All Drugs and Chemicals

Gedatolisib

Protein Kinase Inhibitors

Enzyme Inhibitors

PF-05212384 (also known as PKI-587)

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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.

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

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

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.

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.

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 \[\<0.8\*LLN or \>1.2\*ULN\]).

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.

RP2D of PF-05212384 was determined based on the safety profile including laboratory and clinical assessments and pharmacodynamics findings.

Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (Clast).

Plasma decay half-life is the time measured for the plasma concentration of drug to decrease by one half.

AUCinf= Area under the plasma concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0 - inf).

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.

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.

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).

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.

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.

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.

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The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.

PF-05212384 10 milligram (mg), intravenous (IV) infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Part 1: PF-05212384 10 mg

PF-05212384 21 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Part 1: PF-05212384 21 mg

PF-05212384 43 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Part 1: PF-05212384 43 mg

PF-05212384 89 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Part 1: PF-05212384 89 mg

PF-05212384 154 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) and Part 2 (MTD confirmation) of the study.

Part 1 and 2: PF-05212384 154 mg

PF-05212384 222 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Part 1: PF-05212384 222 mg

PF-05212384-266 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Part 1: PF-05212384 266 mg

PF-05212384-319 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Part 1: PF-05212384 319 mg

Total

Age, Categorical

Sex: Female, Male

Safety analysis set included all participants who received at least 1 dose of study medication.

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SAEs

Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) or Serious Adverse Events (SAEs)

Number of Participants With Laboratory Abnormalities

DLT evaluable analysis set included all enrolled participants who started treatment and did not have had a major treatment deviation in the first cycle of treatment.

Number of Participants With Dose Limiting Toxicities (DLTs)

All participants who received PF-05212384 10 mg or 21 mg or 43 mg or 89 mg or 154 mg or 222 mg or 266 mg or 319 mg, intravenous infusion, once weekly in each 28 day cycle until progression of disease, uncontrollable toxicity, or a decision by the participant or investigator to discontinue.

PF-05212384 : All Participants

Safety analysis population included all participants who received at least 1 dose of study medication.

Recommended Phase-2 Dose (RP2D)

Cycle 1

Cycle 2

PK parameter analysis population included all enrolled participants who received at least 1 dose of study drug and had at least 1 of the PK parameters of interest estimated.

Maximum Observed Plasma Concentration (Cmax) of PF-05212384: Single and Multiple Dose

PK parameter analysis population included all enrolled participants who received at least 1 dose of study drug and had at least 1 of the PK parameters of interest estimated. Here 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05212384: Single Dose

Plasma Decay Half-Life (t1/2) of PF-05212384: Single and Multiple Dose

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-05212384: Single Dose

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

QTcB: Change <30

QTcB: <= 30 and <60

QTcB: Change >=60

QTcF: Change <30

QTcF: <= 30 and <60

QTcF: Change >=60

The QTc analysis set included all enrolled participants who had at least one ECG assessment after receiving PF-05212384

Number of Participants With Maximum Increase From Baseline in Corrected QT Interval

Baseline

Change at Cycle 1 Day 2

Change at Cycle 2 Day 1

Change at Cycle 3 Day 1

Change at Cycle 4 Day 1

Change at Cycle 5 Day 1

Change at Cycle 6 Day 1

Change at Cycle 7 Day 1

Change at Cycle 8 Day 1

Change at Cycle 9 Day 1

Change at Cycle 10 Day 1

Change at Cycle 11 Day 1

Change at Cycle 12 Day 1

Change at Cycle 13 Day 1

Change at Cycle 14 Day 1

Change at EOT

Serum biomarker analysis set included all enrolled participants who started treatment and had baseline and on-treatment serum biomarker samples successfully analyzed for at least 1 biomarker.

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 ( n=4,1,3,2,35,4,4,3)

Change at Cycle 1 Day 2 (n =4,1,3,2,37,6,7,4)

Change at Cycle 2 Day 1 (n =0,0,0,2,27,5,3,1)

Change at Cycle 3 Day 1 (n =0,1,1,1,14,1,3,1)

Change at Cycle 4 Day 1 (n =0,0,1,1,8,0,3,2)

Change at Cycle 5 Day 1 (n =0,1,0,1,5,0,3,1)

Change at C6D1 (n=0,1,0,1,3,0,2,2)

Change at Cycle 7 Day 1 (n=0,1,0,1,2,0,3,1)

Change at Cycle 8 Day 1 (n =0,1,0,1,2,0,3,1)

Change at Cycle 9 Day 1 ( n=0,1,0,1,0,0,2,1)

Change at Cycle 10 Day 1 (n =1,1,0,0,0,0,0,1)

Change at Cycle 11 Day 1 (n =1,1,0,0,0,0,1,0)

Change at Cycle 12 Day 1 (n =1,0,0,0,0,0,0,0)

Change at Cycle 13 D 1 (n =0,0,0,0,0,0,1,0)

Change at Cycle 14 Day 1 (n =0,0,0,0,0,0,1,0)

Change at EOT (n =1,0,1,1,21,4,6,1)

Serum biomarker analysis set. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure (OM).

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

Serum biomarker analysis set. Here, N= participants evaluable for this outcome measure. Data for this outcome measure was not planned to be analyzed for reporting arms: PF-05212384 10 mg, 21 mg, 43 mg, 89 mg, and 319 mg, as pre specified in protocol Amendment 5.

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: pAkt S473

Baseline: pAkt T308

Baseline: pStat3 (Y705)

Baseline: Ki-67

Baseline: pPRAS40 (T246)

Change at C1D1 2H:pAkt S473

Change at C1D1 2H:pAkt T308

Change at C1D1 2H:pStat3 (Y705)

Change at C1D1 2H:Ki-67

Change at C1D1 2H:pPRAS40-T246

Change at C1D1 3hr: pAkt S473

Change at C1D1 3hr: pAkt T308

Change at C1D1 3H: pStat3 (Y705)

Change at C1D1 3hr: Ki-67

Change at C1D1 3H:pPRAS40-T246

Change at C1D4 72H:pAkt S473

Change at C1D4 72H:pAkt-T308

Change at C1D4 72H: pStat3 (Y705)

Change at C1D4 72hr: Ki-67

Change atC1D4-72H:pPRAS40 T246

Hair follicle analysis set. Here, N= participants evaluable for this outcome measure. Data for this outcome measure was not planned to be analyzed for reporting arms: PF-05212384 10 mg, 21 mg, 43 mg, 89 mg, and 319 mg, as pre specified in protocol Amendment 5.

Change From Baseline in Hair Follicle Biopsy Biomarkers at Cycle 1 Day 1

Baseline: AKT S473

Baseline: AKT T308

Baseline: FKHR T24 / FKHR1 T32

Baseline: STAT3

Change at C1D22: AKT S473

Change at C1D22: AKT T308

Change at C1D22: FKHR T24 / FKHR1 T32

Change at C1D22: STAT3

Tumor biopsy analysis set=all enrolled participants who had treatment \&had baseline,on-treatment tumor tissue successfully analyzed for at least 1 biomarker.N=participants evaluable for this OM. This OM was planned to analyzed only in reporting arm- Part 1 and 2:PF-05212384 154 mg.

Change From Baseline in Fresh Tumor Biopsy Biomarkers at Cycle 1 Day 22

PTEN Mutation: Present

PTEN Mutation: Absent

PTEN Deletion: Present

PTEN Deletion: Absent

PTEN Amplification: Present

PTEN Amplification: Absent

PIK3CA Mutation: Present

PIK3CA Mutation: Absent

PIK3CA Deletion: Present

PIK3CA Deletion: Absent

PIK3CA Amplification: Present

PIK3CA Amplification: Absent

PF-05212384-10,21,43,89,154,222,266,319 milligram (mg) intravenous infusion over approximately 30 minutes once weekly in each 28 day cycle until progression of disease, uncontrollable toxicity, or a decision by the patient or investigator to discontinue.

Baseline tumor tissue biomarker analysis set: All enrolled patients who start treatment and had baseline tumor tissues successfully analyzed for at least one of the biomarkers. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Number of Participants With Mutation, Deletion, Amplification in Phosphatidylinositol 3-kinase (PI3K) Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue

Entire study population treated with PF-05212384-10,21,43,89,154,222,266,319 mg intravenous infusion over approximately 30 minutes once weekly in each 28 day cycle until progression of disease, uncontrollable toxicity, or a decision by the participant or investigator to discontinue.

Response-evaluable population included participants who received at least 1 dose of study drug, had an adequate baseline tumor assessment and at least 1 post baseline disease assessment for analyses of response.

Percentage of Participants With Objective Response (OR)

PF-05212384 10 mg IV infusion, once weekly in each 28-day cycle until progression of disease, uncontrollable toxicity or a decision by the participant or investigator to discontinue during Part 1 (MTD estimation) of the study.

Spots Global Cancer Trial Database for Study of PF-05212384 (Also Known as PKI-587)Administered Intravenously To Subjects With Solid Tumors

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Study Description

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