Advanced Malignant Solid Tumors
Conditions
Keywords
Phase 1, PF-00299804, Dextromethorphan, CYP2D6 Inhibition, Cancer Patients
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.
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.
Interventions
DRUGPF-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.
Sponsors
Roswell Park Cancer Institute
South Texas Accelerated Research Therapeutics (START)
Pfizer
Study design
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg 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. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Enrolled but not treated | 1 |
| Overall Study | Objective progression or relapse | 9 |
| Overall Study | Protocol Violation | 4 |
| Overall Study | Study terminated by sponsor | 1 |
Baseline characteristics
| Characteristic | PF-00299804 45 mg + Dextromethorphan 30 mg |
|---|---|
| Age, Continuous | 57.1 Years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 15 |
| serious Total, serious adverse events | 3 / 15 |
Outcome results
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan 3 Days Prior to PF-00299804 Dosing
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan 3 Days Prior to PF-00299804 Dosing | 2266 ng*hr/mL | Standard Deviation 955.97 |
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan on Cycle 2 Day 7
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan on Cycle 2 Day 7 | 2298 ng*hr/mL | Standard Deviation 1245.4 |
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing | Dextromethorphan | 206.4 nanograms*hour/milliliter (ng*hr/mL) | Standard Deviation 404.63 |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing | Dextrorphan | 2199 nanograms*hour/milliliter (ng*hr/mL) | Standard Deviation 1085.7 |
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 | Dextromethorphan | 300.7 ng*hr/mL | Standard Deviation 408.42 |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 | Dextrorphan | 2232 ng*hr/mL | Standard Deviation 1253.2 |
Primary
Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing | Dextromethorphan | 6.598 ng/mL | Standard Deviation 7.4826 |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing | Dextrorphan | 239.2 ng/mL | Standard Deviation 137.56 |
Primary
Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 | Dextromethorphan | 11.11 ng/mL | Standard Deviation 7.8689 |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 | Dextrorphan | 169.2 ng/mL | Standard Deviation 103.18 |
Primary
Oral Clearance For Dextromethorphan 3 Days Prior to PF-00299804 Dosing
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
Population: Results not reported as data did not support calculation since levels of dextromethorphan were not tracked long enough for reliable estimation.
Primary
Oral Clearance For Dextromethorphan on Cycle 2 Day 7
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
Population: Results not reported as data did not support calculation since levels of dextromethorphan were not tracked long enough for reliable estimation.
Primary
Plasma Decay Half-Life (t1/2) For Dextrorphan 3 Days Prior to PF-00299804 Dosing
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Plasma Decay Half-Life (t1/2) For Dextrorphan 3 Days Prior to PF-00299804 Dosing | 20.20 hours | Standard Deviation 28.645 |
Primary
Plasma Decay Half-Life (t1/2) For Dextrorphan on Cycle 2 Day 7
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Plasma Decay Half-Life (t1/2) For Dextrorphan on Cycle 2 Day 7 | 17.25 hours | Standard Deviation 15.935 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing | Dextromethorphan | 2.00 hours |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing | Dextrorphan | 2.00 hours |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 | Dextromethorphan | 3.00 hours |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 | Dextrorphan | 4.00 hours |
Primary
Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan 3 Days Prior to PF-00299804 Dosing
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan 3 Days Prior to PF-00299804 Dosing | 0.008800 ratio | Standard Deviation 0.0176 |
Primary
Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan on Cycle 2 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.
Time frame: 8 hours after dosing on Day 7
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan on Cycle 2 Day 7 | 0.08040 ratio | Standard Deviation 0.11042 |
Secondary
Best Overall Response (BOR)
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)
Population: Response anslysis set: all enrolled participants who received at least 1 dose of study medication and had an adequate baseline tumor assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Best Overall Response (BOR) | Complete response | 0 participants |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Best Overall Response (BOR) | Partial response | 1 participants |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Best Overall Response (BOR) | Stable/No response | 1 participants |
| PF-00299804 45 mg + Dextromethorphan 30 mg | Best Overall Response (BOR) | Objective progression | 5 participants |
Secondary
Duration of Response (DR)
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)
Population: Participants with a response (CR or PR) in response analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Duration of Response (DR) | NA weeks |
Secondary
Time to Tumor Progression (TTP)
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)
Population: All enrolled participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PF-00299804 45 mg + Dextromethorphan 30 mg | Time to Tumor Progression (TTP) | 1.4 months |
Other Pre-specified
Ratio of Dextromethorphan Area Under the Curve to Dextrorphan Area Under the Curve 3 Days Prior to PF-00299804 Dosing
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
Population: 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.
Other Pre-specified
Ratio of Dextromethorphan Area Under the Curve to Dextrorphan Area Under the Curve on Cycle 2 Day 7
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
Population: 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.