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Study of PF-05212384 (Also Known as PKI-587)Administered Intravenously To Subjects With Solid Tumors (B2151001)

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ClinicalTrials.gov Identifier: NCT00940498
Recruitment Status : Completed
First Posted : July 16, 2009
Results First Posted : November 2, 2018
Last Update Posted : November 2, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: PF-05212384 (also known as PKI-587) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 78 participants
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study Of Pf-05212384 (Also Known As Pki-587) Administered As An Intravenous Infusion To Patients With Solid Tumors
Actual Study Start Date : January 2010
Actual Primary Completion Date : August 2011
Actual Study Completion Date : October 2012

Arm Intervention/treatment
Experimental: 1
PF-05212384 (also known as PKI-587)
Drug: PF-05212384 (also known as PKI-587)
Intravenous dosing once weekly infusion




Primary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Cycle 14 (each cycle is 28 days) ]
    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.

  2. Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Cycle 14 (each cycle is 28 days) ]
    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.

  3. Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to Cycle 14 (each cycle is 28 days) ]
    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]).

  4. Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Baseline up to Day 28 ]
    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.

  5. Recommended Phase-2 Dose (RP2D) [ Time Frame: Baseline up to Cycle 14 (each cycle is 28 days) ]
    RP2D of PF-05212384 was determined based on the safety profile including laboratory and clinical assessments and pharmacodynamics findings.


Secondary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of PF-05212384: Single and Multiple Dose [ Time Frame: 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 ]
  2. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05212384: Single Dose [ Time Frame: Cycle 1: predose, 0.5, 2, 3, 6, 24, 72, 120 and 168 hours postdose on Day 1 ]
    Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (Clast).

  3. Plasma Decay Half-Life (t1/2) of PF-05212384: Single and Multiple Dose [ Time Frame: 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 ]
    Plasma decay half-life is the time measured for the plasma concentration of drug to decrease by one half.

  4. Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-05212384: Single Dose [ Time Frame: Cycle 1: predose, 0.5, 2, 3, 6, 24, 72, 120 and 168 hours postdose on Day 1 ]
    AUCinf= Area under the plasma concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0 - inf).

  5. Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05212384: Single and Multiple Dose [ Time Frame: 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 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.

  6. Number of Participants With Maximum Increase From Baseline in Corrected QT Interval [ Time Frame: Baseline up to Cycle 14 (each cycle is 28 days) ]
    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.

  7. 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 [ Time Frame: 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) ]
  8. 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 [ Time Frame: 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) ]
  9. 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 [ Time Frame: 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) ]
  10. Change From Baseline in Hair Follicle Biopsy Biomarkers at Cycle 1 Day 1 [ Time Frame: Baseline, 2, 3 and 72 hours (H) postdose on Day 1 of Cycle 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).

  11. Change From Baseline in Fresh Tumor Biopsy Biomarkers at Cycle 1 Day 22 [ Time Frame: Baseline, Day 22 of Cycle 1 ]
    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.

  12. Number of Participants With Mutation, Deletion, Amplification in Phosphatidylinositol 3-kinase (PI3K) Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue [ Time Frame: Baseline ]
    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.

  13. Percentage of Participants With Objective Response (OR) [ Time Frame: Baseline until disease progression or death due to any cause (up to Cycle 14 [each cycle 28 days]) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00940498


Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana-Farber Cancer Insitute
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10022
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Tennessee
Sarah Cannon Research Institute, Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37203-1632
Spain
Hospital General Vall D'Hebron
Barcelona, Spain, 08035
United Kingdom
King's College London
London, England, United Kingdom, SE1 9RT
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00940498     History of Changes
Other Study ID Numbers: B2151001
3265K1-1002 ( Other Identifier: Alias Study Number )
2009-012379-85 ( EudraCT Number )
First Posted: July 16, 2009    Key Record Dates
Results First Posted: November 2, 2018
Last Update Posted: November 2, 2018
Last Verified: February 2018
Keywords provided by Pfizer:
Phase 1
Dose Finding
Solid Tumors
Tumors
PF-05212384
Additional relevant MeSH terms:
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Gedatolisib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action