Rectal Cancer
Conditions
Brief summary
This study will assess the efficacy and safety of two different neoadjuvant treatment approaches including bevacizumab in newly diagnosed participants with high risk locally advanced rectal cancer. Participants will be randomized into one of two treatment arms (Arm A or Arm B).
Interventions
DRUGBevacizumab
Bevacizumab will be administered at the fixed dose of 5 milligrams per kilogram (mg/kg) as an IV infusion over 30 to 90 minutes.
DRUGOxaliplatin
Oxaliplatin will be administered at a dose of 85 milligrams per square meter (mg/m\^2) as a 2-hour IV infusion.
DRUGFolinic Acid
Folinic acid will be administered at a dose of 200 mg/m\^2 as a 2-hour infusion.
DRUG5-fluorouracil
5-fluorouracil will be administered at a dose of 400 mg/m\^2 as an IV bolus, then at a dose of 600 mg/m\^2 as a continuous infusion for 22 hours in Phase 1, and will be administered at a dose of 225 mg/m\^2 as a 24-hour infusion, 5 days a week, for 5 weeks in Phase 2.
RADIATIONPreoperative Radiotherapy
Radiotherapy will be delivered in fraction of 1.8 gray per day (Gy/day), 5 days a week for 5 weeks, i.e., a total dose of 45 Gy will be administered in 25 fractions over a period of 33 days.
PROCEDURESurgery
Radical rectal excision based on the TME technique.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* histologically confirmed locally advanced rectal cancer; * measurable disease; * Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
Exclusion criteria
* prior treatment with bevacizumab; * prior radiotherapy to pelvic region, or previous cytotoxic chemotherapy; * previous history of malignancy (other than basal and squamous cell cancer of the skin, or in situ cancer of the cervix); * history or evidence of central nervous system (CNS) disease; * clinically significant cardiovascular disease; * chronic treatment with high dose aspirin (more than \[\>\] 325 milligrams per day \[mg/day\]) or non-steroidal anti-inflammatory drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Tumor Sterilization Defined by ypT0-N0 | After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment) | Tumor sterilization was defined as the absence of residual tumor cells in the resected specimen including lymph nodes (ypT0-N0). The rate of sterilization of the tumoral specimen was assessed after surgery on the surgical specimen by local review. Analyses were performed for participants who have been operated as defined by the protocol (within the study and TME technique) and for all participants who have been operated. Reported is the percentage of participants with tumor sterilization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Local and Distant Recurrences | After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment) | The percentage of participants with a recurrence was described by type of recurrence (local and distant recurrence). |
| Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death | Baseline up to approximately 6 years | — |
| Disease-Free Survival (DFS) | From first time of the treatment administration to the date of second cancer, local or regional recurrence, distant metastasis or death from any cause (up to approximately 6 years) | The DFS was defined as the time from the first treatment intake to disease recurrence assessed (second primary cancer, local or distant recurrence, distant metastases) or death from any cause. The DFS was analyzed using Kaplan-Meier method. |
| Percentage of Participants Who Died | Baseline up to approximately 6 years | — |
| Percentage of Participants With Tumor Down-Staging (ypT0-pT2) | After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment) | A participant with a downstaging was defined as a participant with T3 (T describes the size of the original \[primary\] tumor) at inclusion and T2 or T1 or T0 after surgery, or with N+ (N describes lymph nodes involvement) at inclusion and N- after surgery and if T is equal at inclusion and after surgery. The clinical tumor-node-metastasis (cTNM) classification was used at inclusion and the pathological staging tumor and nodes (ypTN) classification after surgery. Reported is the percentage of participants with tumor downstaging of the surgical specimen according to the local review and centralized review. |
| Number of Cycles of Induction Chemotherapy | 6 cycles (12 weeks; cycle length = 14 days) | — |
| Number of Cycles of Chemotherapy | Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7 | — |
| Number of Cycles of Radiotherapy | Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7 | — |
| Percentage of Participants With Surgery | Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment | The surgery involving a radical rectal excision using the TME technique. |
| Overall Survival | From the first treatment administration to the date of death (up to approximately 6 years) | The overall survival was defined as the time from the first treatment intake to death from any cause. |
Countries
France
Participant flow
Pre-assignment details
A total of 92 participants with resectable rectal cancer were selected and 91 participants were randomized into the study. One participant was not randomized due to non-compliance with the inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique. | 46 |
| Arm B (Bevacizumab, Chemoradiotherapy) In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique. | 45 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 11 |
| Overall Study | Lost to Follow-up | 6 | 6 |
| Overall Study | Other | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Arm B (Bevacizumab, Chemoradiotherapy) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 16 Participants | 29 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 29 Participants | 62 Participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Male | 31 Participants | 30 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 46 | 44 / 45 |
| serious Total, serious adverse events | 21 / 46 | 18 / 45 |
Outcome results
Primary
Percentage of Participants With Tumor Sterilization Defined by ypT0-N0
Tumor sterilization was defined as the absence of residual tumor cells in the resected specimen including lymph nodes (ypT0-N0). The rate of sterilization of the tumoral specimen was assessed after surgery on the surgical specimen by local review. Analyses were performed for participants who have been operated as defined by the protocol (within the study and TME technique) and for all participants who have been operated. Reported is the percentage of participants with tumor sterilization.
Time frame: After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants With Tumor Sterilization Defined by ypT0-N0 | 23.8 percentage of participants |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants With Tumor Sterilization Defined by ypT0-N0 | 11.4 percentage of participants |
Comparison: This proportion was described for each treatment arm with a 95% confidence interval (CI) and compared with the standard proportion of 10% (CI) for each treatment arm.p-value: 0.015Binomial test
Comparison: This proportion was described for each treatment arm with a 95% CI and compared with the standard proportion of 10% (CI) using for each treatment arm.p-value: 0.906Binomial test
Secondary
Disease-Free Survival (DFS)
The DFS was defined as the time from the first treatment intake to disease recurrence assessed (second primary cancer, local or distant recurrence, distant metastases) or death from any cause. The DFS was analyzed using Kaplan-Meier method.
Time frame: From first time of the treatment administration to the date of second cancer, local or regional recurrence, distant metastasis or death from any cause (up to approximately 6 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Disease-Free Survival (DFS) | 68.3 months |
| Arm B (Bevacizumab, Chemoradiotherapy) | Disease-Free Survival (DFS) | NA months |
Secondary
Number of Cycles of Chemotherapy
Time frame: Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Number of Cycles of Chemotherapy | 4.4 cycles | Standard Deviation 1.5 |
| Arm B (Bevacizumab, Chemoradiotherapy) | Number of Cycles of Chemotherapy | 4.8 cycles | Standard Deviation 0.5 |
Secondary
Number of Cycles of Induction Chemotherapy
Time frame: 6 cycles (12 weeks; cycle length = 14 days)
Population: ITT population. Only Arm A participants received induction treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Number of Cycles of Induction Chemotherapy | 5.8 cycles | Standard Deviation 0.7 |
Secondary
Number of Cycles of Radiotherapy
Time frame: Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Number of Cycles of Radiotherapy | 4.5 cycles | Standard Deviation 1.5 |
| Arm B (Bevacizumab, Chemoradiotherapy) | Number of Cycles of Radiotherapy | 5.0 cycles | Standard Deviation 0 |
Secondary
Overall Survival
The overall survival was defined as the time from the first treatment intake to death from any cause.
Time frame: From the first treatment administration to the date of death (up to approximately 6 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Overall Survival | NA months |
| Arm B (Bevacizumab, Chemoradiotherapy) | Overall Survival | NA months |
Secondary
Percentage of Participants Who Died
Time frame: Baseline up to approximately 6 years
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants Who Died | 8.7 percentage of participants |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants Who Died | 24.4 percentage of participants |
Secondary
Percentage of Participants With Local and Distant Recurrences
The percentage of participants with a recurrence was described by type of recurrence (local and distant recurrence).
Time frame: After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants With Local and Distant Recurrences | Local recurrence | 2.2 percentage of participants |
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants With Local and Distant Recurrences | Distant recurrence | 17.4 percentage of participants |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants With Local and Distant Recurrences | Local recurrence | 6.7 percentage of participants |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants With Local and Distant Recurrences | Distant recurrence | 13.3 percentage of participants |
Secondary
Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death
Time frame: Baseline up to approximately 6 years
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death | 30.4 percentage of participants |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death | 33.3 percentage of participants |
Secondary
Percentage of Participants With Surgery
The surgery involving a radical rectal excision using the TME technique.
Time frame: Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment
Population: ITT population
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants With Surgery | 91.3 percentage of participants | 0 |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants With Surgery | 97.8 percentage of participants | — |
Secondary
Percentage of Participants With Tumor Down-Staging (ypT0-pT2)
A participant with a downstaging was defined as a participant with T3 (T describes the size of the original \[primary\] tumor) at inclusion and T2 or T1 or T0 after surgery, or with N+ (N describes lymph nodes involvement) at inclusion and N- after surgery and if T is equal at inclusion and after surgery. The clinical tumor-node-metastasis (cTNM) classification was used at inclusion and the pathological staging tumor and nodes (ypTN) classification after surgery. Reported is the percentage of participants with tumor downstaging of the surgical specimen according to the local review and centralized review.
Time frame: After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome. n = participants who were evaluable for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants With Tumor Down-Staging (ypT0-pT2) | Downstaging, local review (n=41, 44) | 65.9 percentage of participants |
| Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) | Percentage of Participants With Tumor Down-Staging (ypT0-pT2) | Downstaging, centralized review (n=39, 43) | 64.1 percentage of participants |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants With Tumor Down-Staging (ypT0-pT2) | Downstaging, local review (n=41, 44) | 54.5 percentage of participants |
| Arm B (Bevacizumab, Chemoradiotherapy) | Percentage of Participants With Tumor Down-Staging (ypT0-pT2) | Downstaging, centralized review (n=39, 43) | 55.8 percentage of participants |