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. ^{1 2 3 4 5}

What safety information is available for the combination of CFT1946 and Trametinib in treating solid tumors?

Trametinib, often used with dabrafenib, has been studied in various cancers and is generally safe, but common side effects include fever, tiredness, nausea, and skin issues. These side effects are usually manageable with proper care. ^{6 7 8 9 10}

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. ^{3 4 5 11 12}

Research Team

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.

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.

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 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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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]

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]

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]

References

1. United States 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). [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. [2022]

3. Germany 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. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Phase I Trial of Definitive Concurrent Chemoradiotherapy and Trametinib for KRAS-Mutated Non-Small Cell Lung Cancer. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

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

6. England 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. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. [2020]

8. Switzerland 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. [2020]

9. France pubmed.ncbi.nlm.nih.gov

Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. [2022]

11. United States 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. [2022]

12. England 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. [2022]