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Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors

NCT03065062

Description:

This research study is studying a combination of drugs as a possible treatment for cancer that might have a specific change in the phosphatidylinositol-3 phosphate (PI3K) pathway.

Related Conditions:
  • Malignant Solid Tumor
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors
  • Official Title: Phase I Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 16-499
  • NCT ID: NCT03065062

Conditions

  • Lung Cancer Squamous Cell
  • Solid Tumors
  • Head & Neck Cancer
  • Pancreatic Cancer

Interventions

DrugSynonymsArms
PalbociclibIBRANCE, PD-0332991Combination Of Palbociclib and Gedatolisib
GedatolisibPF-05212384Combination Of Palbociclib and Gedatolisib

Purpose

This research study is studying a combination of drugs as a possible treatment for cancer that might have a specific change in the phosphatidylinositol-3 phosphate (PI3K) pathway.

Detailed Description

      This research study is an open-label Phase I clinical trial, which tests the safety of an
      investigational drug or combination of investigational drugs and also tries to define the
      appropriate dose of the investigational drug(s) to use for further studies. "Investigational"
      means that the drug is being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved Palbociclib for the
      participant specific disease but it has been approved for other uses. The FDA has not
      approved Gedatolisib alone or in combination with Palbociclb as a treatment option for the
      participant's disease.

      In this research study the investigators hope to determine if treatment with Palbociclib and
      Gedatolisib will be tolerated and will help to shrink or stop the growth of the participant's
      cancer. Palbociclib is an oral drug which has been shown to stop the cell cycle, which is the
      way a cell initiates growth. Gedatolisib is thought to work by controlling a series of events
      directing cell growth and survival. Gedatolisib may work to stop or slow activity within
      tumor cells. By putting these two drugs together the investigators hope that it will have a
      greater effect on cancer growth than either drug alone.
    

Trial Arms

NameTypeDescriptionInterventions
Combination Of Palbociclib and GedatolisibExperimentalPalbociclib will be administered orally once daily on Days 1-21 for each of the 4-week cycles at a pre-determined dose. Gedatolisib will be administered intravenously once weekly on the first day for each of the four weeks during the 4-week cycles at a pre-determined dose.
  • Palbociclib
  • Gedatolisib

Eligibility Criteria

        Inclusion Criteria:

          -  For Part I, participants must have histologically confirmed malignancy that is
             metastatic or unresectable and resistant to standard therapy or for which no standard
             therapy is available. For Part II, participants must have histologically confirmed
             advanced squamous cell lung cancer, advanced pancreatic cancer, advanced head & neck
             cancer (specifically non-oropharynx squamous cell carcinoma or HPV-negative oropharynx
             squamous cell carcinoma), or any tumor with suspected PI3K-pathway dependence (either
             by mutation or by known biologic rationale, such as endometrial cancer. PI3K
             dependence includes the presence of a PIK3CA-mutant hotspot mutation, PIK3CA copy
             number gain, or PTEN loss in the archival or fresh tumor tissue specimen identified in
             a CLIA-certified laboratory. All genetic findings must be reviewed by the study PI,
             prior to study entry.)

          -  For Part I, participants are required to have only evaluable disease (disease that is
             visible on imaging studies but does not meet RECIST criteria for measurable disease).
             For 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.

          -  Participants are permitted to have any number of prior therapies prior to enrollment

          -  Age ≥ 18 years. .

          -  ECOG performance status ≤ 2

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

               -  Absolute neutrophil count ≥ 1,500/mcL

               -  Hemoglobin ≥9.0 gm/dL

               -  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

               -  Fasting glucose ≤ 126 mg/dL (7.0 mmol/L)

               -  HbA1c ≤ 7.0%

          -  The effects of palbociclib and Gedatolisib (PF-05212384) on the developing human fetus
             are unknown. For this reason, women of child-bearing potential and men must agree to
             use adequate contraception (hormonal or barrier method of birth control; abstinence)
             prior to study entry, for the duration of study participation, and 90 days after
             discontinuation.

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

        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 acute effects of any prior therapy to baseline or Grade ≤1 except for
             Alopecia or AEs not constituting a safety risk in the opinion of the investigator.

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

          -  Participants with symptomatic brain metastases that require active treatment are
             excluded.

          -  Current use or anticipated need for food or medications that are known strong CYP3A4
             inhibitors/inducers, including their administration within 7-days prior to the first
             Gedatolisib (PF-05212384) or palbocilib dose and during study treatment.

          -  QTc > 480 msec; history of QT syndrome, Brugada syndrome or known history of QTc
             prolongation, or Torsade de Pointes.

          -  Patients with a history of diabetes.

          -  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 if the mother is
             treated.

          -  Individuals with a history of other malignancy are ineligible except for the following
             circumstances. Individuals with a history of previous malignancies are eligible if
             they have been disease-free for at least 2 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 treated within the past 5 years: cervical cancer
             in situ, and basal cell or squamous cell carcinoma of the skin.

          -  Active and clinically significant bacterial, fungal or viral infection including
             hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or
             acquired immunodeficiency syndrome (AIDS)-related illness.

          -  Concurrent use or anticipated need for medications that are mainly metabolized by
             UGT1A9 including their administration within 7-days prior to the first dose of study
             drug.

          -  Current use or anticipated need for food or medications that are metabolized by
             CYP2D6, and of narrow therapeutic index including their administration within 10-days
             prior to the first Gedatolisib (PF-05212384) dose and during study treatment.

          -  Concurrent use of herbal preparations including saw palmetto.

          -  Current use of drugs known to prolong QT interval.

          -  Concurrent use of proton pump inhibitors (including, but not limited to,
             dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
             with palbociclib is prohibited.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose and Recommended Phase 2 Dose
Time Frame:2 years
Safety Issue:
Description:The dose-escalation schedule will use the mTPI design to discover the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of palbociclib and gedatolisib.

Secondary Outcome Measures

Measure:Progression Free Survival Rate at 4 months
Time Frame:4 months
Safety Issue:
Description:Evaluate the preliminary clinical efficacy of palbociclib and gedatolisib in the following expansion cohorts: 1) advanced squamous cell lung cancer, 2) advanced pancreatic cancer, 3) advanced head & neck cancer, and 4) any tumor with presumed PI3K-pathway dependence using CT and MRI scans per RECIST version 1.
Measure:Target engagement of palbociclib and gedatolisib in paired tumor biopsies
Time Frame:2 years
Safety Issue:
Description:Confirm target engagement of palbociclib and gedatolisib in pre- and on-treatment tumor biopsies from patients enrolled to the MTD expansion cohort through evaluation of changes in immunohistochemical staining for parameters of CDK and PI3K activity.
Measure:Pharmacokinetic parameter (maximum concentration [Cmax]) of gedatolisib in the absence or presence of palbociclib
Time Frame:At 0.5, 1, 2, 4, 6, 8, 10, 24, 72, 120 and 168 hours after dosing (lead-in dose 7 days prior to cycle 1 day 1, and cycle 1 day 15)
Safety Issue:
Description:
Measure:Pharmacokinetic parameter (area under the curve [AUC]) of gedatolisib in the absence or presence of palbociclib
Time Frame:At 0.5, 1, 2, 4, 6, 8, 10, 24, 72, 120 and 168 hours after dosing (lead-in dose 7 days prior to cycle 1 day 1, and cycle 1 day 15)
Safety Issue:
Description:
Measure:Pharmacokinetic parameter (half-life [t1/2]) of gedatolisib in the absence or presence of palbociclib
Time Frame:At 0.5, 1, 2, 4, 6, 8, 10, 24, 72, 120 and 168 hours after dosing (lead-in dose 7 days prior to cycle 1 day 1, and cycle 1 day 15)
Safety Issue:
Description:
Measure:Pharmacokinetic parameters (maximum concentration [Cmax]) of palbociclib in the presence of gedatolisib
Time Frame:At 1, 2, 4, 6, 8, 10, and 24 hours after dosing (cycle 1 day 15)
Safety Issue:
Description:
Measure:Pharmacokinetic parameters (area under the curve [AUC]) of palbociclib in the presence of gedatolisib
Time Frame:At 1, 2, 4, 6, 8, 10, and 24 hours after dosing (cycle 1 day 15)
Safety Issue:
Description:
Measure:Pharmacokinetic parameters (half-life [t1/2]) of palbociclib in the presence of gedatolisib
Time Frame:At 1, 2, 4, 6, 8, 10, and 24 hours after dosing (cycle 1 day 15)
Safety Issue:
Description:
Measure:Overall Response Rate
Time Frame:2 years
Safety Issue:
Description:Evaluate the preliminary clinical efficacy of palbociclib and gedatolisib in advanced solid tumors using CT and MRI scans per RECIST version 1.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Lung Cancer Squamous Cell
  • Head & Neck Cancer
  • Neoplasms
  • Endometrial Cancer

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