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).

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).

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

• Experimental: DL 1
  PF-06821497 75 mg BID
  Intervention: Drug: PF-06821497
• Experimental: DL 2
  PF-06821497 150 mg BID
  Intervention: Drug: PF-06821497
• Experimental: DL 3
  PF-06821497 250 mg BID
  Intervention: Drug: PF-06821497
• Experimental: DL 4
  PF-06821497 375 mg BID
  Intervention: Drug: PF-06821497
• Experimental: DL 5
  PF-06821497 500 mg BID
  Intervention: Drug: PF-06821497
• Experimental: DL 6
  PF-06821497 625 mg BID
  Intervention: Drug: PF-06821497

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.