ATX Study:A Study of Avastin (Bevacizumab), Tarceva (Erlotinib) and Xeloda (Capecitabine) in Patients With Locally Advanced and/or Metastatic Pancreatic Cancer

An Open Label Study to Evaluate the Safety and Effect on Disease Progression of Triple Combination Treatment With Erlotinib (Tarceva), Bevacizumab (Avastin), and Capecitabine (Xeloda) in Patients With Locally Advanced and/or Metastatic Pancreatic Cancer (REBECA-Trial).

This 2 part study will evaluate the safety and efficacy of a combination of Avastin, Tarceva and Xeloda (ATX) as second-line treatment in patients with locally advanced and/or metastatic pancreatic cancer. In the first part of the study, cohorts of patients will receive escalating doses of combination treatment to determine the maximum tolerated dose. The recommended dose will be used in the second part of the study to determine the efficacy of the ATX regime, in terms of its effect on disease progression. The anticipated time on study treatment is 3-12 months, and the target sample size is <100 individuals.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: bevacizumab [Avastin]; Drug: capecitabine [Xeloda]; Drug: erlotinib [Tarceva]

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1100
  • Wien, Austria, 1130

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:

• adult patients, >=18 years of age;
• pancreatic cancer with locally advanced and/or metastatic disease (stage IV);
• chemonaive for metastatic or locally advanced disease;
• ECOG performance status of 0-2.

Exclusion Criteria:

• local (stage IA to IIB)and locally advanced (stage III) pancreatic cancer;
• previous exposure to Avastin, Tarceva or Xeloda;
• other primary tumor within the last 5 years prior to enrollment, except for adequately treated cancer in situ of cervix, or basal cell skin cancer;
• current or recent chronic use of aspirin (>325 mg/day) or full therapeutic dose of anticoagulants or thrombolytic agents.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: bevacizumab [Avastin]; Escalating doses of 5/10mg/kg q2w; Drug: capecitabine [Xeloda]; Escalating doses of 500/650/750/900mg/m2 bid; Drug: erlotinib [Tarceva]; Escalating doses of 100/150mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Maximum Tolerated Dose (MTD) of Capecitabine	MTD for each of the medications was defined as the lowest dose studied which resulted in dose limiting toxicity (DLT) in at least 33 percent (%) of participants of the same quality category. DLT was defined as any greater than or equal to (>=) Grade (G) 3 or G4 toxicity; >= G3 non-hematological toxicities directly related to study treatment (other than untreated nausea/vomiting, alopecia, G3/G4 bilirubinemia for less than 7 days due to edema of the ductus choledochus and anemia); G4 thrombocytopenia, neutropenia lasting >= 7 days or G3 thrombocytopenia with complications, requiring transfusions, febrile neutropenia; stopping of oral CAP and/or ERL intake for >= 7 days, and/or cancellation of one or more BEV infusion(s) due to adverse events (AEs).	Up to Week 6 (Cycle 1-3)
Part 1: MTD of Erlotinib	MTD for each of the medications was defined as the lowest dose studied which resulted in DLT in at least 33% of participants of the same quality category. DLT was defined as >= G3 or G4 toxicity; >= G3 non-hematological toxicities directly related to study treatment (other than untreated nausea/vomiting, alopecia, G3/G4 bilirubinemia for less than 7 days due to edema of the ductus choledochus and anemia); G4 thrombocytopenia, neutropenia lasting >= 7 days or G3 thrombocytopenia with complications, requiring transfusions, febrile neutropenia; stopping of oral CAP and/or ERL intake for >= 7 days, and/or cancellation of one or more BEV infusion(s) due to AEs.	Up to Week 6 (Cycle 1-3)
Part 1: MTD of Bevacizumab	MTD for each of the medications was defined as the lowest dose studied which resulted in DLT in at least 33% of participants of the same quality category. DLT was defined as >= G3 or G4 toxicity; >= G3 non-hematological toxicities directly related to study treatment (other than untreated nausea/vomiting, alopecia, G3/G4 bilirubinemia for less than 7 days due to edema of the ductus choledochus and anemia); G4 thrombocytopenia, neutropenia lasting >= 7 days or G3 thrombocytopenia with complications, requiring transfusions, febrile neutropenia; stopping of oral CAP and/or ERL intake for >= 7 days, and/or cancellation of one or more BEV infusion(s) due to AEs.	Up to Week 6 (Cycle 1-3)
Part 1: Preliminary Recommended Dose (PRD) of Capecitabine for Part 2	Once the MTD was reached then the preceding lower dose level was used as PRD. MTD for each of the medications was defined as the lowest dose studied which resulted in dose limiting toxicity (DLT) in at least 33% of participants of the same quality category. DLT was defined as >= G3 or G4 toxicity; >= G3 non-hematological toxicities directly related to study treatment (other than untreated nausea/vomiting, alopecia, G3/G4 bilirubinemia for less than 7 days due to edema of the ductus choledochus and anemia); G4 thrombocytopenia, neutropenia lasting >= 7 days or G3 thrombocytopenia with complications, requiring transfusions, febrile neutropenia; stopping of oral CAP and/or ERL intake for >= 7 days, and/or cancellation of one or more BEV infusion(s) due to AEs. If MTD was not defined for a drug treatment then the maximum planned dose of that particular drug was considered as PRD for Part 2.	Up to Week 6 (Cycle 1-3)
Part 1: PRD of Erlotinib for Part 2	Once the MTD was reached then the preceding lower dose level was used as PRD. MTD for each of the medications was defined as the lowest dose studied which resulted in DLT in at least 33% of participants of the same quality category. DLT was defined as >= G3 or G4 toxicity; >= G3 non-hematological toxicities directly related to study treatment (other than untreated nausea/vomiting, alopecia, G3/G4 bilirubinemia for less than 7 days due to edema of the ductus choledochus and anemia); G4 thrombocytopenia, neutropenia lasting >= 7 days or G3 thrombocytopenia with complications, requiring transfusions, febrile neutropenia; stopping of oral CAP and/or ERL intake for >= 7 days, and/or cancellation of one or more BEV infusion(s) due to AEs. If MTD was not defined for a drug treatment then the maximum planned dose of that particular drug was considered as PRD for Part 2.	Up to Week 6 (Cycle 1-3)
Part 1: PRD of Bevacizumab for Part 2	Once the MTD was reached then the preceding lower dose level was used as PRD. MTD for each of the medications was defined as the lowest dose studied which resulted in DLT in at least 33% of participants of the same quality category. DLT was defined as >= G3 or G4 toxicity; >= G3 non-hematological toxicities directly related to study treatment (other than untreated nausea/vomiting, alopecia, G3/G4 bilirubinemia for less than 7 days due to edema of the ductus choledochus and anemia); G4 thrombocytopenia, neutropenia lasting >= 7 days or G3 thrombocytopenia with complications, requiring transfusions, febrile neutropenia; stopping of oral CAP and/or ERL intake for >= 7 days, and/or cancellation of one or more BEV infusion(s) due to AEs. If MTD was not defined for a drug treatment then the maximum planned dose of that particular drug was considered as PRD for Part 2.	Up to Week 6 (Cycle 1-3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Maximum Serum Concentration (Cmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-Deoxy-5-Fluorocytidine [5'-DFCR] and 5'-Deoxy-5-Fluorouridine [5'-DFUR])		CAP: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 hours (h) of every 2-week cycle (until Week 259) ERL: 2, 3 4, 5, 6, 7, 8, 10, 24, 28, 48, 52, 72, 76, 96, 100, 120, 124, 144, 148, 168 and 172 h of every 2-week cycle (until Week 259)
Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)		CAP: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 hours (h) of every 2-week cycle (until Week 259) ERL: 2, 3 4, 5, 6, 7, 8, 10, 24, 28, 48, 52, 72, 76, 96, 100, 120, 124, 144, 148, 168 and 172 h of every 2-week cycle (until Week 259)
Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)		CAP: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 hours (h) of every 2-week cycle (until Week 259) ERL: 2, 3 4, 5, 6, 7, 8, 10, 24, 28, 48, 52, 72, 76, 96, 100, 120, 124, 144, 148, 168 and 172 h of every 2-week cycle (until Week 259)
Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUClast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)		CAP: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 hours (h) of every 2-week cycle (until Week 259) ERL: 2, 3 4, 5, 6, 7, 8, 10, 24, 28, 48, 52, 72, 76, 96, 100, 120, 124, 144, 148, 168 and 172 h of every 2-week cycle (until Week 259)
Part 2: Percentage of Participants Free From Disease Progression	As per Response Evaluation Criteria In Solid Tumors (RECIST) version (v) 1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of 1 or more new lesions (target and non-target lesions) or the unequivocal progression of existing non-target lesions.	Month 6
Part 2: Percentage of Participants With Disease Control	A participant was defined as having controlled disease if they sustained a Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) during the assessment. As per RECIST v1.1, CR is defined as the disappearance of all target and non-target lesions and normalization of tumor marker level; PR is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter; SD for target lesions is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the treatment started and SD for non-target lesions defined as persistence of 1 or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.	From baseline thereafter, every 6 weeks (±7 days), then 1 week after last dose (follow-up), thereafter every 6 weeks (±7 days) until disease progression (up to Week 259)
Part 2: Percentage of Participants With Clinical Benefit Response	Clinical benefit response was defined as a composite of pain control, Karnofsky performance status (KPS), and weight. The KPS allows participants to be classified as per their functional impairment (abnormal function). It was recorded on an 11-point scale; 0= "dead" to 100= "Normal, no complaints, no evidence of disease" and sub-divided to 3 categories; 0 to 40 = "Unable to care for self, requires institutional or hospital care or equivalent, disease may be rapidly progressing"; 50 to 70= "Unable to work, able to live at home and care for most personal needs, varying amount of assistance needed and 80 to 100= "Able to carry on normal activity; no special care is needed".	One week before start of study treatment and weekly until disease progression or death (Up to Week 259)
Part 2: Overall Survival	Survival was the interval of time from date of first dose of study medication to date of death at any time. Participants who had not died were censored at the date of last contact when they were known to be alive.	From baseline until death (Up to Week 259)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: April 15, 2009
• First Submitted That Met QC Criteria: June 19, 2009
• First Posted (Estimate): June 22, 2009

Study Record Updates

• Last Update Posted (Estimate): August 7, 2015
• Last Update Submitted That Met QC Criteria: July 13, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Capecitabine; Bevacizumab
• Other Study ID Numbers: ML20784; 2008-004444-36