A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY EVALUATING SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF 06952229 IN ADULT PATIENTS WITH ADVANCED SOLID TUMORS
Overview
- Phase
- Phase 1
- Intervention
- PF-06952229
- Conditions
- Breast Neoplasms
- Sponsor
- Pfizer
- Enrollment
- 49
- Locations
- 15
- Primary Endpoint
- Number of Participants With First-Cycle Dose-Limiting Toxicitys (DLTs) by Treatment
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
A Phase 1 dose escalation and expansion study evaluating safety, tolerability and pharmacokinetics of PF-06952229 in adult patients with advanced solid tumors.
Detailed Description
This is a Phase 1, open label, multi center, multiple dose, dose escalation and expansion, safety, tolerability, PK, and pharmacodynamics study of PF 06952229 in previously treated patients with advanced or metastatic cancers that may have high TGFbeta signatures and EMT expression. The study includes Parts 1A and 1B, which are dose-escalation for monotherapy and combination therapy with enzalutamide, respectively, and Parts 2A and 2B, which are dose expansion for monotherapy and combination therapy with enzalutamide, respectively.
Investigators
Eligibility Criteria
Inclusion Criteria
- •For Part 1A: Histological or cytological diagnosis of a solid tumor that is advanced/metastatic, patients are intolerant to standard treatment, resistant to standard therapy or for which no standard therapy is available for the following tumor types:
- •Breast cancer; Prostate cancer (mCRPC testosterone less than 50 ng/dL); Squamous cell cancer of the head and neck; Melanoma; Mesothelioma; Pancreatic cancer; Colorectal cancer; Renal cell carcinoma; Hepatocellular cancer.
- •For Part 1B:
- •histological or cytological diagnosis of mCRPC 3 Part 2A and Part 2B:
- •Histologically or cytologically confirmed prostate adenocarcinoma metastatic disease.
- •Effective castration with serum testosterone levels 0.5 ng/mL (1.7 nmol/L).
- •Having received 3 or more cycles of prior docetaxel therapy (before or after abiraterone).
- •Having PD while receiving abiraterone acetate within 12 months of abiraterone treatment initiation.
- •Progressive disease (PD) by:
- •Progression in measurable disease per RECIST 1.1 criteria. Patient with measurable disease must have at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be at least 10 mm when measured by computed tomography (CT) (CT scan thickness no greater than 5 mm) or magnetic resonance imaging (MRI). Lymph nodes should be greater than or equal to 15 mm in short axis. As defined by PCWG2, if lymph node metastasis is the only evidence of metastasis, it must be greater than or equal to 20 mm in diameter when measured by spiral CT or MRI. Previously irradiated lesions, primary prostate lesion, and bone lesions will be considered non-measurable disease, or
Exclusion Criteria
- Not provided
Arms & Interventions
Prostate Cancer Dose Level 4 (Part 1B)
PF-06952229 at 750 mg BID in combination with enzalutamide
Intervention: PF-06952229
Dose Level 1 (Part 1A)
PF-06952229 at 20mg twice daily (BID)
Intervention: PF-06952229
Dose Level 2 (Part 1A)
PF-06952229 at 40 mg BID
Intervention: PF-06952229
Dose Level 5 (Part 1A)
PF-06952229 at 250 mg BID
Intervention: PF-06952229
Dose Level 3 (Part 1A)
PF-06952229 at 80 mg BID
Intervention: PF-06952229
Dose Level 4 (Part 1A)
PF-06952229 at 150 mg BID
Intervention: PF-06952229
Dose Level 6 (Part 1A)
PF-06952229 at 375 mg BID
Intervention: PF-06952229
Dose Level 7 (Part 1A)
PF-06952229 at 500 mg BID
Intervention: PF-06952229
Dose Level 8 (Part 1A)
PF-06952229 at 625 mg BID
Intervention: PF-06952229
Dose Level 9 (Part 1A)
PF-06952229 at 750 mg BID
Intervention: PF-06952229
Prostate Cancer Dose Level 1 (Part 1B)
PF-06952229 at 375 mg BID in combination with enzalutamide
Intervention: PF-06952229
Prostate Cancer Dose Level 1 (Part 1B)
PF-06952229 at 375 mg BID in combination with enzalutamide
Intervention: Enzalutamide
Prostate Cancer Dose Level 3 (Part 1B)
PF-06952229 at 625 mg BID in combination with enzalutamide
Intervention: Enzalutamide
Prostate Cancer Dose Level 2 (Part 1B)
PF-06952229 at 500 mg BID in combination with enzalutamide
Intervention: PF-06952229
Prostate Cancer Dose Level 2 (Part 1B)
PF-06952229 at 500 mg BID in combination with enzalutamide
Intervention: Enzalutamide
Prostate Cancer Dose Level 3 (Part 1B)
PF-06952229 at 625 mg BID in combination with enzalutamide
Intervention: PF-06952229
Prostate Cancer Dose Level 4 (Part 1B)
PF-06952229 at 750 mg BID in combination with enzalutamide
Intervention: Enzalutamide
Prostate Cancer (Part 2A)
PF-06952229 at recommended Phase 2 Dose BID
Intervention: PF-06952229
Prostate Cancer (Part 2B)
PF-06952229 at recommended phase 2 dose BID in combination with enzalutamide
Intervention: PF-06952229
Prostate Cancer (Part 2B)
PF-06952229 at recommended phase 2 dose BID in combination with enzalutamide
Intervention: Enzalutamide
Outcomes
Primary Outcomes
Number of Participants With First-Cycle Dose-Limiting Toxicitys (DLTs) by Treatment
Time Frame: Within 28 days of first dose or until the participant completed the first cycle of therapy if there were treatment delayed (on average 28 days).
First cycle DLTs were utilized to determine the max tolerated dose and future escalations or deescalations. Any of the following adverse events occurred in the first cycle of treatment which were clinically significant were classified as DLTs: Hematologic: Thrombocytopenia Grade 4 for \>=7 days, or Grade 3 or 4 associated with \>= Grade 2 clinically significant bleeding or requiring platelet transfusion; Neutropenia Grade 4 for \>=7 days; Grade\>=3 neutropenia with infection; Anemia Grade 4 or Grade 3 requiring blood transfusion. Nonhematologic: Grade\>=3 toxicities that were considered clinically significant; Alanine aminotransferase/aspartate aminotransferase\>3x the upper limit of normal (ULN) with bilirubin\>2x ULN without another explanation; Grade 3 nausea, vomiting or diarrhea that did not resolve within 4 days despite maximal supportive therapy. Nonhematologic and Non-Hepatic: Any toxicity caused\>= 2 weeks of dose delay or preventing participants from receiving 75% of study drug.
Number of Participants With Treatment-Emergent Adverse Events (Treatment Related)
Time Frame: Baseline up to 28 days after last dose of study treatment ( up to approximately 2 years)
Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)
Time Frame: Baseline up to 28 days after last dose of study treatment ( up to approximately 2 years)
Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and serum pregnancy test \[for all female participants\]) and urine (urine pregnancy test \[for all female participants\]). Clinical significance of laboratory parameters was determined at the investigator's discretion.
Secondary Outcomes
- Maximum Observed Plasma Concentration (Cmax) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Maximum Observed Plasma Concentration (Cmax) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 21 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Time of Observed Maximum Plasma Concentration (Tmax) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Time of Observed Maximum Plasma Concentration (Tmax) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 21 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Apparent Clearance (CL/F) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 21 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Apparent Volume of Distribution (Vz/F) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Apparent Clearance (CL/F) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Apparent Volume of Distribution (Vz/F) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Terminal Elimination Half-Life (T1/2) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Terminal Elimination Half-Life (T1/2) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Number of Participants With Prostate Specific Antigen 50 (PSA50) Response(Baseline, Cycle 1 Day 1 (at the beginning of Cycle 1), and then every 3 cycles (each cycle is 28 days) until end of treatment (an average of 1 year))
- Percentage of Participants With Objective Response(Baseline and every 8 to 12 weeks through time of confirmed disease progression, unacceptable toxicity, or through study completion, approximately 2 years.)