CDK4/6 + MEK Inhibitors for Lung Cancer

Recruiting at 1 trial location

Overseen By Geoffrey Shapiro, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A4 inhibitors/inducers, PPIs

Disqualifiers: Symptomatic brain metastases, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks per cycle

34 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is being conducted as a possible treatment for lung cancer with a specific change in the KRAS gene. The drugs involved in this study are: * Palbociclib * Binimetinib

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use strong CYP3A4 inhibitors/inducers or proton-pump inhibitors (PPIs) during certain parts of the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What evidence supports the effectiveness of the drug combination of CDK4/6 and MEK inhibitors for lung cancer?

Research shows that combining CDK4/6 inhibitors like palbociclib with MEK inhibitors can delay resistance in certain lung cancer models, suggesting this combination might be more effective than using either drug alone. This approach has been effective in other cancers, like melanoma, where it helps prevent resistance and improve outcomes. ^{1 2 3 4 5}

How is the drug combination of Binimetinib and Palbociclib unique for lung cancer treatment?

The combination of Binimetinib and Palbociclib is unique for lung cancer treatment because it targets both the CDK4/6 and MEK pathways, which are involved in cell cycle regulation and growth signaling. This dual approach may help overcome resistance that develops with CDK4/6 inhibitors alone, offering a novel strategy for treating KRAS-mutant non-small cell lung cancer. ^{2 5 6 7 8}

Research Team

Geoffrey I. Shapiro

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults with advanced non-small cell lung cancer that has a KRAS gene mutation. They must have measurable disease, be in good physical condition (ECOG < 2), and have normal organ/marrow function. Prior treatments are allowed if recovered from their effects. Participants need to agree to use contraception, undergo tumor biopsies, take oral meds, and have adequate heart function.

Inclusion Criteria

I have a tumor that can be measured with a scan.

You must have a measurable disease according to specific guidelines within 4 weeks of joining the study.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I have a history of eye diseases that cause vision loss.

I have been diagnosed with a specific eye condition after an eye exam.

I am not currently taking any proton-pump inhibitors.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Palbociclib and Binimetinib to determine a safe and tolerable dose

4 weeks per cycle

Weekly visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

Long-term Follow-up

Participants are monitored for progression-free survival and objective response

2 years

Treatment Details

Interventions

• Binimetinib
• Palbociclib

Trial Overview The study tests the combination of two drugs: Palbociclib and Binimetinib as a treatment for lung cancer with KRAS mutations. It aims to see how well these drugs work together against this specific type of cancer.

Participant Groups

Group I: Binimetinib Combine with Palbociclib Phase 1 Experimental Treatment 2 Interventions

* Palbociclib will be administered orally once daily * Patients will be dosed with palbociclib for three weeks out of every four weeks per cycle * Binimetinib will be administered orally twice daily * Patients will be dosed with Binimetinib continuously through the four weeks per cycle

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Array BioPharma

Industry Sponsor

Trials

29

Recruited

1,400+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

The phase I study found that the MEK inhibitor binimetinib, when combined with carboplatin and pemetrexed, has a recommended phase II dose of 30 mg BID and shows manageable toxicity, with 61.5% of patients experiencing grade 3/4 adverse events.

The treatment demonstrated promising efficacy, with a 50% objective response rate and an 83.3% disease control rate in patients with advanced non-squamous NSCLC, particularly in those with KRAS/NRAS mutations, who had a higher response rate of 62.5%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer. Fung, AS., Graham, DM., Chen, EX., et al.[2021]

In a phase II trial involving 162 patients with early HR+/HER2- breast cancer, adjuvant palbociclib combined with endocrine therapy was found to be feasible, with 63% of patients completing the full 2-year treatment course.

The safety profile of palbociclib in this early treatment setting was consistent with its use in metastatic cases, showing manageable toxicity and no cases of febrile neutropenia, although about 56% of patients required dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma. Mayer, EL., DeMichele, A., Rugo, HS., et al.[2023]

Palbociclib, the first oral CDK4/6 inhibitor, significantly improves median progression-free survival in advanced ER-positive/HER2-negative breast cancer, showing 24.8 months with letrozole compared to 14.5 months with placebo, and 9.2 months with fulvestrant compared to 3.8 months with placebo.

The main side effect of palbociclib is neutropenia, which can be managed through dose adjustments, resulting in a favorable safety profile and delayed deterioration of quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib-The First of a New Class of Cell Cycle Inhibitors. Schmidt, M., Sebastian, M.[2018]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer. [2021]

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

Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway in KRAS-mutant non-small cell lung cancer. [2019]

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

Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS-mutant lung cancer. [2022]

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

Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Targeting CDK4/6 in patients with cancer. [2022]

6. England pubmed.ncbi.nlm.nih.gov

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Palbociclib-The First of a New Class of Cell Cycle Inhibitors. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors. [2023]