Trametinib + Navitoclax for Advanced Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

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

Compensation: Varies

Number of Visits: 8

Duration: Up to 29 months

96 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib/II trial studies the side effects and best dose of trametinib and navitoclax and how well they work in treating patients with solid tumors that have spread to other places in the body (advanced or metastatic). Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Navitoclax inhibits members of the BCL2 family of proteins that are believed to play key roles in promoting the survival of cancer cells. It may stop the growth of cancer cells by blocking Bcl-2, Bcl-XL, and Bcl-w, proteins needed for cancer cell survival. Giving trametinib and navitoclax may help stop the growth of tumor cells.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but certain medications are prohibited. You cannot take other anti-cancer therapies, some herbal supplements, or medications that affect platelet function like warfarin and ibuprofen. It's important to discuss your current medications with the trial team to ensure they are not on the prohibited list.

What data supports the effectiveness of the drug combination of Trametinib and Navitoclax for advanced cancer?

Research shows that combining trametinib with navitoclax improved tumor response rates in non-small cell lung cancer models with KRAS mutations, achieving a 50% tumor regression rate compared to lower rates with each drug alone. ^{1 2 3 4 5}

Is the combination of Trametinib and Navitoclax safe for humans?

Trametinib, when used with other drugs like dabrafenib, has shown a tolerable safety profile with mostly mild to moderate side effects that can be managed with dose adjustments. While almost all patients experience some side effects, they are generally reversible and manageable. ^{6 7 8 9 10}

What makes the drug combination of trametinib and navitoclax unique for treating advanced cancer?

The combination of trametinib and navitoclax is unique because it targets specific vulnerabilities in cancer cells, particularly those with KRAS mutations, leading to improved tumor regression rates compared to using each drug alone. This approach is especially promising for non-small cell lung cancer, where effective treatments for KRAS mutations are still needed. ^{1 2 3 5 11}

Research Team

Ryan B. Corcoran

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with advanced or metastatic solid tumors that have a specific mutation (KRAS or NRAS) and have failed previous chemotherapy can join this trial. They must be able to take oral medication, not have significant heart disease, bleeding disorders, brain metastases, certain viral infections, or recent major surgery.

Inclusion Criteria

My heart's pumping ability is within the normal range.

I can take pills and don't have major stomach or bowel issues affecting drug absorption.

Leukocytes >= 3,000/mcL

Exclusion Criteria

Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study drug(s) and during the study

I do not have brain metastases, or if I do, they are stable and treated.

I have hepatitis B or C, but not HIV on treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trametinib and navitoclax orally once daily on days 1-28 of each 28-day cycle

Up to 29 months

CT, PET/CT, or MRI every 8 weeks; biopsy on day 15 or 22 of cycle 1; blood samples on day 1 of cycles 2, 4, 8, and 12

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

Treatment Details

Interventions

• Navitoclax
• Trametinib

Trial Overview The trial is testing the combination of two drugs: Trametinib and Navitoclax. It aims to find the best dose and see how well they work together in stopping tumor growth by blocking enzymes and proteins cancer cells need to survive.

Participant Groups

Group I: Treatment (trametinib, navitoclax) Experimental Treatment 7 Interventions

Patients receive trametinib PO QD and navitoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. If unacceptable toxicity is observed, patients may receive trametinib PO QD on days 1-14.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

In a study of 673 cancer patients, higher systemic exposure to tipifarnib was significantly associated with increased rates of severe neutropenia and thrombocytopenia, indicating that monitoring drug levels could help manage these specific toxicities.

While some nonhaematological toxicities showed weak associations with tipifarnib exposure, the overall incidence was low, suggesting that an exposure-guided dosage adjustment may not be necessary for managing these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-toxicity relationships for tipifarnib in cancer patients. Perez-Ruixo, JJ., Chen, W., Zhang, S., et al.[2018]

The combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib significantly improves outcomes for metastatic melanoma patients compared to single-agent therapies, with a manageable safety profile.

While 98% of patients experience at least one adverse event during combination therapy, these events are mostly mild to moderate and can be effectively managed, highlighting the importance of addressing even minor side effects to maintain patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Knispel, S., Zimmer, L., Kanaki, T., et al.[2017]

The combination of navicixizumab and paclitaxel demonstrated lasting effectiveness in treating patients with platinum-resistant ovarian cancer, indicating a potential new treatment strategy.

This finding suggests that navicixizumab may enhance the therapeutic impact of paclitaxel in a challenging patient population, although specific details on the number of subjects and study duration were not provided.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Navicixizumab plus Paclitaxel Shows Clinical Benefit in Platinum-Resistant Ovarian Cancer. [2022]

References

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

Rare Ovarian Cancer's First Positive Trial. [2022]

2. 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]

3. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma. [2016]

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

Vincristine Enhances the Efficacy of MEK Inhibitors in Preclinical Models of KRAS-mutant Colorectal Cancer. [2023]

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

KRT-232 and navitoclax enhance trametinib's anti-Cancer activity in non-small cell lung cancer patient-derived xenografts with KRAS mutations. [2021]

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

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. [2018]

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

A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non-Small Cell Lung Cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Exposure-toxicity relationships for tipifarnib in cancer patients. [2018]

10. England pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. [2017]

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

Navicixizumab plus Paclitaxel Shows Clinical Benefit in Platinum-Resistant Ovarian Cancer. [2022]