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A Phase Ib, Open-label, Multicenter Study of the Safety and PK of the Combination of rhuMAb2c4 (Omnitarg), a Recombinant Humanized Antibody to HER2, and Capecitabine (Xeloda) in Patients With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT02494596
Recruitment Status : Completed
First Posted : July 10, 2015
Results First Posted : September 30, 2015
Last Update Posted : November 10, 2015
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE July 8, 2015
First Posted Date  ICMJE July 10, 2015
Results First Submitted Date  ICMJE July 30, 2015
Results First Posted Date  ICMJE September 30, 2015
Last Update Posted Date November 10, 2015
Study Start Date  ICMJE January 2004
Actual Primary Completion Date September 2005   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 12, 2015)
Maximum Tolerated Dose (MTD) of the Combination of Pertuzumab and Capecitabine [ Time Frame: Cycle 1 (3 Weeks) ]
MTD was defined as the highest tolerated dose combination of capecitabine (825 mg, 1000 mg or 1250 mg) and pertuzumab, without causing Dose Limiting Toxicities (DLTs). DLTs were defined as follows: 1) Any non-hematological toxicity greater than or equal to (≥) 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 > 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT. MTD was measured in mg/m^2.
Original Primary Outcome Measures  ICMJE
 (submitted: July 9, 2015)
Maximum tolerated dose (MTD) of the combination of rhuMab 2C4 and capecitabine [ Time Frame: up to approximately 10 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 1, 2015)
  • Percentage of Participants With DLTs [ Time Frame: Cycle 1 (3 Weeks) ]
    DLTs were defined as follows: 1)Any non-hematological toxicity greater than or equal to (≥) 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 > 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT.
  • Plasma Half-Life (t1/2) of Pertuzumab [ Time Frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and Predose on Days 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. t1/2 was measured in days.
  • Maximum Plasma Concentration (Cmax) of Pertuzumab [ Time Frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 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 was measured as nanograms per milliliter (ng/mL).
  • Time to Maximum Plasma Concentration (Tmax) of Pertuzumab [ Time Frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 ]
    Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination. Tmax was measured in days.
  • Area Under the Concentration Curve From Time Zero to Last Measurement (AUC 0-last) of Pertuzumab [ Time Frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 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 was measured as ng*day/mL.
  • AUC From Time Zero to Infinity (AUC 0-infinity) of Pertuzumab [ Time Frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 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 nanograms times days per milliliter (ng*day/mL).
  • Apparent Volume of Distribution of Pertuzumab [ Time Frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 ]
    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. Vss was measured in mL
  • Apparent Total Clearance of Pertuzumab [ Time Frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 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).
  • Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab [ Time Frame: Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose ]
    Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). The biological half-life or terminal half-life is the time in days it takes for it to lose half of its pharmacologic activity.
  • Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab [ Time Frame: Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose ]
    Capecitabine is an oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety 5-FU in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-DFCR, 5'-DFUR, and FBAL. 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).
  • Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab [ Time Frame: Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose ]
    Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2015)
  • Incidence of adverse events reported according to Common terminology Criteria for Adverse Events (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 capecitabine and its metabolites [ Time Frame: At pre-dose and post-dose timepoints on Day -7 and during Cycles 1 and 2 ]
  • Area under the concentration-time curve until the last measurable concentration (AUC0-last) of capecitabine and its metabolites [ Time Frame: At pre-dose and post-dose timepoints on Day -7 and during Cycles 1 and 2 ]
  • Maximum plasma concentration (Cmax) of capecitabine and its metabolites [ Time Frame: At pre-dose and post-dose timepoints on Day -7 and during Cycles 1 and 2 ]
  • Apparent terminal elimination half-life (t1/2) of capecitabine and its metabolites [ Time Frame: At pre-dose and post-dose timepoints on Day -7 and during Cycles 1 and 2 ]
  • Time to maximum plasma concentration (Tmax) of capecitabine and its metabolites [ Time Frame: At pre-dose and post-dose timepoints on Day -7 and 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase Ib, Open-label, Multicenter Study of the Safety and PK of the Combination of rhuMAb2c4 (Omnitarg), a Recombinant Humanized Antibody to HER2, and Capecitabine (Xeloda) in Patients With 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 Capecitabine (Xeloda) 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 capecitabine (Xeloda) 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: Capecitabine
    Participants will receive capecitabine on Days 1 to 14 of each 3-week cycle as 825, 1000, or 1250 mg/m^2 PO twice daily. Treatment may continue until disease progression, unacceptable toxicity, or consent withdrawal.
    Other Name: Xeloda
  • Drug: RhuMab 2C4
    Participants will receive rhuMab 2C4 on Day 1 of each 3-week cycle as 1050 mg via IV infusion. Treatment may continue until disease progression, unacceptable toxicity, or consent withdrawal.
    Other Name: Omnitarg
Study Arms  ICMJE
  • Experimental: RhuMab 2C4 + Capecitabine 1000 mg/m^2 (Level 2)
    Participants will receive a single 1000-mg/m^2 dose of oral (PO) capecitabine on Day -7 for pretreatment assessment. Capecitabine will then be administered on Days 1 to 14 of each 3-week cycle at a dose of 1000 mg/m^2 twice daily, and rhuMab 2C4 will be given on Day 1 of each 3-week cycle as a fixed-dose 1050-mg IV infusion. The incidence of DLTs will be used to guide intrapatient dose modification, as well as subsequent enrollment.
    Interventions:
    • Drug: Capecitabine
    • Drug: RhuMab 2C4
  • Experimental: RhuMab 2C4 + Capecitabine 1250 mg/m^2 (Level 3)
    Participants will receive a single 1250-mg/m^2 dose of PO capecitabine on Day -7 for pretreatment assessment. Capecitabine will then be administered on Days 1 to 14 of each 3-week cycle at a dose of 1250 mg/m^2 twice daily, and rhuMab 2C4 will be given on Day 1 of each 3-week cycle as a fixed-dose 1050-mg IV infusion. The incidence of DLTs will be used to guide intrapatient dose modification, as well as subsequent enrollment.
    Interventions:
    • Drug: Capecitabine
    • Drug: RhuMab 2C4
  • Experimental: RhuMab 2C4 + Capecitabine 825 mg/m^2 (Level 1)
    Participants will receive a single 825-mg/m^2 dose of PO capecitabine on Day -7 for pretreatment assessment. Capecitabine will then be administered on Days 1 to 14 of each 3-week cycle at a dose of 825 mg/m^2 twice daily, and rhuMab 2C4 will be given on Day 1 of each 3-week cycle as a fixed-dose 1050-mg IV infusion. The incidence of DLTs will be used to guide intrapatient dose modification, as well as subsequent enrollment.
    Interventions:
    • Drug: Capecitabine
    • 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 9, 2015)
19
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE September 2005
Actual Primary Completion Date September 2005   (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

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 palmar plantar syndrome Grade 2 or worse, or any unresolved residual chemotherapy effects
  • Prior HER2-active agents, continuous intravenous (IV) 5-fluorouracil, capecitabine, or other fluoropyrimidine
  • Any investigational agent within 28 days of study start
  • 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 Spain,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02494596
Other Study ID Numbers  ICMJE BO17003
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 October 2015

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