First in Patient Study for PF-06840003 in Malignant Gliomas

Sponsor
Pfizer (Industry)
Overall Status
Terminated
CT.gov ID
NCT02764151
Collaborator
(none)
17
14
1
27.5
1.2
0

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
17 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND TOLERABILITY OF PF-06840003 IN PATIENTS WITH MALIGNANT GLIOMAS
Actual Study Start Date :
Sep 9, 2016
Actual Primary Completion Date :
Dec 26, 2018
Actual Study Completion Date :
Dec 26, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: PF-06840003

Daily Oral PF-06840003

Drug: PF-06840003
Daily Oral PF-06840003

Outcome Measures

Primary Outcome Measures

  1. Number of Participants With Dose Limiting Toxicities (DLTs) [Part 1] [Baseline to Day 28]

    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.

  2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Part 1] [Baseline up to 1 year]

    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.

  3. 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] [Baseline up to 1 year]

    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.

Secondary Outcome Measures

  1. Objective Response Rate (ORR) [Part 1] [Weeks 8, 16, and 24]

    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.

  2. Disease Control Rate (DCR) Based on the Immunotherapy Response Assessment for Neuro-Oncology (iRANO) Criteria [Part 1] [Weeks 8, 16, and 24]

    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.

  3. 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] [Baseline up to 1 year]

    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.

  4. 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] [Baseline up to 1 year]

    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.

  5. Number of Participants With Clinically Significant Findings in Vital Signs [Part 1] [Baseline up to 1 year]

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

  6. Single Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

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

  7. Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

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

  8. 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] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

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

  9. Single Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

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

  10. Single Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

    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.

  11. Single Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

    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.

  12. Single Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

    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.

  13. 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] [Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose]

    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.

  14. Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

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

  15. Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

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

  16. Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

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

  17. Multiple Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

    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.

  18. Multiple Dose: Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

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

  19. Multiple Dose: Average Concentration for the Dosing Interval (Cav) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

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

  20. Multiple Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

    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).

  21. Multiple Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

    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.

  22. Multiple Dose: Observed Accumulation Ratio (Rac) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

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

  23. Multiple Dose: Steady State Accumulation Ratio (Rss) of PF-06840002 and PF-06840001 [Part 1] [Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post]

    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.

  24. Steady-State Trough Level Ratio [Part 1] [Baseline and Day 15]

    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.

  25. Plasma Kynurenine and Tryptophan [Part 1] [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]

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

  26. Plasma Endogenous Kynurenine/Tryptophan Ratio [Part 1] [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]

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

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Ronald Reagan UCLA Medical Center Los Angeles California United States 90095-6894
2 UCLA Clinical & Translational Research Center Los Angeles California United States 90095
3 UCLA Oncology Center Los Angeles California United States 90095
4 UCLA School of Medicine Los Angeles California United States 90095
5 Massachusetts General Hospital Boston Massachusetts United States 02114
6 Brigham & Women's Hospital Boston Massachusetts United States 02115
7 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
8 University of New Mexico Comprehensive Cancer Center Albuquerque New Mexico United States 87102
9 Columbia University Medical Center New York New York United States 10019
10 Columbia University Medical Center New York New York United States 10032
11 CUMC Research Pharmacy New York New York United States 10032
12 Columbia Doctors Tarrytown Tarrytown New York United States 10591
13 Duke Cancer Center Durham North Carolina United States 27710
14 Duke University Medical Center, Duke Cancer Center Durham North Carolina United States 27710

Sponsors and Collaborators

  • Pfizer

Investigators

  • Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT02764151
Other Study ID Numbers:
  • C0591001
First Posted:
May 6, 2016
Last Update Posted:
Jan 27, 2020
Last Verified:
Jan 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Keywords provided by Pfizer
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail After reviewing efficacy, safety, PK and PD of all available data from enrolled patients, the Sponsor decided to prematurely terminate the study and not to pursue marketing approval for PF-06840003 in the indication of malignant glioma. Part 2 of the study was not initiated.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Period Title: Overall Study
STARTED 2 4 3 8
COMPLETED 2 4 3 5
NOT COMPLETED 0 0 0 3

Baseline Characteristics

Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID Total
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles. Total of all reporting groups
Overall Participants 2 4 3 8 17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
44.5
(19.1)
51.8
(14.5)
49.3
(12.1)
58.1
(14.6)
53.5
(14.1)
Age, Customized (Count of Participants)
18-44 Years
1
50%
2
50%
1
33.3%
1
12.5%
5
29.4%
45-64 Years
1
50%
1
25%
2
66.7%
3
37.5%
7
41.2%
>=65 Years
0
0%
1
25%
0
0%
4
50%
5
29.4%
Sex: Female, Male (Count of Participants)
Female
1
50%
0
0%
1
33.3%
3
37.5%
5
29.4%
Male
1
50%
4
100%
2
66.7%
5
62.5%
12
70.6%
Race/Ethnicity, Customized (Count of Participants)
White
2
100%
4
100%
3
100%
7
87.5%
16
94.1%
Asian
0
0%
0
0%
0
0%
1
12.5%
1
5.9%

Outcome Measures

1. Primary Outcome
Title Number of Participants With Dose Limiting Toxicities (DLTs) [Part 1]
Description 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.
Time Frame Baseline to Day 28

Outcome Measure Data

Analysis Population Description
All Part 1 enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Count of Participants [Participants]
0
0%
0
0%
0
0%
1
12.5%
2. Primary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Part 1]
Description 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.
Time Frame Baseline up to 1 year

Outcome Measure Data

Analysis Population Description
All Part 1 enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
All-causality TEAEs
2
100%
4
100%
3
100%
8
100%
Treatment-related TEAEs
1
50%
4
100%
2
66.7%
7
87.5%
3. Primary Outcome
Title 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]
Description 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.
Time Frame Baseline up to 1 year

Outcome Measure Data

Analysis Population Description
All Part 1 enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Grade 3 or 4
0
0%
1
25%
1
33.3%
2
25%
Grade 5
0
0%
0
0%
0
0%
0
0%
4. Secondary Outcome
Title Objective Response Rate (ORR) [Part 1]
Description 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.
Time Frame Weeks 8, 16, and 24

Outcome Measure Data

Analysis Population Description
The analysis population included all the participants enrolled.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Week 8
0.00
0%
0.00
0%
0.00
0%
0.00
0%
Week 16
0.00
0%
0.00
0%
0.00
0%
0.00
0%
Week 24
0.00
0%
0.00
0%
0.00
0%
0.00
0%
5. Secondary Outcome
Title Disease Control Rate (DCR) Based on the Immunotherapy Response Assessment for Neuro-Oncology (iRANO) Criteria [Part 1]
Description 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.
Time Frame Weeks 8, 16, and 24

Outcome Measure Data

Analysis Population Description
The analysis population included all the participants enrolled.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Week 8
50.0
2500%
50.0
1250%
33.3
1110%
25.0
312.5%
Week 16
50.0
2500%
0.0
0%
66.7
2223.3%
25.0
312.5%
Week 24
0.0
0%
0.0
0%
0.0
0%
25.0
312.5%
6. Secondary Outcome
Title 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]
Description 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.
Time Frame Baseline up to 1 year

Outcome Measure Data

Analysis Population Description
All Part 1 enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Anemia, Grade 0
1
50%
2
50%
0
0%
2
25%
Anemia, Grade 1
0
0%
2
50%
3
100%
6
75%
Anemia, Grade 2
1
50%
0
0%
0
0%
0
0%
Hemoglobin increased, Grade 0
2
100%
4
100%
3
100%
8
100%
Lymphocyte count increased, Grade 0
2
100%
4
100%
3
100%
8
100%
Lymphopenia, Grade 0
1
50%
2
50%
1
33.3%
5
62.5%
Lymphopenia, Grade 1
1
50%
1
25%
0
0%
1
12.5%
Lymphopenia, Grade 2
0
0%
1
25%
1
33.3%
0
0%
Lymphopenia, Grade 3
0
0%
0
0%
1
33.3%
2
25%
Neutrophils (absolute), Grade 0
1
50%
3
75%
2
66.7%
7
87.5%
Neutrophils (absolute), Grade 1
1
50%
1
25%
0
0%
1
12.5%
Neutrophils (absolute), Grade 2
0
0%
0
0%
1
33.3%
0
0%
Platelets, Grade 0
2
100%
2
50%
3
100%
5
62.5%
Platelets, Grade 1
0
0%
2
50%
0
0%
3
37.5%
WBC, Grade 0
2
100%
3
75%
1
33.3%
6
75%
WBC, Grade 1
0
0%
1
25%
1
33.3%
1
12.5%
WBC, Grade 2
0
0%
0
0%
1
33.3%
1
12.5%
7. Secondary Outcome
Title 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]
Description 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.
Time Frame Baseline up to 1 year

Outcome Measure Data

Analysis Population Description
All Part 1 enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
ALT, Grade 0
2
100%
2
50%
3
100%
7
87.5%
ALT, Grade 1
0
0%
1
25%
0
0%
0
0%
ALT, Grade 3
0
0%
1
25%
0
0%
0
0%
ALT, Grade 4
0
0%
0
0%
0
0%
1
12.5%
Alkaline phosphatase, Grade 0
2
100%
3
75%
3
100%
6
75%
Alkaline phosphatase, Grade 1
0
0%
1
25%
0
0%
2
25%
AST, Grade 0
2
100%
3
75%
3
100%
7
87.5%
AST, Grade 2
0
0%
1
25%
0
0%
0
0%
AST, Grade 4
0
0%
0
0%
0
0%
1
12.5%
Bilirubin (total), Grade 0
2
100%
4
100%
3
100%
8
100%
Creatinine, Grade 0
0
0%
0
0%
1
33.3%
0
0%
Creatinine, Grade 1
2
100%
4
100%
2
66.7%
7
87.5%
Creatinine, Grade 2
0
0%
0
0%
0
0%
1
12.5%
Hypercalcemia, Grade 0
1
50%
4
100%
3
100%
8
100%
Hypercalcemia, Grade 1
1
50%
0
0%
0
0%
0
0%
Hyperglycemia, Grade 0
1
50%
0
0%
3
100%
1
12.5%
Hyperglycemia, Grade 1
1
50%
4
100%
0
0%
4
50%
Hyperglycemia, Grade 2
0
0%
0
0%
0
0%
2
25%
Hyperglycemia, Grade 3
0
0%
0
0%
0
0%
1
12.5%
Hyperkalemia, Grade 0
2
100%
4
100%
3
100%
7
87.5%
Hyperkalemia, Grade 3
0
0%
0
0%
0
0%
1
12.5%
Hypermagnesemia, Grade 0
2
100%
4
100%
3
100%
7
87.5%
Hypermagnesemia, Grade 1
0
0%
0
0%
0
0%
1
12.5%
Hypernatremia, Grade 0
2
100%
4
100%
3
100%
7
87.5%
Hypernatremia, Grade 1
0
0%
0
0%
0
0%
1
12.5%
Hypoalbuminemia, Grade 0
2
100%
3
75%
3
100%
5
62.5%
Hypoalbuminemia, Grade 1
0
0%
1
25%
0
0%
2
25%
Hypoalbuminemia, Grade 2
0
0%
0
0%
0
0%
1
12.5%
Hypocalcemia, Grade 0
2
100%
3
75%
0
0%
6
75%
Hypocalcemia, Grade 1
0
0%
1
25%
3
100%
1
12.5%
Hypocalcemia, Grade 2
0
0%
0
0%
0
0%
1
12.5%
Hypoglycemia, Grade 0
2
100%
3
75%
3
100%
8
100%
Hypoglycemia, Grade 1
0
0%
1
25%
0
0%
0
0%
Hypokalemia, Grade 0
2
100%
4
100%
1
33.3%
4
50%
Hypokalemia, Grade 1
0
0%
0
0%
2
66.7%
4
50%
Hypomagnesemia, Grade 0
2
100%
4
100%
2
66.7%
8
100%
Hypomagnesemia, Grade 1
0
0%
0
0%
1
33.3%
0
0%
Hyponatremia, Grade 0
2
100%
4
100%
1
33.3%
7
87.5%
Hyponatremia, Grade 1
0
0%
0
0%
1
33.3%
1
12.5%
Hyponatremia, Grade 3
0
0%
0
0%
1
33.3%
0
0%
Hypophosphatemia, Grade 0
2
100%
4
100%
3
100%
6
75%
Hypophosphatemia, Grade 2
0
0%
0
0%
0
0%
2
25%
8. Secondary Outcome
Title Number of Participants With Clinically Significant Findings in Vital Signs [Part 1]
Description Vital signs included measurements of blood pressure and temperature (oral, tympanic, temporal or axillary). The investigator judged any clinically significant vital signs findings.
Time Frame Baseline up to 1 year

Outcome Measure Data

Analysis Population Description
All Part 1 enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Count of Participants [Participants]
0
0%
0
0%
0
0%
0
0%
9. Secondary Outcome
Title Single Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]
Description Cmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
775.0
(37)
1135
(6)
1407
(23)
PF-06840001
NA
(NA)
1309
(28)
1763
(8)
2286
(20)
10. Secondary Outcome
Title Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]
Description Tmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data as time of first occurence.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
1.58
1.51
1.95
3.02
PF-06840001
2.50
2.05
2.05
3.98
11. Secondary Outcome
Title 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]
Description AUClast of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
4517
(80)
13340
(21)
17720
(78)
PF-06840001
NA
(NA)
7626
(66)
21670
(24)
28250
(71)
12. Secondary Outcome
Title Single Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]
Description AUCtau of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
5356
(60)
7606
(11)
8653
(57)
PF-06840001
NA
(NA)
8999
(49)
12280
(15)
13910
(52)
13. Secondary Outcome
Title Single Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]
Description 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.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
751.6
(85)
1561
(40)
PF-06840001
NA
(NA)
454.6
(69)
965.4
(39)
14. Secondary Outcome
Title Single Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]
Description 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.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
228.4
(27)
277.2
(20)
PF-06840001
NA
(NA)
129.3
(12)
159.6
(25)
15. Secondary Outcome
Title Single Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]
Description 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.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
3.773
(1.5931)
2.090
(0.45033)
PF-06840001
NA
(NA)
3.580
(1.5943)
1.943
(0.39273)
16. Secondary Outcome
Title 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]
Description 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.
Time Frame Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
5549
(85)
5343
(40)
PF-06840001
NA
(NA)
9174
(69)
8645
(39)
17. Secondary Outcome
Title Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]
Description Cmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
779.3
(9)
1763
(25)
2474
(66)
PF-06840001
NA
(NA)
1334
(5)
2810
(24)
3978
(58)
18. Secondary Outcome
Title Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]
Description Tmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data as time of first occurence.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
3.00
3.03
2.00
3.02
PF-06840001
3.00
3.03
2.00
3.95
19. Secondary Outcome
Title Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]
Description AUCtau of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
6680
(75)
12730
(50)
20410
(96)
PF-06840001
NA
(NA)
10440
(64)
21020
(50)
32080
(89)
20. Secondary Outcome
Title Multiple Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]
Description 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.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
5.58
2.90
2.68
2.885
PF-06840001
5.505
2.61
2.50
2.685
21. Secondary Outcome
Title Multiple Dose: Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06840002 and PF-06840001 [Part 1]
Description Cmin of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
15.85
(21.622)
687.3
(409.76)
1611
(1749.7)
PF-06840001
NA
(NA)
21.75
(27.298)
1079
(587.86)
2308
(2161.3)
22. Secondary Outcome
Title Multiple Dose: Average Concentration for the Dosing Interval (Cav) of PF-06840002 and PF-06840001 [Part 1]
Description Cav of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
278
(75)
1060
(50)
1702
(96)
PF-06840001
NA
(NA)
435.1
(64)
1755
(49)
2673
(89)
23. Secondary Outcome
Title Multiple Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]
Description 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).
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
624.2
(75)
327.6
(50)
408.3
(96)
PF-06840001
NA
(NA)
399.1
(64)
198.2
(50)
259.5
(89)
24. Secondary Outcome
Title Multiple Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]
Description 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.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
184.5
216
128
270.5
PF-06840001
102.6
117
72.6
162
25. Secondary Outcome
Title Multiple Dose: Observed Accumulation Ratio (Rac) of PF-06840002 and PF-06840001 [Part 1]
Description Rac of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUCtau (steady state) / AUCtau (single dose).
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
1.244
(31)
1.670
(45)
2.359
(45)
PF-06840001
NA
(NA)
1.163
(31)
1.717
(45)
2.304
(41)
26. Secondary Outcome
Title Multiple Dose: Steady State Accumulation Ratio (Rss) of PF-06840002 and PF-06840001 [Part 1]
Description 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.
Time Frame Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
NA
(NA)
1.289
(37)
1.961
(72)
PF-06840001
NA
(NA)
1.266
(31)
1.895
(61)
27. Secondary Outcome
Title Steady-State Trough Level Ratio [Part 1]
Description 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.
Time Frame Baseline and Day 15

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
PF-06840002
1.00
(0.007)
1.00
(0.692)
PF-06840001
0.89
(0.105)
0.88
(0.619)
28. Secondary Outcome
Title Plasma Kynurenine and Tryptophan [Part 1]
Description The levels of Kynurenine and Tryptophan in blood samples were determined using the qualified analytical method.
Time Frame 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

Outcome Measure Data

Analysis Population Description
The analysis population was the total number of participants in the treatment group in the indicated population.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Kynurenine
1.545
(0.2051)
2.185
(1.7443)
1.144
(0.1479)
1.523
(0.4321)
Tryptophan
48.15
(4.596)
29.55
(4.611)
36.77
(7.681)
33.10
(4.590)
29. Secondary Outcome
Title Plasma Endogenous Kynurenine/Tryptophan Ratio [Part 1]
Description The Kynurenine/Tryptophan ratio was determined by 1000*Kynurenine/Tryptophan.
Time Frame 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
Measure Participants 2 4 3 8
Mean (Standard Deviation) [ratio]
38.467
(0.6791)
53.066
(24.9722)
25.854
(7.6209)
42.463
(NA)

Adverse Events

Time Frame Baseline up to 1 year
Adverse Event Reporting Description 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.
Arm/Group Title PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Arm/Group Description PF-06840003 (formulated 125 mg tablets) was administered orally at 125 mg once daily (QD) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg QD for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 250 mg twice daily (BID) for 28-day cycles. PF-06840003 (formulated 125 mg tablets) was administered orally at 500 mg BID for 28-day cycles.
All Cause Mortality
PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%)
Serious Adverse Events
PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/2 (0%) 1/4 (25%) 0/3 (0%) 3/8 (37.5%)
Infections and infestations
Lung infection 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Investigations
Alanine aminotransferase increased 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Aspartate aminotransferase increased 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioblastoma multiforme 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Nervous system disorders
Encephalopathy 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Generalised tonic-clonic seizure 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Headache 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Hemiparesis 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Other (Not Including Serious) Adverse Events
PF-06840003 125 MG QD PF-06840003 250 MG QD PF-06840003 250 MG BID PF-06840003 500 MG BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/2 (100%) 4/4 (100%) 3/3 (100%) 8/8 (100%)
Blood and lymphatic system disorders
Anaemia 1/2 (50%) 2/4 (50%) 3/3 (100%) 3/8 (37.5%)
Cardiac disorders
Bradycardia 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Left ventricular dysfunction 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Ear and labyrinth disorders
Ear pain 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Tinnitus 0/2 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Vertigo 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Gastrointestinal disorders
Anal incontinence 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Constipation 1/2 (50%) 0/4 (0%) 0/3 (0%) 0/8 (0%)
Diarrhoea 0/2 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Gastrooesophageal reflux disease 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Nausea 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Vomiting 1/2 (50%) 1/4 (25%) 1/3 (33.3%) 1/8 (12.5%)
General disorders
Fatigue 1/2 (50%) 3/4 (75%) 1/3 (33.3%) 4/8 (50%)
Influenza like illness 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Non-cardiac chest pain 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Oedema 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Oedema peripheral 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Pyrexia 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Infections and infestations
Fungal skin infection 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Lung infection 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Upper respiratory tract infection 1/2 (50%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Urinary tract infection 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Injury, poisoning and procedural complications
Fall 0/2 (0%) 0/4 (0%) 2/3 (66.7%) 1/8 (12.5%)
Investigations
Alanine aminotransferase increased 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Aspartate aminotransferase increased 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Blood alkaline phosphatase increased 0/2 (0%) 2/4 (50%) 0/3 (0%) 1/8 (12.5%)
Blood bilirubin increased 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Blood creatinine increased 0/2 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Ejection fraction decreased 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Lymphocyte count decreased 0/2 (0%) 0/4 (0%) 2/3 (66.7%) 1/8 (12.5%)
Neutrophil count decreased 0/2 (0%) 1/4 (25%) 1/3 (33.3%) 1/8 (12.5%)
Platelet count decreased 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Protein total increased 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Weight decreased 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
White blood cell count decreased 0/2 (0%) 1/4 (25%) 2/3 (66.7%) 1/8 (12.5%)
Metabolism and nutrition disorders
Decreased appetite 1/2 (50%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Hyperglycaemia 0/2 (0%) 3/4 (75%) 0/3 (0%) 2/8 (25%)
Hypocalcaemia 0/2 (0%) 0/4 (0%) 3/3 (100%) 1/8 (12.5%)
Hypokalaemia 0/2 (0%) 0/4 (0%) 2/3 (66.7%) 3/8 (37.5%)
Hypomagnesaemia 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Hyponatraemia 0/2 (0%) 0/4 (0%) 2/3 (66.7%) 1/8 (12.5%)
Hypophosphataemia 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%)
Muscular weakness 1/2 (50%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Myalgia 0/2 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Neck pain 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Pain in extremity 0/2 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Temporomandibular joint syndrome 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioblastoma multiforme 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Haemangioma of skin 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Nervous system disorders
Amnesia 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Aphasia 1/2 (50%) 0/4 (0%) 0/3 (0%) 4/8 (50%)
Apraxia 1/2 (50%) 0/4 (0%) 0/3 (0%) 0/8 (0%)
Ataxia 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Brain oedema 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Disturbance in attention 1/2 (50%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Dizziness 1/2 (50%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Dysarthria 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 2/8 (25%)
Facial paralysis 1/2 (50%) 0/4 (0%) 0/3 (0%) 0/8 (0%)
Facial paresis 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Headache 0/2 (0%) 2/4 (50%) 1/3 (33.3%) 2/8 (25%)
Hemianopia homonymous 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Hemiparesis 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Memory impairment 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Nystagmus 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Paraesthesia 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Partial seizures 1/2 (50%) 0/4 (0%) 0/3 (0%) 0/8 (0%)
Peripheral sensory neuropathy 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Peroneal nerve palsy 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Pyramidal tract syndrome 0/2 (0%) 0/4 (0%) 2/3 (66.7%) 1/8 (12.5%)
Seizure 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%)
Somnolence 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Tremor 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%)
Visual field defect 1/2 (50%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Psychiatric disorders
Agitation 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Confusional state 0/2 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%)
Depression 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Dysphoria 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Insomnia 0/2 (0%) 1/4 (25%) 1/3 (33.3%) 0/8 (0%)
Personality change 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Renal and urinary disorders
Chromaturia 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Micturition urgency 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Polyuria 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Proteinuria 1/2 (50%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Urinary incontinence 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion 1/2 (50%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Oropharyngeal pain 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Productive cough 1/2 (50%) 0/4 (0%) 0/3 (0%) 0/8 (0%)
Rhinitis allergic 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Sneezing 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)
Skin and subcutaneous tissue disorders
Acne 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Alopecia 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Dry skin 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%)
Rash 0/2 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%)
Vascular disorders
Hypertension 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%)
Hypotension 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%)

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

Name/Title Pfizer ClinicalTrials.gov Call Center
Organization Pfizer, Inc.
Phone 1-800-718-1021
Email ClinicalTrials.gov_Inquiries@pfizer.com
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT02764151
Other Study ID Numbers:
  • C0591001
First Posted:
May 6, 2016
Last Update Posted:
Jan 27, 2020
Last Verified:
Jan 1, 2020