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

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

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).

Study Overview

• Status: Completed
• Conditions: Solid Tumor
• Intervention / Treatment: Drug: Capecitabine; Drug: RhuMab 2C4

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
• United Kingdom
  • Manchester, United Kingdom, M20 4BX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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 Names: 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 Names: Omnitarg
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.	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 Names: 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 Names: Omnitarg
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.	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 Names: 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 Names: Omnitarg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of the Combination of Pertuzumab and Capecitabine	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.	Cycle 1 (3 Weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With 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.	Cycle 1 (3 Weeks)
Plasma Half-Life (t1/2) of Pertuzumab	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.	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
Maximum Plasma Concentration (Cmax) of Pertuzumab	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).	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
Time to Maximum Plasma Concentration (Tmax) of Pertuzumab	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.	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
Area Under the Concentration Curve From Time Zero to Last Measurement (AUC 0-last) of Pertuzumab	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.	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
AUC From Time Zero to Infinity (AUC 0-infinity) of Pertuzumab	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).	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
Apparent Volume of Distribution of Pertuzumab	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	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
Apparent Total Clearance of Pertuzumab	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).	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
Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab	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.	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
Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab	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).	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
Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab	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.	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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Primary Completion (Actual): September 1, 2005
• Study Completion (Actual): September 1, 2005

Study Registration Dates

• First Submitted: July 8, 2015
• First Submitted That Met QC Criteria: July 9, 2015
• First Posted (Estimate): July 10, 2015

Study Record Updates

• Last Update Posted (Estimate): November 10, 2015
• Last Update Submitted That Met QC Criteria: October 12, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Capecitabine; Pertuzumab
• Other Study ID Numbers: BO17003