. [2023]The recent US Food and Drug Administration (FDA) approval of the dabrafenib/trametinib combination as a tissue-agnostic treatment for solid tumors with BRAF V600E mutation is the result of more than 20 years of extensive research into BRAF mutations in human cancer, the underlying biological mechanisms that drive BRAF-mediated tumor growth, and the clinical testing and refinement of selective RAF and MEK kinase inhibitors. Such approval marks a significant achievement in the field of oncology and represents a major step forward in our ability to treat cancer. Early evidence supported the use of dabrafenib/trametinib combination in melanoma, non-small-cell lung cancer, and anaplastic thyroid cancer. Furthermore, data from basket trials have demonstrated consistently good response rates in various tumors, including biliary tract cancer, low-grade glioma, high-grade glioma, hairy cell leukemia, and multiple other malignancies, which has been the basis for FDA approval of a tissue-agnostic indication in adult and pediatric patients with BRAF V600E-positive solid tumors. From a clinical standpoint, our review delves into the efficacy of the dabrafenib/trametinib combination for BRAF V600E-positive tumors: examining the underlying rationale for its use, evaluating the latest evidence on its potential benefits, and discussing the possible associated adverse effects and strategies to minimize their impact. Additionally, we explore potential resistance mechanisms and future landscape of BRAF-targeted therapies.
FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations. [2019]On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open-label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B, n = 57) or were treatment-naïve (Cohort C, n = 36). All patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily. In Cohort B, overall response rate (ORR) was 63% (95% confidence interval [CI] 49%-76%) with response durations ≥6 months in 64% of responders. In Cohort C, ORR was 61% (95% CI 44%-77%) with response durations ≥6 months in 59% of responders. Results were evaluated in the context of the Intergroupe Francophone de Cancérologie Thoracique registry and a chart review of U.S. electronic health records at two academic sites, characterizing treatment outcomes data for patients with metastatic NSCLC with or without BRAF V600E mutations. The treatment effect of dabrafenib 150 mg twice daily was evaluated in 78 patients with previously treated BRAF mutant NSCLC, yielding an ORR of 27% (95% CI 18%-38%), establishing that dabrafenib alone is active, but that the addition of trametinib is necessary to achieve an ORR of >40%. The most common adverse reactions (≥20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.
Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. [2020]Therapies for advanced non-small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600-mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression-free survival of 10-11 months. BRAF mutations are a high-frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical-trial and real-world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. IMPLICATIONS FOR PRACTICE: The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E-mutant non-small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.
Efficacy of Dabrafenib Plus Trametinib Combination in Patients with BRAF V600E-Mutant NSCLC in Real-World Setting: GFPC 01-2019. [2020]Dabrafenib plus trametinib combination is approved in Europe for BRAF V600E-mutant metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to assess efficacy and safety of this combination in a real-world setting. This retrospective multicentric study included 40 patients with advanced NSCLC harboring BRAF V600E mutation and receiving dabrafenib plus trametinib. The median progression-free survival (PFS) and overall survival (OS) were 17.5 (95% CI 7.1-23.0) months and 25.5 (95% CI 16.6-not reached) months in the entire cohort, respectively. For the 9 patients with first-line treatment, median PFS was 16.8 (95% CI 6.1-23.2) months and median OS was 21.8 (95% CI 1.0-not reached) months; for the 31 patients with second-line or more treatments, median PFS and OS were 16.8 (95% CI 6.1-23.2) months and 25.5 (95% CI 16.6-not reached) months, respectively. Adverse events led to permanent discontinuation in 7 (18%) patients, treatment interruption in 8 (20%) and dose reduction in 12 (30%). In conclusion, these results suggest that efficacy and safety of dabrafenib plus trametinib combination in patients with BRAF V600E metastatic NSCLC are comparable in a real-world setting and in clinical trials for both previously untreated and treated patients.
Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE.
Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. [2022]Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.
Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. [2022]Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.
Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. [2022]Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.