Clinical Trials /

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

NCT03170206

Description:

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

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: Phase I/II 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

Clinical Trial IDs

  • ORG STUDY ID: 16-531
  • NCT ID: NCT03170206

Conditions

  • Lung Cancer

Interventions

DrugSynonymsArms
BinimetinibMEK162Binimetinib Combine with Palbociclib Phase 1
PalbociclibIBRANCEBinimetinib Combine with Palbociclib Phase 1

Purpose

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/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.
    

Trial Arms

NameTypeDescriptionInterventions
Binimetinib Combine with Palbociclib Phase 1ExperimentalPalbociclib 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
  • Palbociclib
Binimetinib Combine with Palbociclib Phase 2ExperimentalPalbociclib 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
  • Palbociclib
Binimetinib Phase 2ExperimentalBinimetinib will be administered orally twice daily Patients will be dosed with Binimetinib continuously through the four weeks per cycle
  • Binimetinib
Palbociclib Phase 2ExperimentalPalbociclib will be administered orally once daily Patients will be dosed with palbociclib for three weeks out of every four weeks per cycle
  • Palbociclib

Eligibility Criteria

        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 known. For this reason, women of child-bearing potential and men must agree to
             use adequate contraception (combination hormonal and barrier method of birth control;
             abstinence) prior to study entry, for the duration of study participation, and for 90
             days after discontinuation. Should a woman become pregnant or suspect she is pregnant
             while participating in this study, she should inform her treating physician
             immediately.

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

          -  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.

          -  Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments
             (excluding neuropathy which can be ≤ Grade 2, and alopecia).

          -  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.

          -  Patients must be able to take oral medications.

          -  Patients must have adequate cardiac function, defined as:

               -  Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram
                  or multigated acquisition scan (MUGA).

               -  QTc < 480 msec.

        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 QT syndrome, Brugada syndrome, known history of QTc prolongation, or
             Torsades de Pointes.

          -  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).

          -  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 1. Subjects with localized prostate cancer that has been treated with curative
             intent will be allowed

          -  Patients planning to embark on a new strenuous exercise regimen after the first dose
             of study treatment.

          -  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.

          -  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.

          -  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.

          -  Patients with known active hepatitis B and/or active hepatitis C infection.

          -  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.).

          -  History of retinal degenerative disease.

          -  Presence of neurosensory retinal detachment, retinal vein occlusion (RVO), or
             neovascular macular degeneration on screening ophthalmologic exam.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:2 years
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Pharmacokinetics
Time Frame:15 days
Safety Issue:
Description:The pharmacokinetic properties-Cmax maximum plasma concentration for the combination of palbociclib and PD-0325901 will be evaluated utilizing serial blood draws on cycle 1 day 1 and a steady state trough level drawn on cycle 1 day 15.
Measure:Target engagement of palbociclib and binimetinib
Time Frame:2 years
Safety Issue:
Description:Confirm target engagement of palbociclib and binimetinib in pre- and on-treatment tumor biopsies from patients enrolled to an MTD expansion cohort.
Measure:Objective Response
Time Frame:2 years
Safety Issue:
Description:Determine the best objective response rate, as determined by RECIST 1.1, of the combination of palbociclib and binimetinib, palbociclib alone and binimetinib alone in patients with advanced KRAS mutant NSCLC.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Lung Cancer

Last Updated

May 25, 2017