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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).

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00925769
Enrollment
32
Registered
2009-06-22
Start date
2009-01-31
Completion date
2013-12-31
Last updated
2015-08-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pancreatic Cancer

Brief summary

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.

Interventions

DRUGbevacizumab [Avastin]

Escalating doses of 5/10mg/kg q2w

DRUGcapecitabine [Xeloda]

Escalating doses of 500/650/750/900mg/m2 bid

DRUGerlotinib [Tarceva]

Escalating doses of 100/150mg daily

Sponsors

Hoffmann-La Roche
Lead SponsorINDUSTRY

Study design

Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

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.

Design outcomes

Primary

MeasureTime frameDescription
Part 1: Maximum Tolerated Dose (MTD) of CapecitabineUp to Week 6 (Cycle 1-3)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).
Part 1: MTD of ErlotinibUp to Week 6 (Cycle 1-3)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.
Part 1: MTD of BevacizumabUp to Week 6 (Cycle 1-3)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.
Part 1: Preliminary Recommended Dose (PRD) of Capecitabine for Part 2Up to Week 6 (Cycle 1-3)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.
Part 1: PRD of Erlotinib for Part 2Up to Week 6 (Cycle 1-3)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.
Part 1: PRD of Bevacizumab for Part 2Up to Week 6 (Cycle 1-3)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.

Secondary

MeasureTime frameDescription
Part 2: Percentage of Participants With Clinical Benefit ResponseOne week before start of study treatment and weekly until disease progression or death (Up to Week 259)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.
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 2: Overall SurvivalFrom baseline until death (Up to Week 259)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.
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 ProgressionMonth 6As 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.
Part 2: Percentage of Participants With Disease ControlFrom 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)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.

Countries

Austria

Participant flow

Pre-assignment details

Thirty two (32) participants were included however, 2 participants discontinued before reaching the end of the evaluation period of 3 cycles of the complete study regimen (of all 3 drugs) at the recommended dose due to progressive disease.

Participants by arm

ArmCount
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)
Dose-escalation was performed using a substance-related toxicity-based dose escalation scheme and was started with capecitabine followed by erlotinib and completed by bevacizumab. Participants in different dose levels (Dose levels \[DL\]-1, 2, 3, 4, 5 and 6) were administered either oral 100 mg or 150 mg of erlotinib tablet daily, 5 mg/kg or 10 mg/kg of bevacizumab IV infusion on Day 1 of each cycle (1 Cycle = 2 Weeks), and any of the different doses of capecitabine BID (500/650/800/900 mg/m\^2) orally. All the medications were continued until confirmed evidence of disease progression or unacceptable toxicity.
30
Total30

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003FG004FG005
Overall StudyAdverse Event000010
Overall StudyDeath001000
Overall StudyDisease progression453423
Overall StudyEnd of study visit not done001000
Overall StudyMajor toxicity101100
Overall StudyMissing documentation010000
Overall StudyParticipant is unable to swallow drug000100
Overall StudyPhysician Decision100000

Baseline characteristics

CharacteristicTriple Combination (Bevacizumab/Erlotinib/Capecitabine)
Age, Continuous63.9 years
STANDARD_DEVIATION 8.4
Sex: Female, Male
Female
15 Participants
Sex: Female, Male
Male
15 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —— / —— / —— / —
other
Total, other adverse events
6 / 65 / 66 / 66 / 63 / 33 / 3
serious
Total, serious adverse events
3 / 62 / 64 / 65 / 63 / 33 / 3

Outcome results

Primary

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).

Time frame: Up to Week 6 (Cycle 1-3)

Population: Per-protocol population.

ArmMeasureValue (NUMBER)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Maximum Tolerated Dose (MTD) of Capecitabine900 mg/m^2 BID
Primary

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.

Time frame: Up to Week 6 (Cycle 1-3)

Population: Per-protocol population.

ArmMeasureValue (NUMBER)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: MTD of BevacizumabNA mg/kg once every 2 weeks (Q2W)
Primary

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.

Time frame: Up to Week 6 (Cycle 1-3)

Population: Per-protocol population.

ArmMeasureValue (NUMBER)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: MTD of ErlotinibNA mg/day
Primary

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.

Time frame: Up to Week 6 (Cycle 1-3)

Population: Per-protocol population.

ArmMeasureValue (NUMBER)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: PRD of Bevacizumab for Part 210 mg/kg Q2W
Primary

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.

Time frame: Up to Week 6 (Cycle 1-3)

Population: Per-protocol population.

ArmMeasureValue (NUMBER)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: PRD of Erlotinib for Part 2150 mg/day
Primary

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.

Time frame: Up to Week 6 (Cycle 1-3)

Population: Per-protocol population.

ArmMeasureValue (NUMBER)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Preliminary Recommended Dose (PRD) of Capecitabine for Part 2800 mg/m^2 BID
Secondary

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)

Time frame: 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)

Population: Per-protocol population. Here n signifies the number of participants who were evaluable for each drug for each arm, respectively.

ArmMeasureGroupValue (MEAN)Dispersion
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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)Erlotinib (n=6,6,6,6,3,3)15.81 h*µg/mLStandard Deviation 12.91
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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)OSI-420 (n=6,6,6,6,3,3)1.15 h*µg/mLStandard Deviation 1.21
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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)Capecitabine (n=6,6,6,6,3,3)1.43 h*µg/mLStandard Deviation 1.02
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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)5'-DFCR (n=5,5,6,6,3,3)3.97 h*µg/mLStandard Deviation 2.65
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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)5'-DFUR (n=4,5,6,6,3,3)15.42 h*µg/mLStandard Deviation 9.45
ERL+BEV+CAP Dose Level-2Part 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)Erlotinib (n=6,6,6,6,3,3)11.06 h*µg/mLStandard Deviation 5.41
ERL+BEV+CAP Dose Level-2Part 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)Capecitabine (n=6,6,6,6,3,3)1.63 h*µg/mLStandard Deviation 1.01
ERL+BEV+CAP Dose Level-2Part 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)OSI-420 (n=6,6,6,6,3,3)0.48 h*µg/mLStandard Deviation 0.35
ERL+BEV+CAP Dose Level-2Part 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)5'-DFUR (n=4,5,6,6,3,3)13.58 h*µg/mLStandard Deviation 7.84
ERL+BEV+CAP Dose Level-2Part 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)5'-DFCR (n=5,5,6,6,3,3)7.01 h*µg/mLStandard Deviation 1.89
ERL+BEV+CAP Dose Level-3Part 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)5'-DFUR (n=4,5,6,6,3,3)9.76 h*µg/mLStandard Deviation 4.6
ERL+BEV+CAP Dose Level-3Part 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)OSI-420 (n=6,6,6,6,3,3)0.41 h*µg/mLStandard Deviation 0.18
ERL+BEV+CAP Dose Level-3Part 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)Capecitabine (n=6,6,6,6,3,3)5.88 h*µg/mLStandard Deviation 6.28
ERL+BEV+CAP Dose Level-3Part 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)5'-DFCR (n=5,5,6,6,3,3)20.27 h*µg/mLStandard Deviation 11.53
ERL+BEV+CAP Dose Level-3Part 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)Erlotinib (n=6,6,6,6,3,3)9.15 h*µg/mLStandard Deviation 4.39
ERL+BEV+CAP Dose Level-4Part 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)5'-DFUR (n=4,5,6,6,3,3)10.86 h*µg/mLStandard Deviation 4.96
ERL+BEV+CAP Dose Level-4Part 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)OSI-420 (n=6,6,6,6,3,3)0.99 h*µg/mLStandard Deviation 0.73
ERL+BEV+CAP Dose Level-4Part 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)Erlotinib (n=6,6,6,6,3,3)13.07 h*µg/mLStandard Deviation 11.03
ERL+BEV+CAP Dose Level-4Part 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)Capecitabine (n=6,6,6,6,3,3)5.28 h*µg/mLStandard Deviation 3.25
ERL+BEV+CAP Dose Level-4Part 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)5'-DFCR (n=5,5,6,6,3,3)9.35 h*µg/mLStandard Deviation 3.26
ERL+BEV+CAP Dose Level-5Part 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)5'-DFUR (n=4,5,6,6,3,3)5.17 h*µg/mLStandard Deviation 0.89
ERL+BEV+CAP Dose Level-5Part 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)Erlotinib (n=6,6,6,6,3,3)8.54 h*µg/mLStandard Deviation 1.96
ERL+BEV+CAP Dose Level-5Part 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)OSI-420 (n=6,6,6,6,3,3)0.36 h*µg/mLStandard Deviation 0.03
ERL+BEV+CAP Dose Level-5Part 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)Capecitabine (n=6,6,6,6,3,3)13.63 h*µg/mLStandard Deviation 8.63
ERL+BEV+CAP Dose Level-5Part 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)5'-DFCR (n=5,5,6,6,3,3)12.63 h*µg/mLStandard Deviation 9.89
ERL+BEV+CAP Dose Level-6Part 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)5'-DFUR (n=4,5,6,6,3,3)8.53 h*µg/mLStandard Deviation 1.87
ERL+BEV+CAP Dose Level-6Part 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)OSI-420 (n=6,6,6,6,3,3)1.42 h*µg/mLStandard Deviation 0.17
ERL+BEV+CAP Dose Level-6Part 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)5'-DFCR (n=5,5,6,6,3,3)8.06 h*µg/mLStandard Deviation 2.14
ERL+BEV+CAP Dose Level-6Part 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)Erlotinib (n=6,6,6,6,3,3)19.88 h*µg/mLStandard Deviation 4.75
ERL+BEV+CAP Dose Level-6Part 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)Capecitabine (n=6,6,6,6,3,3)9.74 h*µg/mLStandard Deviation 3.02
Secondary

Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)

Time frame: 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)

Population: Per-protocol population. Here n signifies the number of participants who were evaluable for each drug for each arm, respectively.

ArmMeasureGroupValue (MEAN)Dispersion
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)0.23 µg/mLStandard Deviation 0.23
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)0.04 µg/mLStandard Deviation 0.06
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)0.37 µg/mLStandard Deviation 0.36
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)2.54 µg/mLStandard Deviation 0.14
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.05 µg/mLStandard Deviation 0.06
ERL+BEV+CAP Dose Level-2Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)0.02 µg/mLStandard Deviation 0.01
ERL+BEV+CAP Dose Level-2Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)0.08 µg/mLStandard Deviation 0.04
ERL+BEV+CAP Dose Level-2Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)0.31 µg/mLStandard Deviation 0.19
ERL+BEV+CAP Dose Level-2Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)1.03 µg/mLStandard Deviation 1.05
ERL+BEV+CAP Dose Level-2Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.2 µg/mLStandard Deviation 0.2
ERL+BEV+CAP Dose Level-3Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)0.01 µg/mLStandard Deviation 0.01
ERL+BEV+CAP Dose Level-3Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)0.64 µg/mLStandard Deviation 0.6
ERL+BEV+CAP Dose Level-3Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)0.77 µg/mLStandard Deviation 0.92
ERL+BEV+CAP Dose Level-3Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.17 µg/mLStandard Deviation 0.15
ERL+BEV+CAP Dose Level-3Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)0.23 µg/mLStandard Deviation 0.11
ERL+BEV+CAP Dose Level-4Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.06 µg/mLStandard Deviation 0.03
ERL+BEV+CAP Dose Level-4Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)0.39 µg/mLStandard Deviation 0.39
ERL+BEV+CAP Dose Level-4Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)0.04 µg/mLStandard Deviation 0.04
ERL+BEV+CAP Dose Level-4Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)0.75 µg/mLStandard Deviation 0.89
ERL+BEV+CAP Dose Level-4Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)0.58 µg/mLStandard Deviation 0.49
ERL+BEV+CAP Dose Level-5Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)0.99 µg/mLStandard Deviation 1.22
ERL+BEV+CAP Dose Level-5Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)0.23 µg/mLStandard Deviation 0.02
ERL+BEV+CAP Dose Level-5Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)0.14 µg/mLStandard Deviation 0.08
ERL+BEV+CAP Dose Level-5Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)0.01 µg/mLStandard Deviation 0
ERL+BEV+CAP Dose Level-5Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.29 µg/mLStandard Deviation 0.26
ERL+BEV+CAP Dose Level-6Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)0.52 µg/mLStandard Deviation 0.19
ERL+BEV+CAP Dose Level-6Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)0.3 µg/mLStandard Deviation 0.1
ERL+BEV+CAP Dose Level-6Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)0.04 µg/mLStandard Deviation 0.01
ERL+BEV+CAP Dose Level-6Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)0.14 µg/mLStandard Deviation 0.05
ERL+BEV+CAP Dose Level-6Part 1: Last Quantifiable Drug Concentration (Clast) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.17 µg/mLStandard Deviation 0.1
Secondary

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])

Time frame: 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)

Population: Per-protocol population. Here n signifies the number of participants who were evaluable for each drug for each arm, respectively.

ArmMeasureGroupValue (MEAN)Dispersion
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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])Erlotinib (n=6,6,6,6,3,3)1.50 micrograms per milliliter (µg/mL)Standard Deviation 1.21
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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])5'-DFCR (n=5,5,6,6,3,3)3.5 micrograms per milliliter (µg/mL)Standard Deviation 3.02
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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])Capecitabine (n=6,6,6,6,3,3)1.69 micrograms per milliliter (µg/mL)Standard Deviation 1.22
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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])5'-DFUR (n=4,5,6,6,3,3)7.9 micrograms per milliliter (µg/mL)Standard Deviation 4.41
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)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])OSI-420 (n=6,6,6,6,3,3)0.09 micrograms per milliliter (µg/mL)Standard Deviation 0.07
ERL+BEV+CAP Dose Level-2Part 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])5'-DFCR (n=5,5,6,6,3,3)4.28 micrograms per milliliter (µg/mL)Standard Deviation 1.61
ERL+BEV+CAP Dose Level-2Part 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])OSI-420 (n=6,6,6,6,3,3)0.05 micrograms per milliliter (µg/mL)Standard Deviation 0.03
ERL+BEV+CAP Dose Level-2Part 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])Erlotinib (n=6,6,6,6,3,3)0.95 micrograms per milliliter (µg/mL)Standard Deviation 0.58
ERL+BEV+CAP Dose Level-2Part 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])Capecitabine (n=6,6,6,6,3,3)1.13 micrograms per milliliter (µg/mL)Standard Deviation 0.61
ERL+BEV+CAP Dose Level-2Part 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])5'-DFUR (n=4,5,6,6,3,3)7.3 micrograms per milliliter (µg/mL)Standard Deviation 2.74
ERL+BEV+CAP Dose Level-3Part 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])OSI-420 (n=6,6,6,6,3,3)0.04 micrograms per milliliter (µg/mL)Standard Deviation 0.02
ERL+BEV+CAP Dose Level-3Part 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])Erlotinib (n=6,6,6,6,3,3)0.68 micrograms per milliliter (µg/mL)Standard Deviation 0.34
ERL+BEV+CAP Dose Level-3Part 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])5'-DFUR (n=4,5,6,6,3,3)6.17 micrograms per milliliter (µg/mL)Standard Deviation 2.63
ERL+BEV+CAP Dose Level-3Part 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])5'-DFCR (n=5,5,6,6,3,3)11.46 micrograms per milliliter (µg/mL)Standard Deviation 5.32
ERL+BEV+CAP Dose Level-3Part 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])Capecitabine (n=6,6,6,6,3,3)4.89 micrograms per milliliter (µg/mL)Standard Deviation 4.23
ERL+BEV+CAP Dose Level-4Part 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])OSI-420 (n=6,6,6,6,3,3)0.06 micrograms per milliliter (µg/mL)Standard Deviation 0.04
ERL+BEV+CAP Dose Level-4Part 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])5'-DFUR (n=4,5,6,6,3,3)7.24 micrograms per milliliter (µg/mL)Standard Deviation 3.35
ERL+BEV+CAP Dose Level-4Part 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])Erlotinib (n=6,6,6,6,3,3)0.93 micrograms per milliliter (µg/mL)Standard Deviation 0.63
ERL+BEV+CAP Dose Level-4Part 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])5'-DFCR (n=5,5,6,6,3,3)6.26 micrograms per milliliter (µg/mL)Standard Deviation 2.05
ERL+BEV+CAP Dose Level-4Part 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])Capecitabine (n=6,6,6,6,3,3)5.48 micrograms per milliliter (µg/mL)Standard Deviation 4.51
ERL+BEV+CAP Dose Level-5Part 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])5'-DFCR (n=5,5,6,6,3,3)5.44 micrograms per milliliter (µg/mL)Standard Deviation 2.43
ERL+BEV+CAP Dose Level-5Part 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])Erlotinib (n=6,6,6,6,3,3)0.58 micrograms per milliliter (µg/mL)Standard Deviation 0.15
ERL+BEV+CAP Dose Level-5Part 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])OSI-420 (n=6,6,6,6,3,3)0.03 micrograms per milliliter (µg/mL)Standard Deviation 0.01
ERL+BEV+CAP Dose Level-5Part 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])Capecitabine (n=6,6,6,6,3,3)9.47 micrograms per milliliter (µg/mL)Standard Deviation 5.19
ERL+BEV+CAP Dose Level-5Part 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])5'-DFUR (n=4,5,6,6,3,3)3.28 micrograms per milliliter (µg/mL)Standard Deviation 0.72
ERL+BEV+CAP Dose Level-6Part 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])Capecitabine (n=6,6,6,6,3,3)9.9 micrograms per milliliter (µg/mL)Standard Deviation 5.01
ERL+BEV+CAP Dose Level-6Part 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])OSI-420 (n=6,6,6,6,3,3)0.10 micrograms per milliliter (µg/mL)Standard Deviation 0.02
ERL+BEV+CAP Dose Level-6Part 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])Erlotinib (n=6,6,6,6,3,3)1.69 micrograms per milliliter (µg/mL)Standard Deviation 0.67
ERL+BEV+CAP Dose Level-6Part 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])5'-DFUR (n=4,5,6,6,3,3)5.1 micrograms per milliliter (µg/mL)Standard Deviation 2.35
ERL+BEV+CAP Dose Level-6Part 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])5'-DFCR (n=5,5,6,6,3,3)4.15 micrograms per milliliter (µg/mL)Standard Deviation 1.24
Secondary

Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)

Time frame: 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)

Population: Per-protocol population. Here n signifies the number of participants who were evaluable for each drug for each arm, respectively.

ArmMeasureGroupValue (MEDIAN)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)0.5 hours (h)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)3.00 hours (h)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)2.50 hours (h)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)1 hours (h)
Triple Combination (Bevacizumab/Erlotinib/Capecitabine)Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.5 hours (h)
ERL+BEV+CAP Dose Level-2Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)2.00 hours (h)
ERL+BEV+CAP Dose Level-2Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)1 hours (h)
ERL+BEV+CAP Dose Level-2Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)2.00 hours (h)
ERL+BEV+CAP Dose Level-2Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)1.5 hours (h)
ERL+BEV+CAP Dose Level-2Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)1 hours (h)
ERL+BEV+CAP Dose Level-3Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)2.00 hours (h)
ERL+BEV+CAP Dose Level-3Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)1.5 hours (h)
ERL+BEV+CAP Dose Level-3Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)1.5 hours (h)
ERL+BEV+CAP Dose Level-3Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)1.5 hours (h)
ERL+BEV+CAP Dose Level-3Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)2.00 hours (h)
ERL+BEV+CAP Dose Level-4Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.75 hours (h)
ERL+BEV+CAP Dose Level-4Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)3.00 hours (h)
ERL+BEV+CAP Dose Level-4Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)7.00 hours (h)
ERL+BEV+CAP Dose Level-4Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)1 hours (h)
ERL+BEV+CAP Dose Level-4Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)1.5 hours (h)
ERL+BEV+CAP Dose Level-5Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)1 hours (h)
ERL+BEV+CAP Dose Level-5Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)5.00 hours (h)
ERL+BEV+CAP Dose Level-5Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)1 hours (h)
ERL+BEV+CAP Dose Level-5Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)6.00 hours (h)
ERL+BEV+CAP Dose Level-5Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)1 hours (h)
ERL+BEV+CAP Dose Level-6Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Erlotinib (n=6,6,6,6,3,3)2.00 hours (h)
ERL+BEV+CAP Dose Level-6Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFCR (n=5,5,6,6,3,3)1.5 hours (h)
ERL+BEV+CAP Dose Level-6Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)OSI-420 (n=6,6,6,6,3,3)4.00 hours (h)
ERL+BEV+CAP Dose Level-6Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)5'-DFUR (n=4,5,6,6,3,3)1.5 hours (h)
ERL+BEV+CAP Dose Level-6Part 1: Time to Reach Cmax (Tmax) of Erlotinib and Its Metabolite OSI-420 (CP373420), Capecitabine and Its Metabolites (5'-DFCR and 5'-DFUR)Capecitabine (n=6,6,6,6,3,3)0.5 hours (h)
Secondary

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.

Time frame: From baseline until death (Up to Week 259)

Population: Data was not reported as there were no participants analyzed since Part 2 of the study was not fully implemented.

Secondary

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.

Time frame: Month 6

Population: Data was not reported as there were no participants analyzed since Part 2 of the study was not fully implemented.

Secondary

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.

Time frame: One week before start of study treatment and weekly until disease progression or death (Up to Week 259)

Population: Data was not reported as there were no participants analyzed since Part 2 of the study was not fully implemented.

Secondary

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.

Time frame: 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)

Population: Data was not reported as there were no participants analyzed since Part 2 of the study was not fully implemented.

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026