Clinical Trials /

PF-06821497 Treatment Of Relapsed/Refractory SCLC, Castration Resistant Prostate Cancer, and Follicular Lymphoma

NCT03460977

Description:

A Phase 1 Dose Escalation and Expanded Cohort Study Of PF-06821497 In The Treatment Of Adult Patients With Relapsed/Refractory Small Cell Lung Cancer (SCLC), Castration Resistant Prostate Cancer (CRPC) And Follicular Lymphoma (FL).

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Prostate Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: PF-06821497 Treatment Of Relapsed/Refractory SCLC, Castration Resistant Prostate Cancer, and Follicular Lymphoma
  • Official Title: A PHASE I DOSE ESCALATION AND EXPANDED COHORT STUDY OF PF-06821497 IN THE TREATMENT OF ADULT PATIENTS WITH RELAPSED/REFRACTORY SMALL CELL LUNG CANCER (SCLC), CASTRATION RESISTANT PROSTATE CANCER (CRPC) AND FOLLICULAR LYMPHOMA (FL)

Clinical Trial IDs

  • ORG STUDY ID: C2321001
  • NCT ID: NCT03460977

Conditions

  • Small Cell Lung Cancer (SCLC)
  • Follicular Lymphoma (FL)
  • Castration Resistant Prostate Cancer (CRPC)
  • Diffuse Large B-Cell Lymphoma (DLBCL)

Interventions

DrugSynonymsArms
PF-06821497DL 1

Purpose

A Phase 1 Dose Escalation and Expanded Cohort Study Of PF-06821497 In The Treatment Of Adult Patients With Relapsed/Refractory Small Cell Lung Cancer (SCLC), Castration Resistant Prostate Cancer (CRPC) And Follicular Lymphoma (FL).

Detailed Description

      This is an open label, multi center, Phase 1 dose escalation study of PF 06821497
      administered orally as a single agent BID to patients with SCLC, CRPC, DLBCL and FL (Part
      1A). For Part 1B (dose escalation monotherapy), PF 06821497 will be administered as
      monotherapy in patients with FL. For Part 2A (dose escalation combination therapy), PF
      06821497 will be administered in combination with SOC in patients with SCLC and CRPC. For
      Part 2B (dose expansion), PF 06821497 will be administered in combination with SOC in
      patients with SCLC and CRPC, and as monotherapy in patients with FL.

      Part 1A (escalation monotherapy) will assess PF 06821497 administered as a single agent twice
      daily in a continuous regimen to patients with advanced tumors (SCLC CRPC, DLBCL and FL). A
      modified toxicity probability interval (mTPI) dose finding design will be applied in 2 4
      patient cohorts. The starting dose of PF 06821497 will be 75 mg BID (DL1). Once the safety
      and adequate target modulation has been established Parts 1B and 2A of the trial will be
      initiated. Additional dose levels may be investigated, if adequate target inhibition has not
      been achieved at DL3.

      Part 1B [escalation recommended Phase 2 dose (RP2D) finding - monotherapy] will determine the
      maximum tolerated dose (MTD) of monotherapy in FL (MTD1).

      Part 2A (escalation RP2D finding -combination) will determine the MTD of the combination with
      SOC in patients with SCLC (cisplatin or carboplatin with etoposide, MTD2, MTD3) and CRPC
      (MTD4). Part 2B (dose expansion) will assess the efficacy of PF 06821497 at the RP2D
      identified from the Part 2A, in combination with SOC in patients with SCLC (n=16 to 30 for
      the 2 combination regimens), and CRPC (n=8 to 20) in addition to as a single agent twice
      daily in patients with FL (n=8 to 20).
    

Trial Arms

NameTypeDescriptionInterventions
DL 1ExperimentalPF-06821497 75 mg BID
  • PF-06821497
DL 2ExperimentalPF-06821497 150 mg BID
  • PF-06821497
DL 3ExperimentalPF-06821497 250 mg BID
  • PF-06821497
DL 4ExperimentalPF-06821497 375 mg BID
  • PF-06821497
DL 5ExperimentalPF-06821497 500 mg BID
  • PF-06821497
DL 6ExperimentalPF-06821497 625 mg BID
  • PF-06821497

Eligibility Criteria

        Key Inclusion Criteria:

        Histological or cytological diagnosis of advanced / metastatic solid tumor with the
        following tumor types in individual study parts:

        Part 1A:

        -Histologically / cytologically confirmed advanced/unresectable or metastatic SCLC, CRPC,
        DLBCL and FL that is refractory to or intolerable of standard treatment, or for which no
        curative treatment is available. Note for FL (Parts 1A and 1B) during the dose finding
        phase of study, follicular lymphoma patients must have exhausted all standard of care
        therapies.

        Part 1B:

        Histologically confirmed FL patients that have exhausted all curative therapies and have
        relapsed or refractory disease.

        Part 2:

          -  Histologically or cytologically confirmed treatment naïve extensive disease SCLC
             patients;

          -  Histologically confirmed FL patients that are intolerant of or resistant to standard
             therapy or for which no curative therapy is available and have relapsed or refractory
             disease (Part 2B).

          -  Histological / cytological diagnosis of castration resistant prostate cancer. Received
             either abiraterone and/or enzalutamide treatment and has evidence of prostate cancer
             progression (per PWG3):

               -  SCLC patients entering the study in the expansion cohort with at least one
                  measurable lesion as defined by Response Evaluation Criteria in Solid Tumors
                  (RECIST) version 1.1.

               -  FL patients entering the study in the expansion cohort with at least one
                  measurable lesion as defined by Response Evaluation Criteria in Lymphoma (RECIL)
                  criteria.

               -  Females and/or male patients age 18 years.

               -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.

               -  Adequate Bone Marrow Function

               -  Adequate Renal Function

               -  Adequate Liver Function

               -  Serum pregnancy test (for females of childbearing potential) negative at
                  screening, and negative serum or urine pregnancy test at baseline prior to
                  treatment administration.

        Exclusion Criteria:

          -  Known symptomatic brain metastases requiring steroids or CNS involvement in FL.
             Previously diagnosed brain metastases are eligible if they have been treated and
             recovered from the acute effects of radiation therapy or surgery prior to study entry,
             have discontinued corticosteroid treatment for these metastases for at least 4 weeks
             and are neurologically stable. Physiologic replacement doses of corticosteroids are
             permissible.

          -  At least 3 weeks since last major surgery (a lesser period is acceptable if decided to
             be in the best interest of the SCLC patient).

          -  Treatment with more than 2gm acetaminophen per day within 14 days of study entry and
             on study if required.

          -  Chronic liver diseases.

          -  History of alcohol abuse or binge drinking in the last 6 months prior to screening.

          -  Radiation therapy within 4 weeks prior to study entry. Note, patients who have
             received radiotherapy must have recovered from any reversible side effects, such as
             nausea and vomiting.

          -  Systemic anti cancer therapy - approved or investigational - within 4 weeks or 5
             half-lives, whichever is shorter, prior to study entry, including antibody based
             agents. Prostate cancer cohorts 2A and 2B must have not received more than 1 previous
             regimen of systemic chemotherapy in mCPRC setting. SCLC cohorts must be chemotherapy
             naive for SCLC however may have received one cycle of chemotherapy after discussion
             with the sponsor.

          -  Last anti hormonal therapy within 2 weeks prior to C1D1.

          -  Prior stem cell transplant, autologous or allogenic, within 100 days prior to study
             enrollment or patients who experienced graft veses host disease or who require
             systemic immune suppressive therapy.

          -  Prior irradiation to >25% of the bone marrow.

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

          -  Any of the following in the previous 6 months: myocardial infarction, congenital long
             QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular
             tachyarrhythmia and ventricular fibrillation), right bundle branch block and left
             anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery
             bypass graft, symptomatic congestive heart failure (New York Heart Association class
             III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic
             pulmonary embolism; ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, atrial
             fibrillation of any grade, or QTcF interval >480 msec at screening.

          -  Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal
             medical therapy).

          -  Known or suspected hypersensitivity to PF 06821497 or any components or enzalutamide
             (CRPC) or platinum compound.

          -  Other acute or chronic medical or psychiatric condition, including recent (within the
             past year) or active suicidal ideation or behavior or laboratory abnormality that may
             increase the risk associated with study participation or investigational product
             administration or may interfere with the interpretation of study results and, in the
             judgment of the investigator, would make the patient inappropriate for entry into this
             study.

          -  Investigator site staff members directly involved in the conduct of the study and
             their family members, site staff members otherwise supervised by the investigator, or
             patients who are Pfizer employees, including their family members, directly involved
             in the conduct of the study.

          -  Pregnant female patients; breastfeeding female patients; fertile male patients and
             female patients of childbearing potential who are unwilling or unable to use 2 highly
             effective methods of contraception as outlined in this protocol for the duration of
             the study and for at least 28days after the last dose of investigational product.

          -  Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular
             disease or previous gastric resection or lap band surgery. Gastroesophageal reflux
             disease under treatment with proton pump inhibitors is allowed.

          -  Current use or anticipated need for food or drugs that are known strong CYP3A4/5
             inhibitors, including their administration within 10 days or 5 half lives of the
             CYP3A4/5 inhibitor, whichever is longer prior to first dose of investigational
             product.

          -  Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers,
             including their administration within 10 days or 5 half lives of the CYP3A4/5 inducer,
             whichever is longer prior to the first dose of investigational product.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients with dose limiting toxicities (DLTs) to determine the maximum tolerated dose (MTD)
Time Frame:Baseline up to 90 days
Safety Issue:
Description:First cycle DLTs will be utilized to determine the MTD and future dose escalations or de-escalations. A DLT is any of the predefined set of unacceptable adverse events observed and at least possibly related to investigational agents.

Secondary Outcome Measures

Measure:Evaluate time to event anti-tumor activity of PF-06821497 including progression-free survival (PFS), and metastatic free survival (MFS)
Time Frame:Baseline and every 21 days through time of confirmed disease progression, unacceptable toxicity, or through study completion, approximately 2 years.
Safety Issue:
Description:Time to event endpoints based on Response Evaluation Criteria in Lymphoma (RECIL) for lymphoma, Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for solid tumors including Small Cell Lung Cancer (SCLC) and Prostate Working Group 3 (PWG3) for Castration Resistant Prostate Cancer (CRPC)
Measure:Evaluate overall survival
Time Frame:Baseline up to approximately 2 years
Safety Issue:
Description:Median time to death proportion of patients alive at 6 months, 1 year, and 2 years.
Measure:Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax)
Time Frame:Cycle 1, Day 1, pre dose, 0.25, 0.5, 1, 2, 3, 4, 6, and 10 or 12 hours post dose; Cycle 1 Day 8, pre dose; Cycle 1 Day 15 pre dose, 0.25, 0.5, 1, 2, 3, 4, 6 and 10 or 12 hours post dose, Cycle ≥2 Day 1 pre dose; End of Treatment visit
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Maximum Observed Plasma Concentration (Cmax).
Measure:Pharmacokinetic Parameters: Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time Frame:Cycle 1, Day 1, pre dose, 0.25, 0.5, 1, 2, 3, 4, 6, and 10 or 12 hours post dose; Cycle 1 Day 8, pre dose; Cycle 1 Day 15 pre dose, 0.25, 0.5, 1, 2, 3, 4, 6 and 10 or 12 hours post dose, Cycle ≥2 Day 1 pre dose; End of Treatment visit
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Time to Reach Maximum Observed Plasma Concentration (Tmax).
Measure:Pharmacokinetic Parameters: Area Under the Curve (AUC)
Time Frame:Cycle 1, Day 1, pre dose, 0.25, 0.5, 1, 2, 3, 4, 6, and 10 or 12 hours post dose; Cycle 1 Day 8, pre dose; Cycle 1 Day 15 pre dose, 0.25, 0.5, 1, 2, 3, 4, 6 and 10 or 12 hours post dose, Cycle ≥2 Day 1 pre dose; End of Treatment visit
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Area Under the Cuvce (AUC).
Measure:Pharmacokinetic Parameters: Apparent Oral Clearance (CL/F)
Time Frame:Cycle 1, Day 1, pre dose, 0.25, 0.5, 1, 2, 3, 4, 6, and 10 or 12 hours post dose; Cycle 1 Day 8, pre dose; Cycle 1 Day 15 pre dose, 0.25, 0.5, 1, 2, 3, 4, 6 and 10 or 12 hours post dose, Cycle ≥2 Day 1 pre dose; End of Treatment visit
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Apparent Oral Clearance (CL/F). Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Measure:Pharmacokinetic Parameters: Apparent Volume of Distribution (Vz/F)
Time Frame:Cycle 1, Day 1, pre dose, 0.25, 0.5, 1, 2, 3, 4, 6, and 10 or 12 hours post dose; Cycle 1 Day 8, pre dose; Cycle 1 Day 15 pre dose, 0.25, 0.5, 1, 2, 3, 4, 6 and 10 or 12 hours post dose, Cycle ≥2 Day 1 pre dose; End of Treatment visit
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Apparent Volume of Distribution (Vz/F). Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Measure:Pharmacokinetic Parameters: Plasma Decay Half-Life (t1/2)
Time Frame:Cycle 1, Day 1, pre dose, 0.25, 0.5, 1, 2, 3, 4, 6, and 10 or 12 hours post dose; Cycle 1 Day 8, pre dose; Cycle 1 Day 15 pre dose, 0.25, 0.5, 1, 2, 3, 4, 6 and 10 or 12 hours post dose, Cycle ≥2 Day 1 pre dose; End of Treatment visit
Safety Issue:
Description:Singe dose and multiple dose PK will be calculated as data permits including Plasma Decay Half-Life (t1/2). Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • efficacy
  • safety
  • pharmacokinetics
  • pharmacodynamics
  • dose escalation
  • dose expansion
  • open-label
  • EZH2
  • enhancer of zeste homolog 2
  • castrate resistant prostate cancer
  • CRPC
  • small cell lung cancer
  • SCLC
  • follicular lymphoma
  • FL
  • relapsed
  • refractory

Last Updated

November 14, 2019