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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00728468
First Posted: August 5, 2008
Last Update Posted: August 2, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Roswell Park Cancer Institute
South Texas Accelerated Research Therapeutics (START)
Information provided by (Responsible Party):
Pfizer
  Purpose
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 Intervention Phase
Advanced Malignant Solid Tumors Drug: PF-00299804 Phase 1

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Pfizer:

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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    Dextrorphan is an active metabolite of dextromethorphan.

  • Maximum Observed Plasma Concentration (Cmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 [ 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 ]
    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 [ 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 ]
    Dextrorphan is an active metabolite of dextromethorphan.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) For Dextromethorphan and Dextrorphan on Cycle 2 Day 7 [ 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 ]
    Dextrorphan is an active metabolite of dextromethorphan.

  • Plasma Decay Half-Life (t1/2) For Dextrorphan 3 Days Prior to PF-00299804 Dosing [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ 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 ]
    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 [ 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 ]
    Dextrorphan is an active metabolite of dextromethorphan.


Enrollment: 16
Study Start Date: September 2008
Study Completion Date: July 2014
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00728468


Locations
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, Texas
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
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00728468     History of Changes
Other Study ID Numbers: A7471014
First Submitted: July 31, 2008
First Posted: August 5, 2008
Results First Submitted: July 17, 2015
Results First Posted: August 2, 2017
Last Update Posted: August 2, 2017
Last Verified: April 2017

Keywords provided by Pfizer:
Phase 1
PF-00299804
Dextromethorphan
CYP2D6 Inhibition
Cancer Patients

Additional relevant MeSH terms:
Neoplasms
Dextromethorphan
Antitussive Agents
Respiratory System Agents
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs