A Phase 1 interventional study of bevacizumab [Avastin] and capecitabine [Xeloda] in Pancreatic Cancer, sponsored by Hoffmann-La Roche. Completed at 2 sites in Austria. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2015-08-07.
Sponsored by Hoffmann-La Roche · Phase 1, Interventional, and Treatment
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.
3,235 studies on the registry are indexed under Pancreatic Neoplasms; 899 are open to participants now.
This study's enrollment of 32 is below the median of 46 across 2,424 interventional studies indexed under Pancreatic Neoplasms.
Browse Pancreatic Neoplasms studies →Hoffmann-La Roche is the lead sponsor of 2,061 studies on the registry; 85 are open to participants now.
Of its 319 completed or terminated interventional studies of FDA-regulated products, 239 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Drug: bevacizumab [Avastin] · Drug: capecitabine [Xeloda] · Drug: erlotinib [Tarceva]
Escalating doses of 5/10mg/kg q2w
Escalating doses of 500/650/750/900mg/m2 bid
Escalating doses of 100/150mg daily
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
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)
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)
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)
| Milestone | ERL+BEV+CAP Dose Level-1 | ERL+BEV+CAP Dose Level-2 | ERL+BEV+CAP Dose Level-3 | ERL+BEV+CAP Dose Level-4 | ERL+BEV+CAP Dose Level-5 | ERL+BEV+CAP Dose Level-6 |
|---|---|---|---|---|---|---|
| Started | 6 | 6 | 6 | 6 | 3 | 3 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 6 | 6 | 6 | 6 | 3 | 3 |
| Withdrew: Major toxicity | 1 | 0 | 1 | 1 | 0 | 0 |
| Withdrew: Disease progression | 4 | 5 | 3 | 4 | 2 | 3 |
| Withdrew: Death | 0 | 0 | 1 | 0 | 0 | 0 |
| Withdrew: Physician decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Missing documentation | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: End of study visit not done | 0 | 0 | 1 | 0 | 0 | 0 |
| Withdrew: Participant is unable to swallow drug | 0 | 0 | 0 | 1 | 0 | 0 |
| Withdrew: Adverse event | 0 | 0 | 0 | 0 | 1 | 0 |
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).
| mg/m^2 BID | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Part 1: Maximum Tolerated Dose (MTD) of Capecitabine | 900 |
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.
| mg/day | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Part 1: MTD of Erlotinib | NA |
| micrograms per milliliter (µg/mL) | ERL+BEV+CAP Dose Level-1 | ERL+BEV+CAP Dose Level-2 | ERL+BEV+CAP Dose Level-3 | ERL+BEV+CAP Dose Level-4 | ERL+BEV+CAP Dose Level-5 | ERL+BEV+CAP Dose Level-6 |
|---|---|---|---|---|---|---|
| Erlotinib (n=6,6,6,6,3,3) | 1.50 ± 1.21 | 0.95 ± 0.58 | 0.68 ± 0.34 | 0.93 ± 0.63 | 0.58 ± 0.15 | 1.69 ± 0.67 |
| OSI-420 (n=6,6,6,6,3,3) | 0.09 ± 0.07 | 0.05 ± 0.03 | 0.04 ± 0.02 | 0.06 ± 0.04 | 0.03 ± 0.01 | 0.10 ± 0.02 |
| Capecitabine (n=6,6,6,6,3,3) | 1.69 ± 1.22 | 1.13 ± 0.61 | 4.89 ± 4.23 | 5.48 ± 4.51 | 9.47 ± 5.19 | 9.9 ± 5.01 |
| 5'-DFCR (n=5,5,6,6,3,3) | 3.5 ± 3.02 | 4.28 ± 1.61 | 11.46 ± 5.32 | 6.26 ± 2.05 | 5.44 ± 2.43 | 4.15 ± 1.24 |
| 5'-DFUR (n=4,5,6,6,3,3) | 7.9 ± 4.41 | 7.3 ± 2.74 | 6.17 ± 2.63 | 7.24 ± 3.35 | 3.28 ± 0.72 | 5.1 ± 2.35 |
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.
| mg/kg once every 2 weeks (Q2W) | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Part 1: MTD of Bevacizumab | NA |
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.
| mg/m^2 BID | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Part 1: Preliminary Recommended Dose (PRD) of Capecitabine for Part 2 | 800 |
| hours (h) | ERL+BEV+CAP Dose Level-1 | ERL+BEV+CAP Dose Level-2 | ERL+BEV+CAP Dose Level-3 | ERL+BEV+CAP Dose Level-4 | ERL+BEV+CAP Dose Level-5 | ERL+BEV+CAP Dose Level-6 |
|---|---|---|---|---|---|---|
| Erlotinib (n=6,6,6,6,3,3) | 2.50 (1.00 to 8.00) | 2.00 (2.00 to 8.00) | 2.00 (1.00 to 6.00) | 3.00 (2.00 to 8.00) | 5.00 (4.00 to 6.00) | 2.00 (2.00 to 3.00) |
| OSI-420 (n=6,6,6,6,3,3) | 3.00 (1.00 to 8.00) | 2.00 (2.00 to 24.00) | 2.00 (1.00 to 8.00) | 7.00 (2.00 to 24.00) | 6.00 (6.00 to 6.00) | 4.00 (2.00 to 4.00) |
| Capecitabine (n=6,6,6,6,3,3) | 0.5 (0.5 to 5) | 1 (0.5 to 3) | 1.5 (0.5 to 3) | 0.75 (0.5 to 2) | 1 (0.5 to 2) | 0.5 (0.5 to 1) |
| 5'-DFCR (n=5,5,6,6,3,3) | 0.5 (0.5 to 2.5) | 1 (1 to 1.5) | 1.5 (0.5 to 2.5) | 1 (0.5 to 2) | 1 (0.5 to 2.5) | 1.5 (0.5 to 2.5) |
| 5'-DFUR (n=4,5,6,6,3,3) | 1 (1 to 2.5) | 1.5 (1 to 2) | 1.5 (0.5 to 2.5) | 1.5 (0.5 to 2) | 1 (0.5 to 2.5) | 1.5 (1 to 2) |
| µg/mL | ERL+BEV+CAP Dose Level-1 | ERL+BEV+CAP Dose Level-2 | ERL+BEV+CAP Dose Level-3 | ERL+BEV+CAP Dose Level-4 | ERL+BEV+CAP Dose Level-5 | ERL+BEV+CAP Dose Level-6 |
|---|---|---|---|---|---|---|
| Erlotinib (n=6,6,6,6,3,3) | 0.37 ± 0.36 | 0.31 ± 0.19 | 0.23 ± 0.11 | 0.39 ± 0.39 | 0.23 ± 0.02 | 0.52 ± 0.19 |
| OSI-420 (n=6,6,6,6,3,3) | 0.04 ± 0.06 | 0.02 ± 0.01 | 0.01 ± 0.01 | 0.04 ± 0.04 | 0.01 ± 0.00 | 0.04 ± 0.01 |
| Capecitabine (n=6,6,6,6,3,3) | 0.05 ± 0.06 | 0.2 ± 0.2 | 0.17 ± 0.15 | 0.06 ± 0.03 | 0.29 ± 0.26 | 0.17 ± 0.1 |
| 5'-DFCR (n=5,5,6,6,3,3) | 0.23 ± 0.23 | 0.08 ± 0.04 | 0.64 ± 0.6 | 0.75 ± 0.89 | 0.99 ± 1.22 | 0.3 ± 0.1 |
| 5'-DFUR (n=4,5,6,6,3,3) | 2.54 ± 0.14 | 1.03 ± 1.05 | 0.77 ± 0.92 | 0.58 ± 0.49 | 0.14 ± 0.08 | 0.14 ± 0.05 |
| h*µg/mL | ERL+BEV+CAP Dose Level-1 | ERL+BEV+CAP Dose Level-2 | ERL+BEV+CAP Dose Level-3 | ERL+BEV+CAP Dose Level-4 | ERL+BEV+CAP Dose Level-5 | ERL+BEV+CAP Dose Level-6 |
|---|---|---|---|---|---|---|
| Erlotinib (n=6,6,6,6,3,3) | 15.81 ± 12.91 | 11.06 ± 5.41 | 9.15 ± 4.39 | 13.07 ± 11.03 | 8.54 ± 1.96 | 19.88 ± 4.75 |
| OSI-420 (n=6,6,6,6,3,3) | 1.15 ± 1.21 | 0.48 ± 0.35 | 0.41 ± 0.18 | 0.99 ± 0.73 | 0.36 ± 0.03 | 1.42 ± 0.17 |
| Capecitabine (n=6,6,6,6,3,3) | 1.43 ± 1.02 | 1.63 ± 1.01 | 5.88 ± 6.28 | 5.28 ± 3.25 | 13.63 ± 8.63 | 9.74 ± 3.02 |
| 5'-DFCR (n=5,5,6,6,3,3) | 3.97 ± 2.65 | 7.01 ± 1.89 | 20.27 ± 11.53 | 9.35 ± 3.26 | 12.63 ± 9.89 | 8.06 ± 2.14 |
| 5'-DFUR (n=4,5,6,6,3,3) | 15.42 ± 9.45 | 13.58 ± 7.84 | 9.76 ± 4.60 | 10.86 ± 4.96 | 5.17 ± 0.89 | 8.53 ± 1.87 |
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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".
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
| mg/day | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Part 1: PRD of Erlotinib for Part 2 | 150 |
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.
| mg/kg Q2W | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Part 1: PRD of Bevacizumab for Part 2 | 10 |
Collected over From screening up to 30 days after the last chemotherapy treatment.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| ERL+BEV+CAP Dose Level-1 | — | 3/6 (50%) | 6/6 (100%) |
| ERL+BEV+CAP Dose Level-2 | — | 2/6 (33.3%) | 5/6 (83.3%) |
| ERL+BEV+CAP Dose Level-3 | — | 4/6 (66.7%) | 6/6 (100%) |
| ERL+BEV+CAP Dose Level-4 | — | 5/6 (83.3%) | 6/6 (100%) |
| ERL+BEV+CAP Dose Level-5 | — | 3/3 (100%) | 3/3 (100%) |
| ERL+BEV+CAP Dose Level-6 | — | 3/3 (100%) | 3/3 (100%) |
| Event | ERL+BEV+CAP Dose Level-1 | ERL+BEV+CAP Dose Level-2 | ERL+BEV+CAP Dose Level-3 | ERL+BEV+CAP Dose Level-4 | ERL+BEV+CAP Dose Level-5 | ERL+BEV+CAP Dose Level-6 |
|---|---|---|---|---|---|---|
| AnemiaBlood and lymphatic system disorders | 0/6 | 0/6 | 0/6 | 0/6 | 0/3 | 1/3 |
| Abdominal painGastrointestinal disorders | 0/6 | 0/6 | 0/6 | 0/6 | 0/3 | 1/3 |
| Gastrointestinal haemorrhageGastrointestinal disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/3 | 0/3 |
| VomitingGastrointestinal disorders | 1/6 | 0/6 | 0/6 | 0/6 | 1/3 | 0/3 |
| InfectionInfections and infestations | 0/6 | 0/6 | 0/6 | 0/6 | 1/3 | 0/3 |
| Skeletal painMusculoskeletal and connective tissue disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/3 | 0/3 |
| AphasiaNervous system disorders | 0/6 | 0/6 | 0/6 | 0/6 | 0/3 | 1/3 |
| VertigoNervous system disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/3 | 1/3 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 0/6 | 0/6 | 1/6 | 2/6 | 0/3 | 0/3 |
| PneumoniaRespiratory, thoracic and mediastinal disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/3 | 0/3 |
| Event | ERL+BEV+CAP Dose Level-1 | ERL+BEV+CAP Dose Level-2 | ERL+BEV+CAP Dose Level-3 | ERL+BEV+CAP Dose Level-4 | ERL+BEV+CAP Dose Level-5 | ERL+BEV+CAP Dose Level-6 |
|---|---|---|---|---|---|---|
| FatigueGeneral disorders | 6/6 | 3/6 | 3/6 | 3/6 | 2/3 | 2/3 |
| Palmar-plantar erythrodyesthesiaSkin and subcutaneous tissue disorders | 2/6 | 5/6 | 3/6 | 3/6 | 1/3 | 0/3 |
| Rash erythematousSkin and subcutaneous tissue disorders | 3/6 | 5/6 | 4/6 | 4/6 | 2/3 | 2/3 |
| Abdominal painGastrointestinal disorders | 3/6 | 4/6 | 3/6 | 2/6 | 1/3 | 0/3 |
| DiarrhoeaGastrointestinal disorders | 2/6 | 4/6 | 4/6 | 4/6 | 0/3 | 2/3 |
| NauseaGastrointestinal disorders | 4/6 | 2/6 | 4/6 | 4/6 | 2/3 | 2/3 |
| VomitingGastrointestinal disorders | 1/6 | 3/6 | 4/6 | 4/6 | 1/3 | 1/3 |
| Appetite lossMetabolism and nutrition disorders | 4/6 | 1/6 | 2/6 | 4/6 | 0/3 | 1/3 |
| VertigoNervous system disorders | 1/6 | 1/6 | 1/6 | 1/6 | 2/3 | 1/3 |
| RhinitisRespiratory, thoracic and mediastinal disorders | 1/6 | 0/6 | 1/6 | 2/6 | 0/3 | 2/3 |
Per-protocol population: All participants who received at least 1 evaluation period of 3 cycles of the complete study regimen (of all 3 drugs) at the recommended dose unless withdrawn from therapy earlier because of toxicity.
| Age, Continuous(years) | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Mean | 63.9 ± 8.4 |
| Sex: Female, Male(Participants) | Triple Combination (Bevacizumab/Erlotinib/Capecitabine) |
|---|---|
| Female | 15 |
| Male | 15 |
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Hoffmann-La Roche