Neoplasms

All Conditions

Rare Diseases

Glioma

Astrocytoma

Oligodendroglioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

PF-06840003

Pfizer CT.gov Call Center

This study will evaluate the safety and tolerability of increasing doses of PF-06840003 in patients with malignant gliomas.

First in Patient Study for PF-06840003 in Malignant Gliomas

A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND TOLERABILITY OF PF-06840003 IN PATIENTS WITH MALIGNANT GLIOMAS

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

DLTs: Any of the following adverse events (AE) occurring in the first cycle of treatment, unless there is a clear alternative explanation. Hematologic: Grade (Gr) 4 neutropenia lasting \>=5 days; febrile neutropenia; Gr\>=3 neutropenic with infection; Gr\>=3 thrombocytopenia with bleeding; Gr 4 thrombocytopenia. Non-Hematologic: Any toxicity attributable to PF-06840003 that resulted in administration of less than 80% of the planned doses during Cycle 1; Gr 4 non-hematologic AE; Gr 3 AE lasting \>7 days despite optimal supportive care; Gr 3 central nervous system (CNS) AE regardless of duration; Gr 3 QTc prolongation (QTc \>500 milliseconds) (a DLT only if persisting after correction of any reversible causes); Concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3\*upper limit of normal (ULN) and total bilirubin \>2\*ULN.

An AE was any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. TEAEs were those with initial onset or increasing in severity after the first dose of study treatment.

Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.

Objective response rate (ORR), defined as the percentage of patients achieving complete response (CR) or partial response (PR) as assessed by Macdonald criteria: CR: complete disappearance of all enhancing measurable and non-measurable disease on consecutive MRI at least 4 weeks apart, off steroid, sustained for at least 4 weeks; PR: \>=50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks.

Disease control rate (DCR) was defined as the percentage of patients achieving CR, PR, or stable disease (SD). Overall DCR was based on iRANO criteria: CR: complete disappearance of all enhancing measurable and non-measurable disease on consecutive MRI at least 4 weeks apart, off steroid, sustained for at least 4 weeks; PR: \>=50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; SD: does not qualify for CR, PR, or progression disease, and stable clinically.

Following parameters were analyzed for hematology laboratory test: hemoglobin, platelets, white blood cell (WBC), absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, and absolute basophils. Laboratory abnormalities were graded per NCI CTCAE version 4.03 and those with at least 1 participant are presented here.

Following parameters were analyzed for chemistry laboratory test: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, and phosphorous or phosphate. Laboratory abnormalities were graded per NCI CTCAE version 4.03 and those with at least 1 participant are presented here.

Vital signs included measurements of blood pressure and temperature (oral, tympanic, temporal or axillary). The investigator judged any clinically significant vital signs findings.

Cmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data.

Tmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data as time of first occurence.

AUClast of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.

AUCtau of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.

CL/F of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Dose/Area under the concentration-time profile from time 0 extrapolated to infinite time (AUCinf). The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest.

Vz/F of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Dose/(AUC\*kel). AUC is the area under concentration curve and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest.

t1/2 of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration-time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest.

AUCinf of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUClast + (Clast/kel), where AUClast is the area under the concentration-time profile from time zero to the time of the last quantifiable concentration, Clast is the predicted serum concentration at the last quantifiable time point estimated from the log linear regression analysis and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest.

Cmin of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data.

Cav of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data.

CL/F of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Dose/Area under the concentration-time profile from time 0 extrapolated to infinite time (AUCinf).

Rac of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUCtau (steady state) / AUCtau (single dose).

Rss of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUCtau (steady state) / AUCinf (single dose). The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest.

Steady-State trough level ratio was determined by cerebrospinal fluid (CSF)/Plasma. CSF/Plasma ratio was calculated based on the unbound concentration of each analyte. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest.

The levels of Kynurenine and Tryptophan in blood samples were determined using the qualified analytical method.

The Kynurenine/Tryptophan ratio was determined by 1000\*Kynurenine/Tryptophan.

Pfizer

The same event may appear as both an AE and an SAE. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study. Total number at risk below refers to the number of participants evaluable for SAEs or AEs.

PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles.

PF-06840003 125 MG QD

PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles.

PF-06840003 250 MG QD

PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles.

PF-06840003 250 MG BID

PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.

PF-06840003 500 MG BID

Total

Age, Continuous

Age, Customized

Sex: Female, Male

Race/Ethnicity, Customized

All Part 1 enrolled participants who received at least 1 dose of study treatment.

Part 2 of the study was not initiated. Because after reviewing efficacy, safety, PK and PD of all available data from enrolled patients, the Sponsor decided to prematurely terminate the study.

Pfizer ClinicalTrials.gov Call Center

Number of Participants With Dose Limiting Toxicities (DLTs) [Part 1]

All-causality TEAEs

Treatment-related TEAEs

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Part 1]

Grade 3 or 4

Grade 5

Number of Participants With TEAEs by Severity (as Graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Event [CTCAE] Version 4.03) [Part 1]

Week 8

Week 16

Week 24

The analysis population included all the participants enrolled.

Objective Response Rate (ORR) [Part 1]

Disease Control Rate (DCR) Based on the Immunotherapy Response Assessment for Neuro-Oncology (iRANO) Criteria [Part 1]

Anemia, Grade 0

Anemia, Grade 1

Anemia, Grade 2

Hemoglobin increased, Grade 0

Lymphocyte count increased, Grade 0

Lymphopenia, Grade 0

Lymphopenia, Grade 1

Lymphopenia, Grade 2

Lymphopenia, Grade 3

Neutrophils (absolute), Grade 0

Neutrophils (absolute), Grade 1

Neutrophils (absolute), Grade 2

Platelets, Grade 0

Platelets, Grade 1

WBC, Grade 0

WBC, Grade 1

WBC, Grade 2

Number of Participants With Hematology Laboratory Abnormalities by Severity (as Graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Event [CTCAE] Version 4.03) [Part 1]

ALT, Grade 0

ALT, Grade 1

ALT, Grade 3

ALT, Grade 4

Alkaline phosphatase, Grade 0

Alkaline phosphatase, Grade 1

AST, Grade 0

AST, Grade 2

AST, Grade 4

Bilirubin (total), Grade 0

Creatinine, Grade 0

Creatinine, Grade 1

Creatinine, Grade 2

Hypercalcemia, Grade 0

Hypercalcemia, Grade 1

Hyperglycemia, Grade 0

Hyperglycemia, Grade 1

Hyperglycemia, Grade 2

Hyperglycemia, Grade 3

Hyperkalemia, Grade 0

Hyperkalemia, Grade 3

Hypermagnesemia, Grade 0

Hypermagnesemia, Grade 1

Hypernatremia, Grade 0

Hypernatremia, Grade 1

Hypoalbuminemia, Grade 0

Hypoalbuminemia, Grade 1

Hypoalbuminemia, Grade 2

Hypocalcemia, Grade 0

Hypocalcemia, Grade 1

Hypocalcemia, Grade 2

Hypoglycemia, Grade 0

Hypoglycemia, Grade 1

Hypokalemia, Grade 0

Hypokalemia, Grade 1

Hypomagnesemia, Grade 0

Hypomagnesemia, Grade 1

Hyponatremia, Grade 0

Hyponatremia, Grade 1

Hyponatremia, Grade 3

Hypophosphatemia, Grade 0

Hypophosphatemia, Grade 2

Number of Participants With Chemistries Laboratory Abnormalities by Severity (as Graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Event [CTCAE] Version 4.03) [Part 1]

Number of Participants With Clinically Significant Findings in Vital Signs [Part 1]

PF-06840002

PF-06840001

The analysis population was defined as all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest.

Single Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]

Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]

Single Dose: Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PF-06840002 and PF-06840001 [Part 1]

Single Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]

The "Overall Number of Participants Analyzed" represents the total number of participants in the treatment group in the indicated population. The "Number Analyzed" represents the number of participants contributing to the summary statistics, i.e. number of participants where CL/F was determined.

Single Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]

The "Overall Number of Participants Analyzed" represents the total number of participants in the treatment group in the indicated population. The "Number Analyzed" represents the number of participants contributing to the summary statistics, i.e. number of participants where Vz/F was determined.

Single Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]

The "Overall Number of Participants Analyzed" represents the total number of participants in the treatment group in the indicated population. The "Number Analyzed" represents the number of participants contributing to the summary statistics, i.e. number of participants where t1/2 was determined.

Single Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]

The "Overall Number of Participants Analyzed" represents the total number of participants in the treatment group in the indicated population. The "Number Analyzed" represents the number of participants contributing to the summary statistics, i.e. number of participants where AUCinf was determined.

Single Dose: Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Average Concentration for the Dosing Interval (Cav) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]

Multiple Dose: Observed Accumulation Ratio (Rac) of PF-06840002 and PF-06840001 [Part 1]

The "Overall Number of Participants Analyzed" represents the total number of participants in the treatment group in the indicated population. The "Number Analyzed" represents the number of participants contributing to the summary statistics, i.e. number of participants where Rss was determined.

Multiple Dose: Steady State Accumulation Ratio (Rss) of PF-06840002 and PF-06840001 [Part 1]

The "Overall Number of Participants Analyzed" represents the total number of participants in the treatment group in the indicated population. The "Number Analyzed" represents the number of participants contributing to the summary statistics, i.e. number of participants where CSF/Plasma ratio was determined.

Steady-State Trough Level Ratio [Part 1]

Kynurenine

Tryptophan

The analysis population was the total number of participants in the treatment group in the indicated population.

Plasma Kynurenine and Tryptophan [Part 1]

The "Number of Participants Analyzed" represents the total number of participants in the treatment group in the indicated population on Cycle 1 Day. The "Number Analyzed" represents the number of participants contributing to the summary statistics at the end of treatment.

Spots Global Cancer Trial Database for First in Patient Study for PF-06840003 in Malignant Gliomas

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

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