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A Multiple-Dose Study of RhuMab 2C4 and Docetaxel in the Treatment of Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT02490475
Recruitment Status : Completed
First Posted : July 3, 2015
Results First Posted : November 25, 2015
Last Update Posted : May 17, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE July 2, 2015
First Posted Date  ICMJE July 3, 2015
Results First Submitted Date  ICMJE July 28, 2015
Results First Posted Date  ICMJE November 25, 2015
Last Update Posted Date May 17, 2017
Study Start Date  ICMJE February 2004
Actual Primary Completion Date April 2006   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 26, 2015)
Maximum Tolerated Dose (MTD) of Docetaxel in Combination of Pertuzumab [ Time Frame: Cycle 1 Up to Day 15 ]
A prior dose level was defined as an MTD if at a certain dose level, there were greater than or equal to (≥) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs). If there were no DLTs or DLTs were seen in less than (<) 2 participants in the highest dose level, that was considered as MTD. Participants received escalating doses of docetaxel and pertuzumab until DLTs were observed. DLTs were defined as any of the following: 1) Any non-hematological toxicity ≥ Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management, 2) Grade 4 neutropenia lasting greater than (>) 7 days, 3) Febrile neutropenia, 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion or 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds.
Original Primary Outcome Measures  ICMJE
 (submitted: July 2, 2015)
Maximum tolerated dose (MTD) of the combination of rhuMab 2C4 and docetaxel [ Time Frame: At Screening and during each treatment cycle until 4 weeks after the end of treatment (up to approximately 10 months) ]
Change History Complete list of historical versions of study NCT02490475 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 26, 2015)
  • Plasma Decay Half Life (t1/2) for Pertuzumab in Combination With Docetaxel [ Time Frame: Cycle1: Day 2 Pre-dose and 15 minutes, 1.5, 4 and 8 hours Post-dose, and Days 3, 6, 9 and 16; Cycle 2: Day 1 Pre-dose and 15 minutes Post-dose on Days 1, 8, 15 and 22 ]
    The biological half-life or terminal half-life of pertuzumab is the time in days it takes for it to lose half of its pharmacologic activity.
  • Maximum Observed Plasma Concentration (Cmax) for Pertuzumab in Combination With Docetaxel [ Time Frame: Cycle1: Day 2 Pre-dose and 15 minutes, 1.5, 4 and 8 hours Post-dose, and Days 3, 6, 9 and 16; Cycle 2: Day 1 Pre-dose and 15 minutes Post-dose on Days 1, 8, 15 and 22 ]
    Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and is measures as micrograms per milliliter (μg/mL).
  • Area Under the Concentration Curve From Time Zero to the Last Visit (AUC [0-last]) for Pertuzumab in Combination With Docetaxel [ Time Frame: Cycle1: Day 2 Pre-dose and 15 minutes, 1.5, 4 and 8 hours Post-dose, and Days 3, 6, 9 and 16; Cycle 2: Day 1 Pre-dose and 15 minutes Post-dose on Days 1, 8, 15 and 22 ]
    The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The AUC0-last is calculated from time 0 (prior to administration of medication) to last measured data point. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC is measured as micrograms times days per milliliter (μg*day/mL).
  • AUC From Time Zero to Infinity (AUC [0-infinity]) for Pertuzumab in Combination With Docetaxel [ Time Frame: Cycle1: Day 2 Pre-dose and 15 minutes, 1.5, 4 and 8 hours Post-dose, and Days 3, 6, 9 and 16; Cycle 2: Day 1 Pre-dose and 15 minutes Post-dose on Days 1, 8, 15 and 22 ]
    The AUC0-infinity is calculated from time 0 (prior to administration of medication) to infinity (the time of complete elimination of the drug). The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC is measured as μg*day/mL.
  • Clearance (Cl) of Pertuzimab in Combination With Docetaxel [ Time Frame: Cycle1: Day 2 Pre-dose and 15 minutes, 1.5, 4 and 8 hours Post-dose, and Days 3, 6, 9 and 16; Cycle 2: Day 1 Pre-dose and 15 minutes Post-dose on Days 1, 8, 15 and 22 ]
    Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It is measured as milliliters per day (mL/day).
  • Volume of Distribution (Vz) at Steady State of Pertuzumab in Combination With Docetaxel [ Time Frame: Cycle1: Day 2 Pre-dose and 15 minutes, 1.5, 4 and 8 hours Post-dose, and Days 3, 6, 9 and 16; Cycle 2: Day 1 Pre-dose and 15 minutes Post-dose on Days 1, 8, 15 and 22 ]
    The volume of distribution at steady state (Vz), also known as apparent volume of distribution, is a pharmacological, theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma.
  • Mean Residence Time (MRT) of Pertuzumab [ Time Frame: Cycle1: Day 2 Pre-dose and 15 minutes, 1.5, 4 and 8 hours Post-dose, and Days 3, 6, 9 and 16; Cycle 2: Day 1 Pre-dose and 15 minutes Post-dose on Days 1, 8, 15 and 22 ]
    MRT is the average time that pertuzumab is present in the systemic circulation and is measured in days.
  • Percentage of Participants by Best Overall Response Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria [ Time Frame: Weeks 7 (Cycle 2),13 (Cycle 4) and Final Visit Up to 22 weeks ]
    Best Overall response was evaluated as Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). CR: complete disappearance of all target lesions. PR: at least a 30 percent (%) decrease in the sum of the longest diameters. SD: neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameters since the treatment started. PD: at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters of the target lesions recorded since the treatment started, including screening, or the appearance of one or more new lesions. If participants withdrew due to insufficient therapeutic response or death and had no tumor measurements at the final visit, they were counted under progressive disease for final visit.
  • Percentage of Participants With Decrease in Left Ventricular Ejection Fraction (LVEF) by Category of Decrease and Timepoint [ Time Frame: Baseline, Weeks 7(Cycle 2), 13 (Cycle 4) and Final Visit Up to Week 22 ]
    Ejection fraction (EF) is the fraction of outbound blood pumped from the heart with each heartbeat. It is commonly measured by echocardiogram and serves as a general measure of a person's cardiac function. Changes in LVEF were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. The decrease in LVEF has been categorized as follows: A) Increase, no change, decrease from baseline less than (<) 10%; B) Absolute value <50% and decrease from baseline greater than or equal to (≥) 10%; C) Absolute value <50% and decrease from baseline≥15% ; D) Other. If participants withdrew due to insufficient therapeutic response or death and had no tumor measurements at the final visit, they were counted under progressive disease for final visit.
  • t1/2 for Docetaxel Alone and in Combination With Pertuzumab [ Time Frame: Cycles 1 and 2: Pre-dose, 30 and 55 minutes during dosing, 15 minutes, 30 minutes, 1, 2, 4, 8, and 23 hours Post-dose ]
    The biological half-life or terminal half-life of docetaxel is the time in hours it takes for it to lose half of its pharmacologic activity. Data for "docetaxel alone" arms were analyzed for the timepoints on Day 1 prior to the administration of pertuzumab. The pharmacokinetic parameters were derived by non-compartmental methods using WinNonLin version 5.0.1.
  • Tmax for Docetaxel Alone and in Combination With Pertuzumab [ Time Frame: Cycles 1 and 2: Pre-dose, 30 and 55 minutes during dosing, 15 minutes, 30 minutes, 1, 2, 4, 8, and 23 hours Post-dose ]
    Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; Data for "docetaxel alone" arms were analyzed for the timepoints on Day 1 prior to the administration of pertuzumab. When the rate of absorption equals the rate of elimination. The pharmacokinetic parameters were derived by non-compartmental methods using WinNonLin version 5.0.1.
  • Cmax for Docetaxel Alone and in Combination With Pertuzumab [ Time Frame: Cycles 1 and 2: Pre-dose, 30 and 55 minutes during dosing, 15 minutes, 30 minutes, 1, 2, 4, 8, and 23 hours Post-dose ]
    Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and is measures as nanograms per milliliter (ng/mL). The pharmacokinetic parameters were derived by non-compartmental methods using WinNonLin version 5.0.1.
  • AUC(0-∞) for Docetaxel Alone and in Combination With Pertuzumab [ Time Frame: Cycles 1 and 2: Pre-dose, 30 and 55 minutes during dosing, 15 minutes, 30 minutes, 1, 2, 4, 8, and 23 hours Post-dose ]
    The AUC0-infinity is calculated from time 0 (prior to administration of medication) to infinity (the time of complete elimination of the drug). The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC is measured as ng*h/mL. The pharmacokinetic parameters were derived by non-compartmental methods using WinNonLin version 5.0.1.
  • Vss for Docetaxel Alone and in Combination With Pertuzumab [ Time Frame: Cycles 1 and 2: Pre-dose, 30 and 55 minutes during dosing, 15 minutes, 30 minutes, 1, 2, 4, 8, and 23 hours Post-dose ]
    The volume of distribution at steady state (Vss), also known as apparent volume of distribution, is a pharmacological, theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. The pharmacokinetic parameters were derived by non-compartmental methods using WinNonLin version 5.0.1.
  • CL for Docetaxel Alone and in Combination With Pertuzumab [ Time Frame: Cycles 1 and 2: Pre-dose, 30 and 55 minutes during dosing, 15 minutes, 30 minutes, 1, 2, 4, 8, and 23 hours Post-dose ]
    Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It is measured as milliliters per hour per meter squared (mL/h/m^2). The pharmacokinetic parameters were derived by non-compartmental methods using WinNonLin version 5.0.1.
  • Number of Participants With DLTs [ Time Frame: From Baseline until 4 weeks after the end of treatment ]
    DLTs were defined as any of the following: 1) Any non-hematological toxicity greter than or equal to (≥) Grade 3 according t0 CTCAE version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management, 2) Grade 4 neutropenia lasting greater than (>) 7 days, 3) Febrile neutropenia, 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion or 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 2, 2015)
  • Incidence of adverse events according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 3.0 [ Time Frame: up to approximately 10 months ]
  • Incidence of DLTs [ Time Frame: up to approximately 10 months ]
  • Area under the concentration-time curve extrapolated to infinity (AUC0-inf) of docetaxel and rhuMab 2C4 [ Time Frame: At pre-dose and post-dose timepoints during Cycles 1 and 2 ]
  • Elimination half-life (t1/2) of docetaxel and rhuMab 2C4 [ Time Frame: At pre-dose and post-dose timepoints during Cycles 1 and 2 ]
  • Clearance (Cl) of docetaxel and rhuMab 2C4 [ Time Frame: At pre-dose and post-dose timepoints during Cycles 1 and 2 ]
  • Maximum plasma concentration (Cmax) of rhuMab 2C4 [ Time Frame: At pre-dose and post-dose timepoints during Cycles 1 and 2 ]
  • Volume of distribution (Vss) of rhuMab 2C4 [ Time Frame: At pre-dose and post-dose timepoints during Cycles 1 and 2 ]
  • Mean residence time (MRT) of rhuMab 2C4 [ Time Frame: At pre-dose and post-dose timepoints during Cycles 1 and 2 ]
  • Left ventricular ejection fraction (LVEF) [ Time Frame: up to approximately 10 months ]
  • Percentage of participants by best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: up to approximately 10 months ]
  • Objective Response Rate (ORR) [ Time Frame: Up to approximately 10 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Multiple-Dose Study of RhuMab 2C4 and Docetaxel in the Treatment of Advanced Solid Tumors
Official Title  ICMJE A Phase Ib, Open-Label, Multicenter Study of the Safety and Pharmacokinetics of the Combination of RhuMab 2C4 (Omnitarg), a Recombinant Humanized Antibody to HER2, and Docetaxel (Taxotere) in Patients With Advanced Solid Tumors
Brief Summary This study will evaluate the safety, tolerability, and pharmacokinetics of the combination of rhuMab 2C4 (Perjeta) and docetaxel (Taxotere) in participants with advanced solid tumors that have progressed during or after standard therapy, or for which no standard therapy is available. Participants will be enrolled and evaluated for dose-limiting toxicities (DLTs) in escalating-dose cohorts in order to determine the maximum tolerated dose (MTD).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumor
Intervention  ICMJE
  • Drug: Docetaxel
    Participants will receive docetaxel on Day 1 of each 3-week cycle as 60, 75, or 100 mg/m^2 via IV infusion. Treatment may continue until disease progression, unacceptable toxicity, or consent withdrawal.
    Other Name: Taxotere
  • Drug: RhuMab 2C4
    Participants will receive rhuMab 2C4 on Day 1 of each 3-week cycle as 420 mg via IV infusion. For Cycle 1 ony, rhuMab will be administered on Day 2, at least 24 hours after docetaxel and following an initial 840-mg loading dose. Treatment may continue until disease progression, unacceptable toxicity, or consent withdrawal.
    Other Name: Omnitarg
Study Arms  ICMJE
  • Experimental: RhuMab 2C4 + Docetaxel 100 mg/m^2 (Level 3)
    Docetaxel will be administered via intravenous (IV) infusion on Day 1 of each 3-week cycle at a dose of 100 mg/m^2 per day, and rhuMab 2C4 will be given on Day 1 of each 3-week cycle as a fixed-dose 420-mg IV infusion. For Cycle 1 only, rhuMab 2C4 administration will be delayed to Day 2 with an initial 840-mg loading dose. The incidence of DLTs will be used to guide intrapatient dose modification, as well as subsequent enrollment.
    Interventions:
    • Drug: Docetaxel
    • Drug: RhuMab 2C4
  • Experimental: RhuMab 2C4 + Docetaxel 60 mg/m^2 (Level 1)
    Docetaxel will be administered via IV infusion on Day 1 of each 3-week cycle at a dose of 60 mg/m^2 per day, and rhuMab 2C4 will be given on Day 1 of each 3-week cycle as a fixed-dose 420-mg IV infusion. For Cycle 1 only, rhuMab 2C4 administration will be delayed to Day 2 with an initial 840-mg loading dose. The incidence of DLTs will be used to guide intrapatient dose modification, as well as subsequent enrollment.
    Interventions:
    • Drug: Docetaxel
    • Drug: RhuMab 2C4
  • Experimental: RhuMab 2C4 + Docetaxel 75 mg/m^2 (Level 2)
    Docetaxel will be administered via IV infusion on Day 1 of each 3-week cycle at a dose of 75 mg/m^2 per day, and rhuMab 2C4 will be given on Day 1 of each 3-week cycle as a fixed-dose 420-mg IV infusion. For Cycle 1 only, rhuMab 2C4 administration will be delayed to Day 2 with an initial 840-mg loading dose. The incidence of DLTs will be used to guide intrapatient dose modification, as well as subsequent enrollment.
    Interventions:
    • Drug: Docetaxel
    • Drug: RhuMab 2C4
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 2, 2015)
19
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 2006
Actual Primary Completion Date April 2006   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adults at least 18 years of age
  • Easter Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy at least 12 weeks
  • Locally advanced or metastatic solid tumor with at least 1 measurable lesion, which has progressed during/after standard therapy
  • Human epidermal growth factor receptor 2 (HER2)-negative among participants with breast cancer
  • Negative pregnancy test or use of an adequate contraceptive method among women of childbearing potential
  • Adequate hematologic, hepatic, and renal function
  • Signed informed consent, histologically or cytologicall confirmed advanced solid tumor, adequate cardiac function as documented by LVEF >50% by ECHO or MUGA

Exclusion Criteria:

  • Clinical evidence of central nervous system (CNS) metastases
  • Prior chemotherapy, radiotherapy, or immunotherapy within 4 weeks, or hormone therapy within 2 weeks of study Day 1
  • History of neuropathy Grade 2 or worse, or any unresolved residual chemotherapy effects
  • Prior HER2-active agents or docetaxel
  • Any investigational agent within 28 days of study drug
  • Prior cumulative doxorubicin dose greater than (>) 360 mg/m^2 or equivalent
  • Significant cardiovascular disease
  • Active/uncontrolled concurrent illness or infection-
  • Major surgery or trauma within 4 weeks of study Day 1
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02490475
Other Study ID Numbers  ICMJE BO17021
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP