Colorectal Cancer
Conditions
Brief summary
The multicenter, open-label, single-arm, non-randomized, two-stage Simon's design, phase II study (The CLMO-001 Trial) will evaluate the efficacy and safety of bevacizumab in combination with mFOLFOX-6 (Levofolinic acid, 5-Fluorouracil \[5-FU\] and oxaliplatin) in participants with colorectal cancer and liver metastases. Participants will receive combination therapy of bevacizumab 5 milligrams per kilogram (mg/kg) intravenous (IV) dose and mFOLFOX-6 every 2 weeks during Cycles 1-5 and Cycles 7-12. Participants will receive mFOLFOX-6 alone (without bevacizumab) on Cycle 6. In between Cycle 6 and 7, participants will undergo liver surgery if operable. Thereafter participants will receive bevacizumab (5 mg/kg IV every 2 weeks) alone for 52 weeks (26 cycles) after the end of the post-operative phase (maintenance therapy). At the end of the preoperative treatment phase (Cycles 1-6), participants showing different alternative conditions admitted by the protocol will undergo different management (alternative study designs 1 to 3).
Interventions
DRUG5-Fluorouracil (5-FU)
Participants will receive 5-FU 400 mg per meter-squared (mg/m\^2) IV dose on Day 1 of each 2 weeks' cycle followed by 2400 mg/m\^2, continuous infusion over 46 hours up to 12 cycles.
DRUGBevacizumab
Participants will receive 5 mg/kg bevacizumab IV dose on Day 1 of each 2 weeks' cycle up to Cycle 5 and thereafter cycles 7 to 12; followed by maintenance therapy of 5 mg/kg IV every 2 weeks up to 52 weeks (26 cycles).
DRUGLevofolinic acid
Participants will receive levofolinic acid 200 mg/m\^2 IV infusion over 2 hours on Day 1 of each 2 weeks' cycle up to 12 cycles.
DRUGOxaliplatin
Participants will receive oxaliplatin 85 mg/m\^2 IV infusion over 2 hours on Day 1 of each 2 weeks' cycle up to 12 cycles.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
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 participants (male or female), greater than (\>) 18 years of age * Histologically confirmed adenocarcinoma of the colon or the rectum * Primitive lesion is at a distance \>12 centimeter (cm) from the anal margin for participants with primitive rectal tumor * Measurable metastatic disease confined to the liver * Eastern cooperative oncology group (ECOG) performance status 0-1 * No previous chemotherapy for metastatic disease or treatment with drugs targeting vascular endothelial growth factor receptor (VEGF) or epidermal growth factor receptor (EGFR) * Adequate bone marrow, liver and renal function * Urine analysis with proteinuria less than (\<) 2+ * Use of at least one approved contraceptive method by participants with reproductive potential * Written informed consent from the participants * Surgical criteria for hepatic resection * Adjuvant treatment (either only surgery on primitive tumor or surgery on primitive tumor + adjuvant chemotherapy) must have been concluded greater than or equal to (\>/=) 6 months before enrollment
Exclusion criteria
* Presence of extrahepatic metastases * Evidence of lumbo-aortic and celiac lymph nodes involvement * Radiotherapy within 4 weeks before study start * History of inflammatory bowel disease and/or acute/sub-acute bowel occlusion * Presence of serious non-healing wound or ulcer * Evidence of bleeding diathesis or coagulopathy * Clinically significant cardiovascular disease * Uncontrolled hypertension * Current or recent ongoing treatment with anticoagulants * Chronic, daily treatment with high-dose aspirin (\>325 mg/day) or other medications known to predispose to gastrointestinal ulceration * Treatment with any investigational drug within 30 days prior to enrollment * Known allergy to Chinese hamster ovary cell proteins, or any of the components of the study medications * Co-existing malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study. Interval between endoscopic biopsy or colorectal stenting and bevacizumab administration should be evaluated by oncologist/endoscopist * Pregnant or lactating women * Any other disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complication * Participants with known Human immunodeficiency virus (HIV) infection * Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection with concomitant cirrhosis or undergoing active treatment for the same * Participants who are unable or unwilling to comply with the requirements of the protocol and follow-up procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in the Intent-to-treat (ITT) Analysis Set | Up to 11 cycles of treatment (up to Week 22) | ORR was defined as the percentage of participants with shrinkage (partial response \[PR\]) or disappearance of cancer (complete response \[CR\]). Tumor response was evaluated according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). The same method of tumor measurement and assessment had to be used to characterize each lesion throughout the study. Tumor assessment consisted of computerized tomography (CT) scan (abdomen + pelvis + chest) or contrast-enhanced magnetic resonance imaging (CE-MRI) (abdomen + pelvis) + non CE-CT (chest) according to the choice of the center. CR, Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Objective Response Rate (ORR) in the Per-protocol Analysis Set (PPAS) | Up to 11 cycles of treatment (up to Week 22) | ORR was defined as the percentage of participants with shrinkage (PR) or disappearance of cancer (CR). Tumor response was evaluated according to the RECIST v1.1. The same method of tumor measurement and assessment had to be used to characterize each lesion throughout the study. Tumor assessment consisted of CT scan (abdomen + pelvis + chest) or CE-MRI (abdomen + pelvis) + non CE-CT (chest) according to the choice of the center. CR, Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving No Residual Tumor (R0)/Surgical Margin With Microscopic Residual Tumor (R1) Liver Resection | End of study up to approximately 3 years | The percentage of participants achieving R0/R1 liver resection was defined as the percentage of participants achieving R0 surgery (no residual tumor) plus percentage of participants achieving R1 surgery (surgical margin with microscopic residual tumor). |
| Disease-free Interval (DFI) | End of study up to approximately 3 years | DFI was defined as the time from the date of R0/R1 surgery to the date of disease relapse or death due to any cause. Participants who did not progress were considered censored at the date of the last assessment performed. For participants receiving two-stage resection, the date of R0/R1 surgery was the date of the second surgery. Participants, who did not receive surgery and participants without R0/R1 surgery were censored at Day 1. DFI was calculated as follows: DFI (months) = (\[Date of R0/R1 surgery - Date of 1st relapse/Death\] + 1)/30 |
| Progression-Free Survival (PFS) | End of study up to approximately 3 years | PFS was defined as the time from the date of first study drug administration to the date of disease progression or death due to any cause, whichever came first. Progression was defined according to RECIST, v1.1 as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Participants, who did not progress were censored at the date of the last assessment performed. Participants who withdrew from the study without documented progression and for whom an electronic case report form (eCRF) existed as evidence that evaluations had been made, were censored at the date of the last tumor assessment when the participant was known to be progression-free. Participants without post-baseline tumor assessments, but known to be alive were censored at the time of first study drug administration. PFS was calculated: PFS (months) = (\[Date of Event - Date of first study drug administration\] + 1)/30. |
| Overall Survival (OS) | End of study up to approximately 3 years | OS was defined as the time from the date of first study drug administration to the date of death due to any cause. Participants who were alive at the time of the analysis were censored at the last date the participant was known to be alive. OS was calculated as follows: OS (months) = (\[Date of Death - first study drug administration\] + 1)/30 |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + mFOLFOX-6 Combination therapy of bevacizumab and mFOLFOX-6 (Levofolinic acid, 5-Fluorouracil \[5-FU\], oxaliplatin) on Day 1 of every 2 weeks' cycle for 5 cycles (Cycle 1-5), followed by 1 cycle (Cycle 6) of mFOLFOX6 alone (preoperative treatment phase). After 3 weeks of preoperative treatment phase, participants satisfying the surgical criteria for hepatic resectability will undergo a liver metastasectomy. Thereafter participants will receive combination therapy of mFOLFOX-6 + bevacizumab for another 6 cycles (Cycle 7-12); (post-operative treatment phase) followed by bevacizumab alone for 52 weeks (26 cycles) (maintenance therapy). 5-FU: 400 mg/meter-squared (mg/m\^2) IV dose on Day 1 of each 2 weeks' cycle followed by 2400 mg/m\^2, continuous infusion over 46 hours; Bevacizumab: 5 mg/kg IV on Day 1 of each 2 weeks' cycle; Levofolinic acid: 200 mg/m\^2 IV infusion over 2 hours on Day 1 of each 2 weeks' cycle; Oxaliplatin: 85 mg/m\^2 IV infusion over 2 hours on Day 1 of each 2 weeks' cycle | 77 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 14 |
| Overall Study | Consent withdrawal | 6 |
| Overall Study | Death | 19 |
| Overall Study | Other | 8 |
| Overall Study | Progressive disease | 23 |
| Overall Study | Sponsor's decision | 2 |
Baseline characteristics
| Characteristic | Bevacizumab + mFOLFOX-6 |
|---|---|
| Age, Continuous | 63.7 years STANDARD_DEVIATION 10.6 |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 77 / 77 |
| serious Total, serious adverse events | 32 / 77 |
Outcome results
Primary
Objective Response Rate (ORR) in the Intent-to-treat (ITT) Analysis Set
ORR was defined as the percentage of participants with shrinkage (partial response \[PR\]) or disappearance of cancer (complete response \[CR\]). Tumor response was evaluated according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). The same method of tumor measurement and assessment had to be used to characterize each lesion throughout the study. Tumor assessment consisted of computerized tomography (CT) scan (abdomen + pelvis + chest) or contrast-enhanced magnetic resonance imaging (CE-MRI) (abdomen + pelvis) + non CE-CT (chest) according to the choice of the center. CR, Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 11 cycles of treatment (up to Week 22)
Population: The ITT set, which included all enrolled participants, who received at least one dose of any study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX-6 | Objective Response Rate (ORR) in the Intent-to-treat (ITT) Analysis Set | 54.5 percentage of participants |
Primary
Objective Response Rate (ORR) in the Per-protocol Analysis Set (PPAS)
ORR was defined as the percentage of participants with shrinkage (PR) or disappearance of cancer (CR). Tumor response was evaluated according to the RECIST v1.1. The same method of tumor measurement and assessment had to be used to characterize each lesion throughout the study. Tumor assessment consisted of CT scan (abdomen + pelvis + chest) or CE-MRI (abdomen + pelvis) + non CE-CT (chest) according to the choice of the center. CR, Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR.
Time frame: Up to 11 cycles of treatment (up to Week 22)
Population: The PPAS included all subjects in the ITT set, who did not experience any major protocol violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX-6 | Objective Response Rate (ORR) in the Per-protocol Analysis Set (PPAS) | 64.1 percentage of participants |
Secondary
Disease-free Interval (DFI)
DFI was defined as the time from the date of R0/R1 surgery to the date of disease relapse or death due to any cause. Participants who did not progress were considered censored at the date of the last assessment performed. For participants receiving two-stage resection, the date of R0/R1 surgery was the date of the second surgery. Participants, who did not receive surgery and participants without R0/R1 surgery were censored at Day 1. DFI was calculated as follows: DFI (months) = (\[Date of R0/R1 surgery - Date of 1st relapse/Death\] + 1)/30
Time frame: End of study up to approximately 3 years
Population: The ITT set, which included all enrolled participants, who received at least one dose of any study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX-6 | Disease-free Interval (DFI) | 10.8 months |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of first study drug administration to the date of death due to any cause. Participants who were alive at the time of the analysis were censored at the last date the participant was known to be alive. OS was calculated as follows: OS (months) = (\[Date of Death - first study drug administration\] + 1)/30
Time frame: End of study up to approximately 3 years
Population: The ITT set, which included all enrolled participants, who received at least one dose of any study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX-6 | Overall Survival (OS) | NA months |
Secondary
Percentage of Participants Achieving No Residual Tumor (R0)/Surgical Margin With Microscopic Residual Tumor (R1) Liver Resection
The percentage of participants achieving R0/R1 liver resection was defined as the percentage of participants achieving R0 surgery (no residual tumor) plus percentage of participants achieving R1 surgery (surgical margin with microscopic residual tumor).
Time frame: End of study up to approximately 3 years
Population: The ITT set, which included all enrolled participants, who received at least one dose of any study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX-6 | Percentage of Participants Achieving No Residual Tumor (R0)/Surgical Margin With Microscopic Residual Tumor (R1) Liver Resection | 29.9 percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time from the date of first study drug administration to the date of disease progression or death due to any cause, whichever came first. Progression was defined according to RECIST, v1.1 as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Participants, who did not progress were censored at the date of the last assessment performed. Participants who withdrew from the study without documented progression and for whom an electronic case report form (eCRF) existed as evidence that evaluations had been made, were censored at the date of the last tumor assessment when the participant was known to be progression-free. Participants without post-baseline tumor assessments, but known to be alive were censored at the time of first study drug administration. PFS was calculated: PFS (months) = (\[Date of Event - Date of first study drug administration\] + 1)/30.
Time frame: End of study up to approximately 3 years
Population: The ITT set, which included all enrolled participants, who received at least one dose of any study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX-6 | Progression-Free Survival (PFS) | 11.7 months |