Clinical Trials /

PALBOCICLIB + PD-0325901 for NSCLC & Solid Tumors

NCT02022982

Description:

This research study is evaluating the experimental drug palbociclib in combination with another experimental drug PD-0325901 as a possible treatment for cancers with KRAS mutations, particularly for those which started in the lung.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PALBOCICLIB + PD-0325901 for NSCLC & Solid Tumors
  • Official Title: Phase I/II Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the MEK Inhibitor PD-0325901 for Patients With KRAS Mutant Non-Small Cell Lung Cancer and Other Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 13-506
  • NCT ID: NCT02022982

Conditions

  • KRAS Mutant Non-Small Cell Lung Cancer
  • Solid Tumors

Interventions

DrugSynonymsArms
PalbociclibPD 0332991-00Palbociclib and PD-0325901
PD-0325901PD-0325901-0000, PF-00192513-00Palbociclib and PD-0325901

Purpose

This research study is evaluating the experimental drug palbociclib in combination with another experimental drug PD-0325901 as a possible treatment for cancers with KRAS mutations, particularly for those which started in the lung.

Detailed Description

      This will be an open label Phase I/II dose escalation study evaluating the combination of the
      CDK4/6 inhibitor palbociclib (PD-0332991) and the MEK inhibitor PD-0325901. To determine the
      maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D), a 3+3 dose escalation
      protocol will be undertaken. Once the RP2D has been determined, the study will then evaluate,
      in a randomized phase II study design, the combination of palbociclib and PD-0325901 compared
      to PD-0325901 alone and palbociclib alone in KRAS mutant NSCLC.

        -  Phase 1: The investigators are looking for the highest dose of the study drug that can
           be administered safely without severe or unmanageable side effects in participants that
           have cancer, not everyone who participates in this research study will receive the same
           dose of the study drug. The dose the participant receives will depend on the number of
           participants who have been enrolled in the study before and how well the dose has been
           tolerated.

        -  Study Drug(s): The participant will be given a study drug-dosing calendar for each
           treatment cycle. Each treatment cycle lasts 4 weeks during which time you will be taking
           the study drug for 3 weeks at a time. The participant will take Palbociclib by mouth
           once a day, every day for 3 weeks. The participant will take PD-0325901 by mouth twice a
           day, every day for 3 weeks.

        -  Clinical Exams: During all cycles the participant will have a physical exam and will be
           asked questions about general health and specific questions about any problems that they
           might be having and any medications they may be taking.

        -  Scans (or Imaging tests): The investigators will assess the participant's tumor by
           either a CT scan or MRI

        -  Blood Tests: These are special tests to check the amount of drug and the amount of tumor
           DNA in the participant's blood at specific points in time.

      Phase II Outcomes:

        -  Determine the response rate, as determined by RECIST 1.1, of the combination of
           palbociclib and PD-0325901 to that of palbociclib or PD-0325901 as single agents in
           patients with advanced KRAS mutant NSCLC

        -  Further evaluate the safety, tolerability and side effect profile for the combination of
           palbociclib and PD-0325901 Phase II Secondary Outcomes

        -  Determine the rate of progression free survival ≥ 4 months and the median PFS for the
           combination of palbociclib and PD-0325901 compared to palbociclib or PD-0325901 as
           single agents in KRAS mutant NSCLC
    

Trial Arms

NameTypeDescriptionInterventions
Palbociclib and PD-0325901ExperimentalPalbociclib by mouth once a day, every day for 3 weeks every 4 in each cycle. PD-0325901 by mouth twice a day, every day for 3 weeks every 4 in each cycle. .
  • Palbociclib
  • PD-0325901

Eligibility Criteria

        Inclusion Criteria:

          -  Dose-escalation/MTD cohorts, participants must have histologically confirmed
             malignancy with a RAS mutation that is metastatic or unresectable and for which
             standard curative or palliative measures do not exist or are no longer effective. For
             the randomized phase 2 component of the study, participants must have histologically
             confirmed NSCLC with a confirmed KRAS mutation (via any CLIA-certified method)

          -  For the dose-escalation component, participants are required to have only evaluable
             disease. For the MTD cohort and phase 2 component of the study, participants must have
             measurable disease.

          -  Participants enrolled to the MTD cohort must agree to pre and on-treatment tumor
             biopsies if assessable disease is identified.

          -  Age ≥18 years.

          -  ECOG performance status ≤ 2 (see Appendix A).

        Participants must have normal organ and marrow function as defined below:

          -  Absolute neutrophils count ≥ 1,500/mcL

          -  Platelets ≥100,000/mcL

          -  total bilirubin within normal institutional limits

          -  AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal (≤ 5.0 X
             institutional upper limit of normal permitted if hepatic metastases present)

          -  Creatinine within 1.5x the ULN institutional limits.

          -  Women of child-bearing potential and men must agree to use adequate contraception
             prior to study entry and for the duration of study participation. Ability to
             understand and the willingness to sign a written informed consent document.

          -  QTc ≤480 msec.

          -  The availability of archival tissue to evaluate retrospectively the participant's Rb
             status

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

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 3 weeks earlier.

          -  Participants may not be receiving any other study agents concurrently with the study
             drugs.

          -  Participants with symptomatic brain metastases that require chronic steroids are
             excluded. Patients with a history of brain metastases are permitted to enroll as long
             as they have been treated, off of steroids and have been stable for one month on
             imaging.

          -  Concurrent use with strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug
             interactions with palbociclib.

          -  Due to potential drug interactions between warfarin and PD-0325901, warfarin use is
             excluded. Other anticoagulants are permitted.

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Pregnant women are excluded from this study because the study agents have the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk of adverse events in nursing infants secondary to treatment of the
             mother with the study agents, breastfeeding should be discontinued.

          -  For Part II only: Individuals with a history of a different malignancy are ineligible
             except if they have been disease-free for at least 2 years and are deemed by the
             investigator to be at low risk for recurrence. Individuals with the following cancers
             are eligible if diagnosed and treated within the past 5 years: cervical cancer in
             situ, and basal cell or squamous cell carcinoma of the skin.

          -  HIV-positive individuals on combination antiretroviral therapy are ineligible because
             of the potential for pharmacokinetic interactions.

          -  Evidence of visible retinal pathology on screening ophthalmologic examination that
             places the participant at an unacceptable risk for ocular toxicity, such as risk
             factors for retinal vein occlusion, related to PF-0325901.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability
Time Frame:2 Years
Safety Issue:
Description:Toxicities will be graded using version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE).

Secondary Outcome Measures

Measure:Pharmacokinetics
Time Frame:2 Years
Safety Issue:
Description:The pharmacokinetic properties 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 PD-0325901
Time Frame:2 Years
Safety Issue:
Description:Confirm target engagement of palbociclib and PD-0325901 in pre- and on-treatment tumor biopsies from patients enrolled to an MTD expansion cohort.
Measure:Overall Response Rate
Time Frame:2 Years
Safety Issue:
Description:Evaluate the preliminary clinical efficacy of palbociclib and PD-0325901 in advanced solid tumors using CT and MRI scans per RECIST version 1.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • KRAS mutant Non-Small Cell Lung Cancer
  • Solid Tumors

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