OPTIMOX-aflibercept as First-line Therapy in Patients With Unresectable Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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Evaluation of feasibility of adding aflibercept to an oxaliplatin-based regimen rather than a continuous administration of chemotherapy until progression, in order to decrease the risk of severe toxicities.

Detailed Description
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The addition of aflibercept to the standard FOLFIRI regimen as second-line therapy was evaluated in a large phase III study (EFC10262-VELOUR). This new combination significantly improved both PFS (4.7 to 6.9 months, HR=0.76; P=.00007) and OS (12.1 to 13.5 months, HR=0.82; P=.0032). In the evaluable population (86.5%), the tumor response rate was also improved when adding aflibercept (ORR=19.8% [16.4-23.2]) to the FOLFIRI regimen (ORR=11.1% [8.5-13.8]). This trial will evaluate the feasibility of adding aflibercept to an oxaliplatin-based regimen as a first-line therapy , using the OPTIMOX strategy rather than a continuous administration of chemotherapy until progression, in order to decrease the risk of severe toxicities.

Official Title
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OPTIMOX-aflibercept as First-line Therapy in 49 Patients With Unresectable Metastatic Colorectal Cancer. A GERCOR Feasibility Single-arm Phase II Study.

Conditions
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Unresectable Metastatic Colorectal Cancer

Intervention / Treatment
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* Biological: aflibercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent, and willing and able to comply with protocol requirements, Histologically proven adenocarcinoma of the colon and/or rectum, Metastatic disease confirmed, No prior therapy for metastatic disease (in case of previous adjuvant therapy, interval from end of chemotherapy to relapse must be >6 months for fluoropyrimidine alone or >12 months for oxaliplatin-based, bevacizumab-based, cetuximab-based therapy, Duly documented inoperable metastatic disease, ie not suitable for complete carcinological surgical resection, At least one measurable or evaluable lesion as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1, Age ≥18 years, ECOG Performance status (PS) 0-2, Hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; haemoglobin ≥9g/dL, Adequate renal function: serum creatinine level <150µM, Adequate liver function: serum bilirubin ≤3 x upper normal limit (ULN), alkaline phosphatase <5xULN, Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour, Baseline evaluations: clinical and blood evaluations performed no more than 2 weeks (14 days) prior to confirmation of eligibility, tumor assessment (chest X ray, CT-scan or MRI, evaluation of non-measurable lesions) no more than 3 weeks (21 days) prior to confirmation of eligibility, For female patients of childbearing potential, negative serum or urine pregnancy test within 1 week (7 days) prior of starting study treatment, Female patients of childbearing potential must commit to using reliable and effective methods of contraception during the trial and until at least six months after the end of study treatment. Females are neither pregnant nor in breastfeeding. Male patients with a partner of childbearing potential must agree to use effective contraception in addition to the contraceptive method used by their partner during the trial and until at least six months after the end of study treatment. Registration in a national health care system (CMU included for France). Exclusion Criteria: History or evidence upon physical examination of CNS metastasis unless adequately treated (e.g. non irradiated CNS metastasis, seizure not controlled with standard medical therapy), Exclusive bone metastasis, Uncontrolled hypercalcemia, Pre-existing permanent neuropathy (NCI grade ≥2), Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg despite optimal medical therapy), or history of hypertensive crisis, or hypertensive encephalopathy, Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy/ radio-immunotherapy), Treatment with any other investigational medicinal product within 28 days prior to study entry, Other serious and uncontrolled non-malignant disease, Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years, Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days Patients with known allergy to any excipient to study drugs, History of myocardial infarction and/or stroke within 6 months prior to study entry, Bowel obstruction.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OPTIMOX-aflibercept<br>Induction therapy (sequence #1) Regimen : aflibercept + modified FOLFOX7 Duration : 6 cycles (3 months) Maintenance after induction (sequence #2) First phase (sequence #2A) Regimen : aflibercept + fluoropyrimidine (simplifed LV5FU2 or capecitabine) Duration : 6 cycles (3 months) Second phase (sequence #2B) Regimen : aflibercept +/- fluoropyrimidine (simplifed LV5FU2 or capecitabine) according to eligibility criteria for chemotherapy-free interval) Duration : until PD or limiting toxicity Reintroduction (sequence #3) Regimen : aflibercept + modified FOLFOX7 Duration : 6 cycles (3 months) Maintenance after reintroduction (sequence #4) Regimen : aflibercept + fluoropyrimidine Duration : until PD or limiting toxicity | Biological: aflibercept<br>* Aflibercept (VEGF Trap) Recombinant human protein, at 25 mg/ml Dose : 4 mg/Kg -Day 1, q2w Route of administration: Intravenous (60 min infusion)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival at 6 months |  | time interval from inclusion to the date of first documented disease progression or death from any cause, whichever occurs first. Assessed at 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival |  | time interval from inclusion to the date of first documented disease progression or death from any cause, whichever occurs first. Assessed up to 3 years after the beginning of the study | 
| duration of disease control (DDC) | DDC excludes: Intervals between disease progression and re-initiation of treatment, PFS of inactive treatment if PD occurs at first evaluation after treatment re-initiation | sum of PFS of each active treatment course. Assessed up to 3 years after the beginning of the study | 
| Overall Survival |  | time interval from inclusion to the date of death from any cause. Assessed up to 3 years after the beginning of the study. | 
| tumor Response Rate (RR) | assessed using RECIST version 1.1 per sequence of therapy. | Assessed every 2 months during treatment period (- Estimated treatment duration per patient : 16 months). | 
| Health related Quality of life | EORTC QLQ C-30 | Assessed from study entry to 1 month after last study drug administration and up to 3 years after the beginning of the study. | 
| Safety | The study will take into account all adverse events observed during and after drug administration, with a particular interest for: Any AE Any AE related to study treatment Any serious AE Any serious AE related to study treatment Any NCI-CTC grade 3 or 4 AE Any NCI-CTC grade 3 or 4 AE related to study treatment Any AE causing discontinuation of study treatment Any AE causing discontinuation of selected treatment only Any AE related to study treatment causing discontinuation Any AE causing a dose reduction of study medication Any AE leading to death Any AE related to study treatment leading to death. | Assessed from study entry to 1 month after last study drug administration, assessed up to 3 years after the beginning of the study | 
| Curative salvage surgery | The number of patient with R0 and R1 curative salvage surgery will be assessed globally and per sequence of therapy. | assessed up to 3 years after the beginning of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unresectable, metastatic, colorectal, cancer, OPTIMOX, aflibercept