Phase I Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the MEK Inhibitor Binimetinib (MEK162) for Patients With Advanced KRAS Mutant Non-Small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 34
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose
Overview
Brief Summary
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
Detailed Description
This research study is a Phase I clinical trial. Participants are being asked to participate in the Phase I portion of the study. A Phase I clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.
Palbociclib is an oral drug which has been shown to stop the cell cycle, which is the way a cell initiates growth. Binimetinib is also an oral drug which stops a signal that a cell receives, instructing it to grow. By putting these two drugs together the investigators hope that it will have a greater affect on cancer growth than either drug alone. The FDA (the U.S. Food and Drug Administration) has not approved binimetinib as a treatment for any disease. The FDA has not approved palbociclib for use in lung cancer but it has been approved for other cancer types.
The purpose of this study is to:
- Test the combination of these two drugs, Palbociclib and Binimetinib, in order to determine a safe and tolerable dose of the combination
- Determine the response rate of the combination
- Further evaluate the safety and side effect profile for the combination of palbociclib and binimetinib.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants must have histologically confirmed advanced NSCLC (with a confirmed KRAS mutation via any CLIA-certified method) for which curable treatment modalities are not an option
- •Part I Dose Escalation: Participants are required to have measurable disease per RECIST 1.1 within 4 weeks of study entry
- •MTD Expansion and Part II: Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 20 mm with conventional techniques or as \> 10 mm with spiral CT scan. See section 10 for the evaluation of measureable disease.
- •Age ≥ 18 years. Because no dosing or adverse event data are currently available in participants \< 18 years of age, children are excluded from this study
- •Participants are permitted to have any number of prior therapies prior to enrollment
- •ECOG performance status \< 2 (see Appendix A).
- •Participants must have normal organ and marrow function as defined below:
- •Absolute neutrophil count \> 1,500mm3
- •Hemoglobin \> 9 g/dL
- •Platelets \> 100,000/mcL
Exclusion Criteria
- •Participants who have had chemotherapy, radiotherapy, or major surgery within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
- •Participants receiving any other study agents concurrently with the study drugs.
- •Participants with symptomatic brain metastases that require chronic steroids. Patients with a history of brain metastases are permitted to enroll as long as they have been treated, are off of steroids, and have been stable for a minimum of one month on imaging.
- •MTD Expansion: Patients currently taking anticoagulants and who cannot safely hold the medication to facilitate pre and on-treatment tumor biopsies are excluded from participation.
- •Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used with caution (see Appendix C).
- •Part I Dose Escalation: Concurrent use of proton-pump inhibitors (PPIs) is prohibited.
- •Uncontrolled intercurrent illness including, but not limited to:
- •ongoing or active infection requiring systemic treatment
- •symptomatic congestive heart failure
- •cardiac arrhythmia
Arms & Interventions
Binimetinib Combine with Palbociclib Phase 1
- 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
Intervention: Binimetinib (Drug)
Binimetinib Combine with Palbociclib Phase 1
- 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
Intervention: Palbociclib (Drug)
Outcomes
Primary Outcomes
Maximum Tolerated Dose
Time Frame: 2 years
A standard 3+3 design will be implemented to discover the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of study drugs. A dose will be declared the MTD if zero or 1 patient out of 6 experience a dose limiting toxicity (DLT) at the highest dose level below the maximally administered dose. This is generally the Recommended Phase 2 dose- RP2D
Safety and tolerability of Palbocilib and Binimetinib
Time Frame: 2 Years
Toxicities will be graded using version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE).
progression free survival
Time Frame: 4 months
Determine the proportion of patients who are alive and progression-free at 4 months in the binimetinib, palbociclib and combination arms.
Secondary Outcomes
- Objective Response(2 years)
- Target engagement of palbociclib and binimetinib(2 years)
- Pharmacokinetic parameters of palbociclib and binimetinib(15 days)
Investigators
Geoffrey Shapiro, MD, PhD
MD, PhD
Dana-Farber Cancer Institute