CFT1946 + Trametinib for Solid Tumors

No longer recruiting at 28 trial locations

Overseen By Study Medical Officer

Age: 18+

Sex: Any

Trial Phase: Phase 1

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 All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 43 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CFT1946 to assess its safety and tolerability in people with certain solid tumors. Researchers aim to determine the best dose of CFT1946 alone and in combination with other drugs like trametinib or cetuximab. Suitable candidates for this trial have solid tumors with a specific BRAF V600 mutation and have previously tried treatments, including a BRAF inhibitor. The trial seeks to assist those whose cancer has not responded to standard treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found CFT1946 to be safe and generally well-tolerated by patients, with most experiencing no serious side effects. Some research suggests that combining CFT1946 with trametinib might enhance its effectiveness, though this combination can sometimes cause skin-related side effects. Overall, evidence so far suggests that CFT1946 is safe for humans, but further research is needed for confirmation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CFT1946 because it targets the V600 mutation seen in various solid tumors, offering a potentially more precise treatment approach. Unlike standard treatments like BRAF inhibitors, CFT1946 is designed to degrade mutant proteins that drive cancer growth, potentially overcoming resistance to existing therapies. When combined with trametinib, which inhibits a different part of the cancer cell growth pathway, CFT1946 might offer a more comprehensive attack on cancer cells, increasing effectiveness and reducing chances of recurrence. This combination could provide new hope for patients whose cancers have stopped responding to conventional treatments.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that CFT1946 has potential in early studies for treating certain tumors with a specific genetic change called BRAF V600. It generally tolerated well and could break down the BRAF V600E mutation, which often promotes cancer growth. Early evidence suggests that CFT1946 can shrink tumors, indicating possible effectiveness.

In this trial, some participants will receive CFT1946 alone, while others will receive a combination of CFT1946 and trametinib, a drug targeting a related cancer pathway. This combination is being tested to determine if it works better together than separately. The goal is to find a treatment that is both safe and effective at reducing tumors in patients with these specific genetic changes. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• CFT1946
• Trametinib

Trial Overview

The 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.

How Is the Trial Designed?

Group I: Phase 2: Arm C1: CFT1946 + cetuximab Experimental Treatment 2 Interventions

Approximately 40 subjects with CRC (post BRAF inhibitor)

Group II: Phase 2: Arm B1: CFT1946 + trametinib Experimental Treatment 2 Interventions

Approximately 20 subjects with V600 melanoma or NSCLC (post BRAF Inhibitor)

Group III: Phase 2: Arm A1: CFT1946 Experimental Treatment 1 Intervention

Approximately 30 subjects with V600 melanoma or NSCLC (post BRAF inhibitor)

Group IV: Phase 1: Arm C: CFT1946 + cetuximab Experimental Treatment 2 Interventions

Approximately 30 subjects with CRC (post BRAF inhibitor)

Group V: Phase 1: Arm B: CFT1946 + trametinib Experimental Treatment 2 Interventions

Approximately 28 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma)

Group VI: Phase 1: Arm A: CFT1946 Experimental Treatment 1 Intervention

Approximately 40 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma, ATC)

Who Is Running the Clinical Trial?

C4 Therapeutics, Inc.

Lead Sponsor

Trials

3

Recruited

480+

Published Research Related to This Trial

In a phase 2 study with a minimum of 5-year follow-up, the combination of dabrafenib and trametinib showed a high overall response rate of 68.4% in pretreated patients and 63.9% in treatment-naive patients with BRAF V600E-mutant metastatic NSCLC, indicating strong efficacy.

The therapy demonstrated a manageable safety profile, with pyrexia being the most common side effect (56%), and provided substantial overall survival benefits, with median overall survival of 18.2 months for pretreated patients and 17.3 months for treatment-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. Planchard, D., Besse, B., Groen, HJM., et al.[2022]

The maximum tolerated dose (MTD) of trametinib, a MEK1/2 inhibitor, when combined with concurrent chemoradiotherapy (cCRT) for KRAS-mutated non-small cell lung cancer (NSCLC), was determined to be 1.5 mg, indicating a safe dosage for further studies.

Preliminary results showed a median progression-free survival (PFS) of 11 months and overall survival (OS) of 38 months, suggesting that this combination therapy could be effective for patients with this specific cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Definitive Concurrent Chemoradiotherapy and Trametinib for KRAS-Mutated Non-Small Cell Lung Cancer. Lin, SH., Lin, HY., Verma, V., et al.[2023]

Dabrafenib plus trametinib has been approved for treating non-small cell lung cancer (NSCLC) with the BRAF V600E mutation, showing a response rate of approximately 65% and a median progression-free survival of 10-11 months based on clinical trials.

While the combination therapy has a manageable safety profile, it presents unique toxicities such as pyrexia, fatigue, and nausea, which may be unfamiliar to oncologists treating lung cancer, but can be effectively managed using strategies developed from experience in melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. Chalmers, A., Cannon, L., Akerley, W.[2020]

In a clinical trial involving 57 pretreated NSCLC patients, the combination of dabrafenib and trametinib showed a high overall response rate (ORR) of 68.4% and a median overall survival (OS) of 18.2 months, indicating its efficacy in treating BRAF V600E mutant non-small cell lung cancer.

The treatment was well tolerated, with manageable side effects such as pyrexia and nausea, leading to its approval for BRAF V600E metastatic NSCLC patients, regardless of prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. Sforza, V., Palumbo, G., Cascetta, P., et al.[2022]

In a study involving 32 patients with solid tumors and lymphomas harboring non-V600 BRAF mutations, the MEK inhibitor trametinib showed limited efficacy, with only 1 patient (3%) achieving a partial response and a clinical benefit rate of 34%.

The median progression-free survival was 1.8 months and overall survival was 5.7 months, indicating that trametinib did not meet its primary endpoint of demonstrating significant clinical activity in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131). Johnson, DB., Zhao, F., Noel, M., et al.[2023]

Dabrafenib and trametinib have been approved for treating metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutations, showing an overall response rate of 63% in previously treated patients and 61% in treatment-naïve patients, indicating their efficacy in this specific cancer subset.

The combination of dabrafenib and trametinib is necessary to achieve a response rate greater than 40%, highlighting the importance of using both drugs together for optimal treatment outcomes, while common side effects include fatigue, nausea, and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations. Odogwu, L., Mathieu, L., Blumenthal, G., et al.[2019]

In a study of 34 patients with metastatic melanoma treated with dabrafenib and trametinib, high plasma concentrations of dabrafenib showed only a weak association with progression-free survival, indicating that monitoring these levels may not effectively predict treatment response.

No significant relationship was found between plasma concentrations of dabrafenib and trametinib and the occurrence of common adverse events, suggesting that these measurements may not be useful for assessing safety in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients. Raynal, M., Alvarez, JC., Saiag, P., et al.[2022]

In a study of 36 patients with BRAF V600E-mutant anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a significant overall response rate of 56%, with three patients achieving complete responses.

The treatment demonstrated manageable safety, with no new adverse effects identified, and improved median progression-free survival of 6.7 months and overall survival of 14.5 months, indicating it is a promising option for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

In a real-world study of 40 patients with BRAF V600E-mutant metastatic non-small-cell lung cancer, the combination of dabrafenib and trametinib showed a median progression-free survival of 17.5 months and overall survival of 25.5 months, indicating effective treatment outcomes.

The safety profile was manageable, with 18% of patients experiencing adverse events that required permanent discontinuation of treatment, while 20% had treatment interruptions and 30% had dose reductions, suggesting that while effective, careful monitoring is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Dabrafenib Plus Trametinib Combination in Patients with BRAF V600E-Mutant NSCLC in Real-World Setting: GFPC 01-2019. Auliac, JB., Bayle, S., Do, P., et al.[2020]

The combination of trametinib and afuresertib was poorly tolerated at the starting dose, leading to dose-limiting toxicities, but an intermittent dosing schedule showed better tolerability, suggesting a potential for safer administration.

Among 20 patients with advanced solid tumors, the study reported one partial response and four cases of stable disease, indicating some efficacy, but the overall response rate was low, warranting further investigation into alternative dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Tolcher, AW., Patnaik, A., Papadopoulos, KP., et al.[2015]

The FDA approved the dabrafenib/trametinib combination as a tissue-agnostic treatment for solid tumors with the BRAF V600E mutation, based on over 20 years of research and clinical testing, highlighting its efficacy across various cancer types.

Clinical trials have shown good response rates for this combination in multiple malignancies, including melanoma and lung cancer, making it a significant advancement in cancer treatment for both adults and children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanding the Benefit: Dabrafenib/Trametinib as Tissue-Agnostic Therapy for BRAF V600E-Positive Adult and Pediatric Solid Tumors. Gouda, MA., Subbiah, V.[2023]

In a phase II trial involving 16 patients with BRAF V600E-mutated anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a high overall response rate of 69%, indicating significant efficacy in a cancer type with previously limited treatment options.

The treatment was well tolerated, with common side effects including fatigue, fever, and nausea, and no new safety concerns were identified, marking a promising advancement for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

Citations

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ir.c4therapeutics.com

ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-presents-monotherapy-data-demonstrating-proof

Release Details

CFT1946 is an investigational, orally bioavailable small molecule degrader of BRAF V600 mutations in solid tumors currently being evaluated in a Phase 1/2 ...

2.

annalsofoncology.org

annalsofoncology.org/article/S0923-7534(24)02198-7/fulltext

612O Preliminary results from a phase I study of CFT1946, ...

CFT1946 was well tolerated with evidence of BRAF V600E degradation and relevant pathway inhibition. Early evidence of monotherapy efficacy was observed; further ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT05668585

NCT05668585 | A Study to Characterize the Safety, ...

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 ...

4.

ir.c4therapeutics.com

ir.c4therapeutics.com/static-files/b648e3ae-c2db-4f5e-9d47-324b0c8a2b2b

Phase 1 CFT1946 Monotherapy Clinical Data

Our actual results could vary significantly from those anticipated in this presentation, and our financial condition and results of operations ...

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clin.larvol.com

clin.larvol.com/trial-detail/NCT05668585

CFT1946-1101 / NCT05668585

A study to characterize the safety, tolerability, and preliminary efficacy of CFT1946 as monotherapy and combination therapy in subjects with BRAF V600 mutant ...

6.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS3163

A phase 1/2 study of CFT1946, a novel, bifunctional ...

These preclinical data provide rationale for a first-in-human (FIH) study to evaluate CFT1946 in BRAF V600 mutant solid tumors. Methods ...