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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.

PF-00299804

Pfizer CT.gov Call Center

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.

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.

A Study To Test The Impact Of PF- 00299804 On How The Body Handles Dextromethorphan In Cancer Patients

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

Dextrorphan is an active metabolite of dextromethorphan.

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.

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.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Dextrorphan is an active metabolite of dextromethorphan.

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.

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.

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.

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 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 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).

Roswell Park Cancer Institute

South Texas Accelerated Research Therapeutics (START)

Pfizer

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.

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.

PF-00299804 45 mg + Dextromethorphan 30 mg

Age, Continuous

Sex: Female, Male

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.

Pfizer ClinicalTrials.gov Call Center

Dextrorphan

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.

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing

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.

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan 3 Days Prior to PF-00299804 Dosing

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) For Dextrorphan on Cycle 2 Day 7

Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing

Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7

Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan 3 Days Prior to PF-00299804 Dosing

Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7

Plasma Decay Half-Life (t1/2) For Dextrorphan 3 Days Prior to PF-00299804 Dosing

Plasma Decay Half-Life (t1/2) For Dextrorphan on Cycle 2 Day 7

Results not reported as data did not support calculation since levels of dextromethorphan were not tracked long enough for reliable estimation.

Oral Clearance For Dextromethorphan 3 Days Prior to PF-00299804 Dosing

Oral Clearance For Dextromethorphan on Cycle 2 Day 7

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.

Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan 3 Days Prior to PF-00299804 Dosing

Urinary Metabolic Ratio (UMR) of Dextromethorphan to Dextrorphan on Cycle 2 Day 7

Complete response

Partial response

Stable/No response

Objective progression

Response anslysis set: all enrolled participants who received at least 1 dose of study medication and had an adequate baseline tumor assessment.

Best Overall Response (BOR)

Participants with a response (CR or PR) in response analysis set.

Duration of Response (DR)

Time to Tumor Progression (TTP)

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.

Spots Global Cancer Trial Database for cyp2d6 inhibition