Trametinib + Navitoclax for Advanced Cancer

Not currently recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, Herbal supplements

Disqualifiers: Other malignancy, Lung disease, Cardiovascular, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, trametinib (Mekinist) and navitoclax, to determine the best dose and assess their ability to stop the growth of advanced cancers that have spread. Trametinib blocks enzymes that help tumor cells grow, while navitoclax targets proteins that keep cancer cells alive. This trial may suit individuals with specific mutations in their cancer, whose cancer has spread and no longer responds to standard treatments. Participants should have already tried chemotherapy that was ineffective or caused severe side effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

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.

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

Research has shown that trametinib and navitoclax are usually well-tolerated, though they can cause some side effects. In earlier studies, participants reported fatigue, low blood counts, and nausea while taking these drugs. However, most found these side effects manageable and not major issues.

Trametinib has FDA approval for other uses, providing extensive safety information. Navitoclax has been tested with trametinib, and research indicates that while some experienced side effects, they were not severe for most participants.

For those considering a trial with these drugs, it's important to know that side effects can occur but are often manageable. Discuss any concerns with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of trametinib and navitoclax for advanced cancer because it targets cancer cells in a unique way. Unlike most treatments that only inhibit one pathway, this duo targets both the MEK and BCL-2/BCL-XL pathways, which are crucial for cancer cell survival and proliferation. Trametinib inhibits MEK, a part of the pathway that helps cancer cells grow, while navitoclax disrupts proteins that prevent cell death. This dual action approach could potentially overcome resistance seen with other treatments and offer a more effective option for patients with advanced cancers.

What evidence suggests that trametinib and navitoclax might be effective treatments for advanced cancer?

Research has shown that using trametinib and navitoclax together might help treat advanced solid tumors. Navitoclax targets proteins that help cancer cells survive, while trametinib blocks enzymes necessary for cancer cell growth. In one study, patients who received a similar treatment experienced an average tumor reduction of 68.8%. This trial will evaluate the combination of trametinib and navitoclax, which could significantly reduce tumors in individuals with certain advanced cancers. These encouraging results highlight the potential of this treatment combination for managing hard-to-treat cancers. ^{1 4 5 6 7}

Who Is on the Research Team?

Ryan B. Corcoran

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11061595/

Phase I/II Study of Combined BCL-xL and MEK Inhibition ... This research study is a phase IB clinical trial to test the safety and efficacy of navitoclax in combination with trametinib in patients with KRAS- or NRAS- ...

2. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)02687-X/fulltext

664P Final results of a phase I/II study of combined BCL-xL ... 664P Final results of a phase I/II study of combined BCL-xL and MEK inhibition with navitoclax and trametinib in KRAS or NRAS mutant advanced solid tumors.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01989585

NCT01989585 | Testing the Addition of Navitoclax to ... Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Navitoclax is in a class of ...

4. onclive.com onclive.com/view/addition-of-navitoclax-to-dabrafenib-trametinib-aims-to-improve-efficacy-of-targeted-therapy-in-braf-metastatic-melanoma

Addition of Navitoclax to Dabrafenib/Trametinib Aims ... Patients treated with dabrafenib plus trametinib and navitoclax, experienced a median maximal tumor decrease of –68.8% (min, –2.1%; max, –100%) ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-3135/735095/am/Phase-1-2-study-of-combined-BCL-xL-and-MEK

Phase 1/2 study of combined BCL-xL and MEK inhibition with ... Data from Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02079740

Study Details | NCT02079740 | Trametinib and Navitoclax ... 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.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9511

Randomized phase II trial of dabrafenib and trametinib with ... In pts with BRAF MT MM, DTN was associated with a CR rate of 20% and ORR of 84%. There was a trend for improved OS in pts treated with DTN compared to DT.