Metastatic Colorectal Cancer
Conditions
Keywords
colorectal cancer, all solid tumors, metastatic, refractory, advanced solid tumors
Brief summary
The Primary Phase I objectives are to determine the recommended phase II dose for the capecitabine and aflibercept doublet combination; and to describe any dose limiting and non-dose limiting toxicities. The Phase II Primary objective is to determine progression free survival associated with this regimen. The Phase II secondary objectives are to determine response rate associated with this regimen; to determine overall survival associated with this regimen; and to explore any correlation of clinical outcome with baseline and on treatment changes in blood-based angiogenesis biomarkers. This open-label, non-randomized phase I/II trial is designed to assess the safety, tolerability and RPTD of capecitabine plus aflibercept in adult subjects with metastatic colorectal cancer.
Interventions
DRUGCapecitabine and aflibercept
Capecitabine given on days 1-14 and off days 15-21. Dose: Phase 1 cohort 1 850mg/m2 Phase 1 cohort 2 1000mg/m2, Phase 2 RPTD. Aflibercept will be held constant at 6 mg/kg, given intravenously every 3 weeks. Both agents will be administered on a 21-day cycle.
Sponsors
Sanofi
John Strickler, M.D.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. For the phase I portion, patients must have histologically and/or cytologically confirmed malignant solid tumor that is refractory to standard therapies. For the phase II portion, patients must have histologically and/or cytologically confirmed metastatic colorectal carcinoma that has progressed on, is intolerant of, or is inappropriate for all standard therapies. Subjects must have been treated with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan and bevacizumab or have contraindication to such treatment. Prior epithelial growth factor receptor (EGFR)-targeting agent (or contraindication to these drugs) is required for subjects with K-Ras wildtype tumors 2. Measurable disease by RECIST 1.1 criteria (see Appendix 1). Previously irradiated sites can be included if there is documented progression of disease in that site. 3. Age 18 years and older. 4. KPS \> 70% (see Appendix 2) 5. Life expectancy \> 3 months. 6. Adequate organ and marrow function as defined below: * Absolute neutrophil count \> 1.5 x 109/L * Platelet count \> 100 x 109/L * Hemoglobin \> 9 g/dl * Total bilirubin \< 1.5 x ULN * AST (SGOT)/ALT (SGPT) \< 2.5 x ULN (or \<5 x ULN if liver metastases) * Creatinine clearance ≥50 mls/min by Cockcroft-Gault * Urine Protein/Creatinine ratio \< 1 (or protein \< 1+ on urinalysis or 24hour urine protein \< 1gram/24 hours) 7. Previous radiotherapy for palliation of recurrent disease is allowed if \>4 weeks have elapsed since completion of therapy. 8. Ability to take oral medications. 9. Ability to understand and the willingness to sign a written informed consent document. 10. Women of childbearing potential must have a negative serum pregnancy test within 7 days from day 1 of study drug; both men and women must be willing to use two methods of contraception, one of them being a barrier method during the study and for 6 months after last study drug administration. 11. Signed informed consent
Exclusion criteria
1. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks from day 1 of study drug (including investigational agents, chemotherapy, radiation therapy, antibody based therapy, etc.) 2. History of severe hypersensitivity reactions/anaphylaxis attributed to humanized and/or chimeric monoclonal antibodies or other such proteins. 3. History of significant intolerance to capecitabine or 5FU (ie. Grade 4 toxicity related to one of these agents; grade 3-4 toxicity related to other concurrently administered agents is not an exclusion). 4. History of abdominal fistula or gastrointestinal perforation at any point within 6 months prior to day 1 of study drug, unless surgically repaired. 5. Active peptic ulcer disease, inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), diverticular disease or other gastrointestinal conditions with increased risk of perforation or gastrointestinal bleeding. 6. Active bleeding diathesis or history of any major bleeding, CNS bleeding, or significant hemoptysis within 6 months of enrollment. 7. Anticoagulation with warfarin (anticoagulation with low molecular weight heparin is not an exclusion). 8. History of arterial thromboembolic events or symptomatic pulmonary embolism within 6 months of study enrollment. 9. Poorly controlled hypertension \[defined as systolic blood pressure (SBP of \>150 mmHg or diastolic blood pressure (DBP) of \>90 mmHg\] 10. Patients who have had a major surgery or significant traumatic injury within 4 weeks from day 1 of study drug. 11. History of active brain metastases or carcinomatous meningitis (treated metastases are permitted, provided the patient is asymptomatic and off steroids for 28 days). 12. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Two acceptable forms of contraceptives must be continued throughout the trial by either sex. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to day 1 of study drug). 13. Any active infection, intercurrent illness, severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination | RPTD for the study will be determined at the completion of Phase I; up to 1 year. | Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I). |
| Number of Dose-Limiting Toxicities (Phase 1) | 28 days | Number of patients experiencing a dose-limiting toxicity in each cohort. A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST \> 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization |
| Median Progression Free Survival (PFS) | approximately 5 months | Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | approximately every 9 weeks and/or restaging, through study completion | The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol. |
| Median Survival | Subjects will be followed until death which is estimated to be on average 6 months - 1 year after coming off protocol therapy | Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks. | 13 |
| Phase 2 Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle. | 50 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death during Treatment period | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1 | Phase 2 | Total |
|---|---|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 12.3 | 57.7 years STANDARD_DEVIATION 9.9 | 57.8 years STANDARD_DEVIATION 10.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 14 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) White | 11 Participants | 29 Participants | 40 Participants |
| Region of Enrollment United States | 13 Participants | 50 Participants | 63 Participants |
| Sex: Female, Male Female | 6 Participants | 20 Participants | 26 Participants |
| Sex: Female, Male Male | 7 Participants | 30 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 46 / 50 |
| serious Total, serious adverse events | 9 / 13 | 18 / 50 |
Outcome results
Primary
Median Progression Free Survival (PFS)
Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.
Time frame: approximately 5 months
Population: Patients enrolled in Phase 2 were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 | Median Progression Free Survival (PFS) | 3.91 Months |
Primary
Number of Dose-Limiting Toxicities (Phase 1)
Number of patients experiencing a dose-limiting toxicity in each cohort. A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST \> 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 | Number of Dose-Limiting Toxicities (Phase 1) | 1 Participants |
| Phase 1 Cohort 2 | Number of Dose-Limiting Toxicities (Phase 1) | 2 Participants |
Primary
Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination
Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).
Time frame: RPTD for the study will be determined at the completion of Phase I; up to 1 year.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 | Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination | 850 mg/m2 |
Secondary
Median Survival
Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.
Time frame: Subjects will be followed until death which is estimated to be on average 6 months - 1 year after coming off protocol therapy
Population: Patients enrolled in Phase 2 were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 | Median Survival | 7.43 months |
Secondary
Response Rate
The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.
Time frame: approximately every 9 weeks and/or restaging, through study completion
Population: All evaluable Phase 2 patients. 5 patients were not evaluable for response and were not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 | Response Rate | 2.22 percentage of participants |