First in Patient Study for PF-06840003 in Malignant Gliomas

Malignant Glioma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02764151
• Other study ID #: C0591001
• Status: Terminated
• Phase: Phase 1
• Start date: September 9, 2016
• Est. completion date: December 26, 2018

Study information

• Verified date: January 2020
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 17
• Est. completion date: December 26, 2018
• Est. primary completion date: December 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of WHO Grade IV glioblastoma or WHO Grade III anaplastic gliomas

• For patients with Grade IV GBM, recurrent disease at the time of the first or second recurrence or progression. For patients with Grade III anaplastic gliomas, recurrent disease at the time of at least a first recurrence but no more than a fourth recurrence or progression

• Karnofsky performance score greater than or equal to 70%

• Adequate bone marrow, kidney and liver function

Exclusion Criteria:

• History of CNS bleeding within 6 months of registration

• Previous anti-angiogenics or anti-vascular endothelial growth factor within 12 months of registration

• Requires treatment with high dose systemic corticosteroids defined as >2 mg/day

• Radiation therapy within 12 weeks of registration

Related Conditions & MeSH terms

• Astrocytoma
• Glioma
• Malignant Glioma
• Oligodendroglioma

Intervention

Drug:
• PF-06840003
Daily Oral PF-06840003

Locations

Country	Name	City	State
United States	University of New Mexico Comprehensive Cancer Center	Albuquerque	New Mexico
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Duke Cancer Center	Durham	North Carolina
United States	Duke University Medical Center, Duke Cancer Center	Durham	North Carolina
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	UCLA Clinical & Translational Research Center	Los Angeles	California
United States	UCLA Oncology Center	Los Angeles	California
United States	UCLA School of Medicine	Los Angeles	California
United States	Columbia University Medical Center	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	CUMC Research Pharmacy	New York	New York
United States	Columbia Doctors Tarrytown	Tarrytown	New York

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities (DLTs) [Part 1]	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.	Baseline to Day 28
Primary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Part 1]	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.	Baseline up to 1 year
Primary	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]	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.	Baseline up to 1 year
Secondary	Objective Response Rate (ORR) [Part 1]	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.	Weeks 8, 16, and 24
Secondary	Disease Control Rate (DCR) Based on the Immunotherapy Response Assessment for Neuro-Oncology (iRANO) Criteria [Part 1]	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.	Weeks 8, 16, and 24
Secondary	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]	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.	Baseline up to 1 year
Secondary	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]	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.	Baseline up to 1 year
Secondary	Number of Participants With Clinically Significant Findings in Vital Signs [Part 1]	Vital signs included measurements of blood pressure and temperature (oral, tympanic, temporal or axillary). The investigator judged any clinically significant vital signs findings.	Baseline up to 1 year
Secondary	Single Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]	Cmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]	Tmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data as time of first occurence.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	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]	AUClast of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	Single Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]	AUCtau of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	Single Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]	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.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	Single Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]	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.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	Single Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]	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.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	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]	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.	Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose
Secondary	Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]	Cmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]	Tmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data as time of first occurence.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]	AUCtau of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]	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.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06840002 and PF-06840001 [Part 1]	Cmin of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Average Concentration for the Dosing Interval (Cav) of PF-06840002 and PF-06840001 [Part 1]	Cav of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]	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).	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]	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.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Observed Accumulation Ratio (Rac) of PF-06840002 and PF-06840001 [Part 1]	Rac of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUCtau (steady state) / AUCtau (single dose).	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Multiple Dose: Steady State Accumulation Ratio (Rss) of PF-06840002 and PF-06840001 [Part 1]	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.	Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post
Secondary	Steady-State Trough Level Ratio [Part 1]	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.	Baseline and Day 15
Secondary	Plasma Kynurenine and Tryptophan [Part 1]	The levels of Kynurenine and Tryptophan in blood samples were determined using the qualified analytical method.	Cycle 1 Day 1 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose; Cycle 1 Day 4 and Day 8 pre-dose; Cycle 1 Day 15 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose
Secondary	Plasma Endogenous Kynurenine/Tryptophan Ratio [Part 1]	The Kynurenine/Tryptophan ratio was determined by 1000*Kynurenine/Tryptophan.	Cycle 1 Day 1 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose; Cycle 1 Day 4 and Day 8 pre-dose; Cycle 1 Day 15 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose

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