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

  • STATUS
    Recruiting
  • End date
    Mar 31, 2024
  • participants needed
    72
  • sponsor
    Dana-Farber Cancer Institute
Updated on 23 March 2022
ct scan
cancer
total bilirubin
absolute neutrophil count
measurable disease
lung cancer
KRAS
metastasis
neutrophil count
liver metastasis
spiral computed tomography
alopecia
lung carcinoma

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

Description

This research study is a Phase I/II 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.

Details
Condition Lung Cancer
Treatment Palbociclib, Binimetinib
Clinical Study IdentifierNCT03170206
SponsorDana-Farber Cancer Institute
Last Modified on23 March 2022

Eligibility

Yes No Not Sure

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
Total bilirubin < 2 X institutional upper limit of normal (ULN)
AST (SGOT)/ALT (SGPT) < 2.5 X ULN -OR-
AST (SGOT)/ALT (SGPT) < 5.0 X ULN if hepatic metastases are present
Creatinine < 1.5 X the institutional ULN -OR-
Calculated creatinine clearance (determined as per Cockcroft-Gault) > 50 mL/min
The effects of palbociclib and binimetinib on the developing human fetus are not fully
Ability to understand and the willingness to sign a written informed consent document
known. For this reason, women of child-bearing potential and men must agree to
use adequate contraception (combination hormonal and barrier method of birth
The availability of archival tissue to evaluate retrospectively the participant's Rb status. The requirement is a minimum of 5 unstained slides with each tissue cut measuring 4 microns in width. Ideally 15 slides will be requested. Patients without available archival tissue may be enrolled at the discretion of the principal investigator
control; abstinence) prior to study entry, for the duration of study
participation, and for 90 days after discontinuation. Should a woman become
MTD Expansion: Patients must be willing to undergo pre- and on-treatment tumor biopsies. Patients are exempt from this requirement if, in the opinion of the investigator, the biopsy procedure would pose a significant risk or if they have only pulmonary metastatic disease
pregnant or suspect she is pregnant while participating in this study, she
Patients must be able to take oral medications
Patients must have adequate cardiac function, defined as
should inform her treating physician immediately
Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram or multigated acquisition scan (MUGA)
QTc < 480 msec
Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments (excluding neuropathy which can be ≤ Grade 2, and alopecia)

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
psychiatric illness/social situations that would limit compliance with study requirements
hypertension, defined as systolic blood pressure > 160 mmHg despite medical management
myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting < 6 months prior to screening
History of Gilbert's syndrome
History of neuromuscular disorders that are associated with elevated CK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
Subjects with localized prostate cancer that has been treated with curative intent will be allowed
History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or
History of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the investigator
Torsades de Pointes
Pregnant women are excluded from this study because the study agents have the potential for teratogenic or abortifacient effects. As there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding must be discontinued if the mother is treated
Part II: Individuals with a history of a different malignancy are ineligible except for the following circumstances
They have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy
Individuals with the following cancers are eligible if diagnosed and curatively treated within the past 5 years: cervical cancer in situ, and basal or squamous cell carcinoma of the skin
History of other malignancy which could affect compliance with the protocol or interpretation of results. History of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are allowed. Subjects with a malignancy that has been treated with curative intent will also be allowed if the malignancy has been in remission without treatment for ≥ 2 years prior to Cycle 1, Day
Patients with known active hepatitis B and/or active hepatitis C infection
Patients planning to embark on a new strenuous exercise regimen after the first dose
Evidence of visible retinal pathology on screening ophthalmologic examination that places the participant at an unacceptable risk for retinal vein occlusion (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity, etc.)
of study treatment
History of retinal degenerative disease
Presence of neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration on screening ophthalmologic exam
Known HIV-positive individuals on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions. Appropriate studies
will be undertaken in participants receiving combination antiretroviral
therapy when indicated
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