A Study To Test The Impact Of PF- 00299804 On How The Body Handles Dextromethorphan In Cancer Patients
Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT00728468
Collaborator
Roswell Park Cancer Institute (Other), South Texas Accelerated Research Therapeutics (START) (Other)
16
2
1
69.9
8
0.1
Study Details
Study Description
Brief Summary
Research in test tubes suggests that may affect cytochrome P450 2D6 (CYP2D6), an important enzyme that is responsible for eliminating many drugs that cancer patients need to take, including dextromethorphan. The purpose of this study is to test the impact of PF-00299804 on the activity of CYP2D6, and how the human body handles dextromethorphan.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
To assess the effect of repeated dosing with 45 mg QD PF-00299804 on the pharmacokinetics of dextromethorphan, a CYP2D6 probe, in cancer patients with advanced malignant solid tumors.
Study Design
Study Type:
Interventional
Actual Enrollment
:
16 participants
Masking:
None (Open Label)
Official Title:
A Phase 1 Open Label, Single Arm Trial To Evaluate The Effect Of Pf-00299804 On The Pharmacokinetics Of Dextromethorphan In Patients With Advanced Malignant Solid Tumors
Study Start Date
:
Sep 1, 2008
Actual Primary Completion Date
:
Apr 1, 2011
Actual Study Completion Date
:
Jul 1, 2014
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment arm
|
Drug: PF-00299804
PF-00299804: Patients take oral 45 mg PF-00299804 once daily starting on Cycle 1 Day 1 until disease progression or unacceptable toxicities occur. One cycle equals 21 days. Dextromethorphan: Patient take a single 30 mg oral dose of dextromethorphan HBr three days prior to Cycle 1 Day 1, and then on Cycle 2 Day 7.
|
Outcome Measures
Primary Outcome Measures
- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing [Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Area under the plasma concentration time-curve from time zero (pre-dose) to the last measured concentration (AUClast). Dextrorphan is an active metabolite of dextromethorphan.
- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 [Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Area under the plasma concentration time-curve from time zero (pre-dose) to the last measured concentration (AUClast). Dextrorphan is an active metabolite of dextromethorphan.
- Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan 3 Days Prior to PF-00299804 Dosing [Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf). Dextrorphan is an active metabolite of dextromethorphan.
- Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan on Cycle 2 Day 7 [Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf). Dextrorphan is an active metabolite of dextromethorphan.
- Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing [Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Dextrorphan is an active metabolite of dextromethorphan.
- Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 [Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Dextrorphan is an active metabolite of dextromethorphan.
- Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing [Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Dextrorphan is an active metabolite of dextromethorphan.
- Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 [Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Dextrorphan is an active metabolite of dextromethorphan.
- Plasma Decay Half-Life (t1/2) For Dextrorphan 3 Days Prior to PF-00299804 Dosing [Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Dextrorphan is an active metabolite of dextromethorphan.
- Plasma Decay Half-Life (t1/2) For Dextrorphan on Cycle 2 Day 7 [Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Dextrorphan is an active metabolite of dextromethorphan.
- Oral Clearance For Dextromethorphan 3 Days Prior to PF-00299804 Dosing [Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
- Oral Clearance For Dextromethorphan on Cycle 2 Day 7 [Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
- Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan 3 Days Prior to PF-00299804 Dosing [8 hours after dosing on Day -3]
The UMR was calculated as the ratio of the amount of dextrmotherphan excreted in urine from time zero to 8 hours post-dose on Day -3 to the amount of dextrorphan excreted in urine from time zero to 8 hours post-dose on Day -3.
- Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan on Cycle 2 Day 7 [8 hours after dosing on Day 7]
The UMR was calculated as the ratio of the amount of dextrmotherphan excreted in urine from time zero to 8 hours post-dose on Day 7 to the amount of dextrorphan excreted in urine from time zero to 8 hours post-dose on Day 7.
Secondary Outcome Measures
- Best Overall Response (BOR) [Baseline, end of every even-numbered cycle until disease progression up to end of treatment (up to 18 months)]
BOR: investigator assessment by Response Evaluation Criteria in Solid Tumors (RECIST), recorded from treatment start until disease progression/recurrence. Complete Response: disappearance of all lesions. Partial Response (PR): >=30% decrease in sum of longest diameters (SLDs) of target lesions (TLs) taking as reference baseline SLD. Progressive disease (PD): >=20% increase in SLD of TLs taking as reference smallest SLD since treatment start, or appearance of >=1 new lesion. Stable disease: neither shrinkage for PR nor increase for PD taking as reference smallest SLD since treatment start.
- Duration of Response (DR) [Baseline, end of every even-numbered cycle until disease progression up to end of treatment (up to 18 months)]
Time in weeks from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response.
- Time to Tumor Progression (TTP) [Baseline, end of every even-numbered cycle until disease progression up to end of treatment (up to 18 months)]
Time in months from start of study treatment to first documentation of objective tumor progression or death due to cancer, whichever comes first. TTP was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.437. Tumor progression was determined from oncologic assessment data (where data meet the criteria for PD).
Other Outcome Measures
- Ratio of Dextromethorphan Area Under the Curve to Dextrorphan Area Under the Curve 3 Days Prior to PF-00299804 Dosing [Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Dextrorphan is an active metabolite of dextromethorphan.
- Ratio of Dextromethorphan Area Under the Curve to Dextrorphan Area Under the Curve on Cycle 2 Day 7 [Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose]
Dextrorphan is an active metabolite of dextromethorphan.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Patients with a histologically or cytologically confirmed advanced malignant solid tumor for which there is no currently approved treatment or which is unresponsive to currently approved therapies;
-
Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Patients with performance status 2 could be eligible upon agreement between sponsors and investigators;
-
Adequate bone marrow, renal, liver and cardiac functions;
Exclusion Criteria:
-
History of Interstitial Lung Disease (ILD).
-
Drugs with known CYP2D6 inhibitory effects
-
Drugs that are highly dependent on CYP2D6 for metabolism.
-
Women who are pregnant or breastfeeding.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
| 2 | South Texas Accelerated Research Therapeutics, LLC | San Antonio | Texas | United States | 78229 |
Sponsors and Collaborators
- Pfizer
- Roswell Park Cancer Institute
- South Texas Accelerated Research Therapeutics (START)
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT00728468
Other Study ID Numbers:
- A7471014
First Posted:
Aug 5, 2008
Last Update Posted:
Aug 2, 2017
Last Verified:
Apr 1, 2017
Keywords provided by Pfizer
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Period Title: Overall Study | |
| STARTED | 16 |
| Treated | 15 |
| COMPLETED | 0 |
| NOT COMPLETED | 16 |
Baseline Characteristics
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Overall Participants | 15 |
| Age (Years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [Years] |
57.1
(12.0)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
6
40%
|
| Male |
9
60%
|
Outcome Measures
| Title | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | Area under the plasma concentration time-curve from time zero (pre-dose) to the last measured concentration (AUClast). Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic (PK) analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Dextromethorphan |
206.4
(404.63)
|
| Dextrorphan |
2199
(1085.7)
|
| Title | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 |
|---|---|
| Description | Area under the plasma concentration time-curve from time zero (pre-dose) to the last measured concentration (AUClast). Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Dextromethorphan |
300.7
(408.42)
|
| Dextrorphan |
2232
(1253.2)
|
| Title | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf). Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Mean (Standard Deviation) [ng*hr/mL] |
2266
(955.97)
|
| Title | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan on Cycle 2 Day 7 |
|---|---|
| Description | AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf). Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Mean (Standard Deviation) [ng*hr/mL] |
2298
(1245.4)
|
| Title | Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Dextromethorphan |
6.598
(7.4826)
|
| Dextrorphan |
239.2
(137.56)
|
| Title | Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 |
|---|---|
| Description | Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Dextromethorphan |
11.11
(7.8689)
|
| Dextrorphan |
169.2
(103.18)
|
| Title | Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Dextromethorphan |
2.00
|
| Dextrorphan |
2.00
|
| Title | Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 |
|---|---|
| Description | Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Dextromethorphan |
3.00
|
| Dextrorphan |
4.00
|
| Title | Plasma Decay Half-Life (t1/2) For Dextrorphan 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Mean (Standard Deviation) [hours] |
20.20
(28.645)
|
| Title | Plasma Decay Half-Life (t1/2) For Dextrorphan on Cycle 2 Day 7 |
|---|---|
| Description | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis population included all participants that were extensive metabolizers and treated, had at least 1 of PK parameters of primary interest in at least 1 treatment period. Here, N (number of participants analyzed) signifies who received PF-00299804 daily without interruptions or dose reductions prior to Day 7 of Cycle 2. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Mean (Standard Deviation) [hours] |
17.25
(15.935)
|
| Title | Oral Clearance For Dextromethorphan 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Time Frame | Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Results not reported as data did not support calculation since levels of dextromethorphan were not tracked long enough for reliable estimation. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 0 |
| Title | Oral Clearance For Dextromethorphan on Cycle 2 Day 7 |
|---|---|
| Description | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Time Frame | Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Results not reported as data did not support calculation since levels of dextromethorphan were not tracked long enough for reliable estimation. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 0 |
| Title | Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | The UMR was calculated as the ratio of the amount of dextrmotherphan excreted in urine from time zero to 8 hours post-dose on Day -3 to the amount of dextrorphan excreted in urine from time zero to 8 hours post-dose on Day -3. |
| Time Frame | 8 hours after dosing on Day -3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK parameter analysis population: all participants enrolled who were extensive metabolizers (EM), & treated who had at least 1 PK parameter of primary interest in at least 1 treatment period. EMs were defined as participants with a baseline UMR ≤0.3 & were either ultrarapid, extensive, or intermediate metabolizers as predicted by CYP2D6 genotyping. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 4 |
| Mean (Standard Deviation) [ratio] |
0.008800
(0.017600)
|
| Title | Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan on Cycle 2 Day 7 |
|---|---|
| Description | The UMR was calculated as the ratio of the amount of dextrmotherphan excreted in urine from time zero to 8 hours post-dose on Day 7 to the amount of dextrorphan excreted in urine from time zero to 8 hours post-dose on Day 7. |
| Time Frame | 8 hours after dosing on Day 7 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK parameter analysis population |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 5 |
| Mean (Standard Deviation) [ratio] |
0.08040
(0.11042)
|
| Title | Best Overall Response (BOR) |
|---|---|
| Description | BOR: investigator assessment by Response Evaluation Criteria in Solid Tumors (RECIST), recorded from treatment start until disease progression/recurrence. Complete Response: disappearance of all lesions. Partial Response (PR): >=30% decrease in sum of longest diameters (SLDs) of target lesions (TLs) taking as reference baseline SLD. Progressive disease (PD): >=20% increase in SLD of TLs taking as reference smallest SLD since treatment start, or appearance of >=1 new lesion. Stable disease: neither shrinkage for PR nor increase for PD taking as reference smallest SLD since treatment start. |
| Time Frame | Baseline, end of every even-numbered cycle until disease progression up to end of treatment (up to 18 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Response anslysis set: all enrolled participants who received at least 1 dose of study medication and had an adequate baseline tumor assessment. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 7 |
| Complete response |
0
0%
|
| Partial response |
1
6.7%
|
| Stable/No response |
1
6.7%
|
| Objective progression |
5
33.3%
|
| Title | Duration of Response (DR) |
|---|---|
| Description | Time in weeks from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response. |
| Time Frame | Baseline, end of every even-numbered cycle until disease progression up to end of treatment (up to 18 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants with a response (CR or PR) in response analysis set. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 1 |
| Median (95% Confidence Interval) [weeks] |
NA
|
| Title | Time to Tumor Progression (TTP) |
|---|---|
| Description | Time in months from start of study treatment to first documentation of objective tumor progression or death due to cancer, whichever comes first. TTP was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.437. Tumor progression was determined from oncologic assessment data (where data meet the criteria for PD). |
| Time Frame | Baseline, end of every even-numbered cycle until disease progression up to end of treatment (up to 18 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 16 |
| Median (95% Confidence Interval) [months] |
1.4
|
| Title | Ratio of Dextromethorphan Area Under the Curve to Dextrorphan Area Under the Curve 3 Days Prior to PF-00299804 Dosing |
|---|---|
| Description | Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Day -3: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Ratio of AUC was a derived parameter. As the primary endpoint for the study was not met, only the primary parameter AUC was analyzed and reported. Other parameters were not derived for this study based on investigator's decision. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 0 |
| Title | Ratio of Dextromethorphan Area Under the Curve to Dextrorphan Area Under the Curve on Cycle 2 Day 7 |
|---|---|
| Description | Dextrorphan is an active metabolite of dextromethorphan. |
| Time Frame | Cycle 2 Day 7: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Ratio of AUC was a derived parameter. As the primary endpoint for the study was not met, only the primary parameter AUC was analyzed and reported. Other parameters were not derived for this study based on investigator's decision. |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. |
| Measure Participants | 0 |
Adverse Events
| Time Frame | Adverse events were recorded from the time that the participant provided informed consent through and including 28 calendar days after the last administration of the investigational product. | |
|---|---|---|
| Adverse Event Reporting Description | The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study. | |
| Arm/Group Title | PF-00299804 45 mg + Dextromethorphan 30 mg | |
| Arm/Group Description | PF-00299804 45 milligram (mg) tablet orally once daily, starting from Cycle 1 Day 1, continuously for 21-day cycles until disease progression or unacceptable toxicities along with single dose of dextromethorphan hydrobromide 30 mg orally 3 days prior to Cycle 1 Day 1 (Day -3) and on Day 7 of Cycle 2. | |
All Cause Mortality |
||
| PF-00299804 45 mg + Dextromethorphan 30 mg | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| PF-00299804 45 mg + Dextromethorphan 30 mg | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/15 (20%) | |
| Gastrointestinal disorders | ||
| Colonic obstruction | 1/15 (6.7%) | |
| Nausea | 1/15 (6.7%) | |
| General disorders | ||
| Vomiting | 1/15 (6.7%) | |
| Chest pain | 1/15 (6.7%) | |
| Disease progression | 1/15 (6.7%) | |
| Infections and infestations | ||
| Pyelonephritis | 1/15 (6.7%) | |
Other (Not Including Serious) Adverse Events |
||
| PF-00299804 45 mg + Dextromethorphan 30 mg | ||
| Affected / at Risk (%) | # Events | |
| Total | 14/15 (93.3%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 1/15 (6.7%) | |
| Lymphopenia | 2/15 (13.3%) | |
| Ear and labyrinth disorders | ||
| Deafness | 1/15 (6.7%) | |
| Ear disorder | 1/15 (6.7%) | |
| Ear pain | 1/15 (6.7%) | |
| Endocrine disorders | ||
| Hypothyroidism | 1/15 (6.7%) | |
| Gastrointestinal disorders | ||
| Abdominal pain | 2/15 (13.3%) | |
| Cheilitis | 1/15 (6.7%) | |
| Constipation | 1/15 (6.7%) | |
| Diarrhoea | 8/15 (53.3%) | |
| Dry mouth | 2/15 (13.3%) | |
| Dysphagia | 1/15 (6.7%) | |
| Flatulence | 1/15 (6.7%) | |
| Nausea | 6/15 (40%) | |
| Oral pain | 2/15 (13.3%) | |
| Stomatitis | 1/15 (6.7%) | |
| Vomiting | 3/15 (20%) | |
| General disorders | ||
| Chest pain | 2/15 (13.3%) | |
| Early satiety | 1/15 (6.7%) | |
| Fatigue | 3/15 (20%) | |
| Mucosal inflammation | 5/15 (33.3%) | |
| Oedema | 1/15 (6.7%) | |
| Infections and infestations | ||
| Cellulitis | 1/15 (6.7%) | |
| Conjunctivitis | 1/15 (6.7%) | |
| Influenza | 2/15 (13.3%) | |
| Localised infection | 2/15 (13.3%) | |
| Oral candidiasis | 1/15 (6.7%) | |
| Pneumonia | 1/15 (6.7%) | |
| Respiratory tract infection | 1/15 (6.7%) | |
| Upper respiratory tract infection | 1/15 (6.7%) | |
| Injury, poisoning and procedural complications | ||
| Ankle fracture | 1/15 (6.7%) | |
| Contusion | 1/15 (6.7%) | |
| Excoriation | 1/15 (6.7%) | |
| Fall | 1/15 (6.7%) | |
| Skeletal injury | 1/15 (6.7%) | |
| Soft tissue injury | 1/15 (6.7%) | |
| Investigations | ||
| Aspartate aminotransferase increased | 1/15 (6.7%) | |
| Blood alkaline phosphatase increased | 1/15 (6.7%) | |
| Blood creatinine increased | 1/15 (6.7%) | |
| Gamma-glutamyltransferase increased | 1/15 (6.7%) | |
| Weight decreased | 3/15 (20%) | |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 7/15 (46.7%) | |
| Dehydration | 1/15 (6.7%) | |
| Hyperkalaemia | 1/15 (6.7%) | |
| Hypernatraemia | 1/15 (6.7%) | |
| Hypoalbuminaemia | 1/15 (6.7%) | |
| Hyponatraemia | 2/15 (13.3%) | |
| Hypophosphataemia | 1/15 (6.7%) | |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 3/15 (20%) | |
| Muscle spasms | 1/15 (6.7%) | |
| Musculoskeletal pain | 1/15 (6.7%) | |
| Musculoskeletal stiffness | 1/15 (6.7%) | |
| Pain in extremity | 1/15 (6.7%) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Seborroeic keratosis | 1/15 (6.7%) | |
| Nervous system disorders | ||
| Dizziness | 2/15 (13.3%) | |
| Dysarthria | 1/15 (6.7%) | |
| Dysgeusia | 5/15 (33.3%) | |
| Neuropathy peripheral | 1/15 (6.7%) | |
| Psychiatric disorders | ||
| Confusional state | 1/15 (6.7%) | |
| Insomnia | 2/15 (13.3%) | |
| Renal and urinary disorders | ||
| Pollakiuria | 1/15 (6.7%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 1/15 (6.7%) | |
| Dysphonia | 2/15 (13.3%) | |
| Dyspnoea | 1/15 (6.7%) | |
| Epistaxis | 2/15 (13.3%) | |
| Haemoptysis | 1/15 (6.7%) | |
| Pulmonary haemorrhage | 1/15 (6.7%) | |
| Rhinorrhoea | 1/15 (6.7%) | |
| Sinus congestion | 1/15 (6.7%) | |
| Sinus disorder | 1/15 (6.7%) | |
| Skin and subcutaneous tissue disorders | ||
| Dermatitis acneiform | 5/15 (33.3%) | |
| Dry skin | 7/15 (46.7%) | |
| Erythema | 1/15 (6.7%) | |
| Exfoliative rash | 1/15 (6.7%) | |
| Nail bed bleeding | 1/15 (6.7%) | |
| Nail disorder | 1/15 (6.7%) | |
| Onychalgia | 1/15 (6.7%) | |
| Palmar-plantar erythrodysaesthesia syndrome | 1/15 (6.7%) | |
| Pruritus | 1/15 (6.7%) | |
| Rash | 3/15 (20%) | |
| Rash erythematous | 1/15 (6.7%) | |
| Rash papular | 2/15 (13.3%) | |
| Rash pruritic | 3/15 (20%) | |
| Skin fissures | 1/15 (6.7%) | |
| Vascular disorders | ||
| Flushing | 1/15 (6.7%) | |
| Hypotension | 1/15 (6.7%) | |
Limitations/Caveats
Dextromethorphan AUCinf and t1/2 results not reported as data did not support calculation since levels of dextromethorphan were not tracked long enough for reliable estimation.
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 |
| ClinicalTrials.gov_Inquiries@pfizer.com |
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT00728468
Other Study ID Numbers:
- A7471014
First Posted:
Aug 5, 2008
Last Update Posted:
Aug 2, 2017
Last Verified:
Apr 1, 2017