A Trial To Assess Safety And Tolerability Of PF-04691502 In Cancer Patients

Study Overview
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Brief Summary
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A phase 1 dose-escalation trial to assess the safety, tolerability, and pharmacodynamics of PF-04691502 in adult cancer patients with solid tumors.

Official Title
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A Phase 1, Open-Label, Dose-Escalation Study To Evaluate Safety, Pharmacokinetics, And Pharmacodynamics Of The PI3K/MTOR Inhibitor PF-04691502 In Adult Patients With Advanced Malignant Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Drug: PF-04691502


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a histologically or cytologically confirmed malignant solid tumor for which there is no currently approved treatment or which is unresponsive to currently approved therapies. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of the first dose of PF-04961502, These patients or their partners must be surgically sterile or be postmenopausal, or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. Male patients or their partners must be surgically sterile or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate Adequate Bone Marrow Function, including: Absolute neutrophil count (ANC) ≥1500 cells/mm3 Platelets ≥75,000 cells/mm3 Hemoglobin ≥9 mg/dL Adequate Renal Function, including: SrCr <1.5 x ULN (upper limit of normal). OR Estimated creatinine clearance ≥60 mL/min, as calculated using method standard for the institution Adequate Liver Function, including: Bilirubin ≤1.5 x ULN AST (SGOT) ≤2.5 x ULN ALT (SGPT) ≤2.5 x ULN Adequate glucose control, including no previous diagnosis of diabetes mellitus and HbA1c <7%. Adequate Cardiac Function, including: 12-Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention. QTc interval ≤470 msec and no history of Torsades des Pointes or other symptomatic QTc abnormality Exclusion Criteria: Patients with known active brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), biological or investigational agents within 2 weeks of Baseline disease assessments Any surgery (not including minor procedures such as lymph node biopsy) within 4 weeks of Baseline disease assessments; or not fully recovered from any side effects of previous procedures Prior therapy with an agent that is known or proposed to be active by action on PI3K and/or mTOR Prior high-dose chemotherapy requiring hematopoetic stem cell transplantation within 12 months of study treatment start Uncontrolled or significant cardiovascular disease: A myocardial infarction within 12 months Uncontrolled angina within 6 months Congestive heart failure within 6 months. Diagnosed or suspected congenital long QT syndrome. Any history of ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Any history of second or third degree heart block (may be eligible if currently have a pacemaker) Heart rate <50/minute on pre-entry electrocardiogram Uncontrolled hypertension. Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors or inducers Current use or anticipated need for food or drugs that are known potent CYP1A2 inhibitors or inducers Concurrent administration of herbal preparations Breast feeding: No studies have been conducted in humans to assess the impact of PF-04691502 on milk production, its presence in breast milk and its effects on the breast-fed child. Because drugs are commonly excreted in human milk and because of the potential for serious adverse reactions in nursing infants, lactating female patients are excluded from this study. Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet form and malabsorption syndrome. Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04691502 Treatment<br> | Drug: PF-04691502<br>* Once daily continuous dosing. Dose escalation to Maximally tolerated dose (MTD) until progression or discontinuation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to 28 days after the last dose | 
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLT was classified as per common terminology criteria for adverse events (CTCAE) version 4.0 and defined as any of the following events occurring after first dose of study medication and considered at least possibly-related to study medication. Hematological: grade 4 neutropenia (absolute neutrophil count [ANC] <500 cells per cubic millimeter [cells/mm^3]) for 1 week or greater, febrile neutropenia (fever >=38.5 degree celsius with ANC <1000/mm^3), grade 3 (50,000 cells/mm^3) and grade 4 (<25,000 cells/mm^3) thrombocytopenia; Non-Hematologic: grade 3 or 4 nausea, vomiting, or diarrhea and any clinically significant grade 3 or greater non-hematologic toxicity, despite the use of adequate/maximal medical intervention and/or prophylaxis, and any persistent, intolerable PF-04691502 related toxicity which delayed retreatment for >14 days. | Baseline up to Cycle 1 Day 21 | 
| Recommended Phase-2 Dose (RP2D) | RP2D was determined based on the safety profile and pharmacodynamic findings, as per investigator's discretion. | Baseline up to Cycle 1 Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) | The pharmacokinetics (PK) of PF-04691502 was assessed following a single oral dose administration in lead-in-dose period (single dose PK) and repeated oral dose administration for 21 days in Cycle 1 (multiple dose PK). | Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hours post-dose on Cycle 1 Day 21 (C1D21) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | The PK of PF-04691502 was assessed following a single oral dose administration in lead-in-dose period (single dose PK) and repeated oral dose administration for 21 days in Cycle 1 (multiple dose PK). | Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hours post-dose on C1D21 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). It was evaluated following a single oral dose in lead-in-dose period (single dose PK) only. | Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half-life of PF-04691502 was assessed following a single oral dose administration in lead-in-dose period (single dose PK) and repeat oral dose administration for 21 days in Cycle 1 (multiple dose PK). | Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours (hrs) post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hrs post-dose on C1D21 | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0-∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-t) plus AUC (t-∞). It was evaluated following a single oral dose in lead-in-dose period (single dose PK) only. | Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | AUCtau is the area under the plasma concentration time-curve from time zero to end of dosing interval (tau), where tau is the dosing interval of 24 hours. It was evaluated following repeated oral dose administration for 21 days in Cycle 1 (multiple dose PK) only. | Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hrs post-dose on C1D21 | 
| Number of Participants With Increase From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2-4 minutes) were performed and average calculated. QT interval is the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF is the QT interval corrected for heart rate. Corrected QT interval using Fridericia's heart rate correction formula: QTcF = QT/RR^1/3, where RR=RR interval in seconds. End of treatment (EOT) data included values from participants who came off-treatment before cycle 8. | Pre-dose, 30 minutes, 1, 2, 4, 8, 24, 48, hrs post-dose in Lead-in period; 1 hour post-dose on C1D8, C1D15; 1, 2, 4, 8 hours post-dose on C1D21; 1 hour post-dose C2D1, C2D15, D1 of subsequent cycles up to C8; EOT | 
| Number of Participants With Maximum Post-dose QT Interval Corrected Using Fridericia's Formula (QTcF) | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2-4 minutes) were performed and average calculated. QT interval is the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF is the QT interval corrected for heart rate. Corrected QT interval using Fridericia's heart rate correction formula: QTcF = QT/RR^1/3, where RR=RR interval in seconds. End of treatment (EOT) data included values from participants who came off-treatment before cycle 8. | Pre-dose, 30 minutes, 1, 2, 4, 8, 24, 48, hrs post-dose in Lead-in period; 1 hour post-dose on C1D8, C1D15; 1, 2, 4, 8 hours post-dose on C1D21; 1 hour post-dose C2D1, C2D15, D1 of subsequent cycles up to C8; EOT | 
| Change From Baseline in Serum Glucose at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT) | Serum glucose level was measured following 4 hours fasting. EOT data included values from participants who came off-treatment before cycle 8. | Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT | 
| Change From Baseline in Serum Insulin at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT) | Serum insulin level was measured following 4 hours fasting. EOT data included values from participants who came off-treatment before cycle 8. | Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT | 
| Change From Baseline in Serum C-peptide at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT) | Serum C-peptide level was measured following 4 hours fasting. EOT data included values from participants who came off-treatment before cycle 8. | Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT | 
| Change From Baseline in Fresh Tumor Biopsy Biomarkers at Cycle 1 Day 21 | Fresh tumor biopsy samples analysis included assessment of status of proteins indicative of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) related pathways signaling status and cell cycle status. The biomarkers included phosphorylated activated kinase (AKT) S473, AKT T308, signal transducer and activator of transcription 3 (STAT3) and forkhead transcription factor Foxo1 (FKHR) T24/forkhead in rhabdomysacoma-like 1 (FKHRL1) T32. The method of analysis was reverse phase microarray (RPMA). The signal (normalized fluorescence unit [NFU]) for each pathway biomarker was normalized against the signal (NFU) for cytokeratin. The final concentration for each pathway biomarker was reported as a cytokeratin normalized fluorescence unit (NFC) value. | Baseline; 4 hours post-dose on C1D21 | 
| Change From Baseline in Hair Follicle Biopsy Biomarkers at Cycle 1 Day 21 | Hair follicle biopsy samples analysis included assessment of status of proteins indicative of PI3K/mTOR related pathways signaling status and cell cycle status. The analytes measured were phosphorylated AKT S473, AKT T308, KI67, STAT3 (Y705) and proline-rich Akt substrate of 40 kilodaltons at Thr246 (PRAS40 T246). The method of analysis was reverse phase microarray (RPMA). The signal for each biomarker expressed as normalized fluorescence intensity (NFI) was normalized by their respective total protein concentration. This normalization was performed by dividing the biomarker NFI by total protein concentration (mg/mL) of the sample printed to give total protein normalized fluorescence unit (NFU). All clinical sample test results are reported in NFU. | Baseline; pre-dose, 2, 4, 24 hours post-dose on C1D21 | 
| Number of Participants With Mutation, Deletion, Amplification in Phosphatidylinositol 3-kinase (PI3K) Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue | Biopsied tumor tissue was analyzed for alterations in the phosphoinositide-3-kinase/rat sarcoma (PI3K/RAS) signaling pathway by molecular approaches. The biomarkers studied were phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) gene mutation, PIK3CA gene amplification, and phosphatase and tensin homolog (PTEN) protein deficiency status by immunohistochemistry. | Baseline; 4 hours post-dose on C1D21 | 
| Number of Participants With Objective Response | Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Baseline, prior to Day 1 of Cycle every odd-numbered cycle or when progressive disease was suspected |