Study of PF-05212384 (Also Known as PKI-587)Administered Intravenously To Subjects With Solid Tumors

Study Overview
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Brief Summary
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This is a two-part study of a compound called PF-05212384 (also known as PKI-587). The purpose of part 1 is to identify the Maximum Tolerated Dose (MTD) of PF-05212384 using a Continual Reassessment Method (CRM). Part 1 will include subjects with any solid tumor. In Part 2 two cohorts will be enrolled. One cohort will assess safety, tolerability and preliminary efficacy in 20 subjects at the MTD and will include subjects with breast cancer, ovarian cancer, endometrial cancer, colorectal cancer renal cancer or glioblastoma (a type of brain tumor). The other cohort will include 5 to 15 subjects with any type of tumor who consent to provide tumor biopsies while participating in the study.

Official Title
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A Phase 1 Study Of Pf-05212384 (Also Known As Pki-587) Administered As An Intravenous Infusion To Patients With Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: PF-05212384 (also known as PKI-587)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic diagnosis of any solid tumor Incurable cancer, with disease progression following at least 1 therapy with no further standard treatment available in the opinion of the investigator. At least 1 evaluable lesion per RECIST criteria Exclusion Criteria: Clinically unstable primary or metastatic CNS tumors Subjects with known diabetes QTc interval greater than 470 ms.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>PF-05212384 (also known as PKI-587) | Drug: PF-05212384 (also known as PKI-587)<br>* Intravenous dosing once weekly infusion<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 were events between first dose of study drug and up to Cycle 14, that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events. | Baseline up to Cycle 14 (each cycle is 28 days) | 
| Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) or Serious Adverse Events (SAEs) | 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 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 Cycle 14, that were absent before treatment or that worsened relative to pretreatment state. Relatedness to drug was assessed by the investigator. Participants with multiple occurrences of an AE within a category were counted once within the category. AEs included both serious and non-serious adverse events. | Baseline up to Cycle 14 (each cycle is 28 days) | 
| Number of Participants With Laboratory Abnormalities | Criteria for laboratory test abnormality: hematology (hemoglobin [less than {<} 0.8*lower limit of normal {LLN}], platelets [<0.5*LLN or greater than {>} 1.75*upper limit of normal {ULN}], white blood cells [<0.6*LLN or >1.5*ULN], lymphocytes [<0.8*LLN or >1.2*ULN], total neutrophils [<0.8*LLN or >1.2*ULN], basophils, eosinophils, monocytes [>1.2*ULN]); coagulation [partial thromboplastin time, prothrombin (PT), PT international ratio [>1.1*ULN]); liver function (total bilirubin [>1.5*ULN], aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase [>0.3*ULN], total protein, albumin [<0.8*LLN or >1.2*ULN]). | Baseline up to Cycle 14 (each cycle is 28 days) | 
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: Grade 3 nonhematologic AE (including nausea, vomiting, or diarrhea despite optimal therapy; or greater than or equal to [>=] grade 3 asthenia >2 days; or fasting serum glucose >250 milligrams per deciliter (mg/dL) despite optimal therapy); >=Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; Grade 4 neutropenia lasting more than 7 days; Febrile neutropenia; other Grade 4 hematologic AE; delay of treatment >2 consecutive weeks due to toxicity. Grades were based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. | Baseline up to Day 28 | 
| Recommended Phase-2 Dose (RP2D) | RP2D of PF-05212384 was determined based on the safety profile including laboratory and clinical assessments and pharmacodynamics findings. | Baseline up to Cycle 14 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of PF-05212384: Single and Multiple Dose |  | Cycle 1: predose, 0.5, 2, 3, 6, 24, 72, 120 and 168 hours postdose on Day 1; Cycle 2: predose, 0.5, 24, 72, 120 hours postdose on Day 1 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05212384: Single Dose | Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (Clast). | Cycle 1: predose, 0.5, 2, 3, 6, 24, 72, 120 and 168 hours postdose on Day 1 | 
| Plasma Decay Half-Life (t1/2) of PF-05212384: Single and Multiple Dose | Plasma decay half-life is the time measured for the plasma concentration of drug to decrease by one half. | Cycle 1: predose, 0.5, 2, 3, 6, 24, 72, 120 and 168 hours postdose on Day 1; Cycle 2: predose, 0.5, 24, 72, 120 hours postdose on Day 1 | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-05212384: Single Dose | AUCinf= Area under the plasma concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0 - inf). | Cycle 1: predose, 0.5, 2, 3, 6, 24, 72, 120 and 168 hours postdose on Day 1 | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05212384: Single and Multiple Dose | Area under the concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 168 hours (1 Week). For Cycle 2, the last PK sample for parameter calculations was on 120 hours after the Day 1 dose, however AUCtau was extrapolated to 168 hours using t1/2. | Cycle 1: predose, 0.5, 2, 3, 6, 24, 72, 120 and 168 hours postdose on Day 1; Cycle 2: predose, 0.5, 24, 72, 120 hours postdose on Day 1 | 
| Number of Participants With Maximum Increase From Baseline in Corrected QT Interval | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Number of Participants with maximum increase from baseline in QTcB and QTcF of < 30 msec, between <=30 to <60 msec and >=60 were reported. | Baseline up to Cycle 14 (each cycle is 28 days) | 
| Change From Baseline in Serum Glucose at Day 2 of Cycle 1, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and End of Treatment |  | Baseline, Day 2 of Cycle 1, thereafter Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 (each cycle 28 days) , end of treatment visit (up to Cycle 14) | 
| Change From Baseline in Serum Insulin at Day 2 of Cycle 1, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and End of Treatment |  | Baseline, Day 2 of Cycle 1, thereafter Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 (each cycle 28 days) , end of treatment visit (up to Cycle 14) | 
| Change From Baseline in Serum C-peptide at Day 2 of Cycle 1, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and End of Treatment |  | Baseline, Day 2 of Cycle 1, thereafter Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 (each cycle 28 days) , end of treatment visit (up to Cycle 14) | 
| Change From Baseline in Hair Follicle Biopsy Biomarkers at Cycle 1 Day 1 | Analysis of hair follicles was conducted using a Reverse Phase Microarrays (RPMA) assay. Phosphoprotein biomarkers measured were pAkt S473, pAkt T308, pStat3 (Y705), Ki-67, and pPRAS40 (T246). | Baseline, 2, 3 and 72 hours (H) postdose on Day 1 of Cycle 1 | 
| Change From Baseline in Fresh Tumor Biopsy Biomarkers at Cycle 1 Day 22 | Tumor biopsies were taken from participants of reporting arm PF-05212384 154 mg dose level at baseline and at Cycle 1/Day 22. Biopsies were fixed in optimal cutting temperature compound and analyzed via RPMA. The biomarkers tested were phosphorylated versions of the proteins: AKT S473, AKT T308, FKHR T24 / FKHR1 T32, and STAT3. This outcome measure was planned to be analyzed only for the reporting arm Part 1 and 2: PF-05212384 154 mg, as pre-specified in protocol. | Baseline, Day 22 of Cycle 1 | 
| 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 PIK3CA and phosphatase and tensin homolog (PTEN) by immunohistochemistry. | Baseline | 
| Percentage of Participants With Objective Response (OR) | Objective response was defined as having complete response (CR) or Partial Response (PR) assessed by RECIST 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). Percentage of participants with objective response were reported. | Baseline until disease progression or death due to any cause (up to Cycle 14 [each cycle 28 days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Dose Finding, Solid Tumors, Tumors, PF-05212384