Multi-Line Therapy Trial in Unresectable Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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STRATEGIC-1 is a study designed to determine the best sequence of therapy in patients with metastatic colorectal cancer.

Detailed Description
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This is a phase III study assessing 2 mutli-line therapeutic strategies in patients with unresectable wild-type RAS metastatic colorectal cancer. All the available treatments are being used in each strategy (oxaliplatine, irinotecan, fluoropyrimidines, bevacizumab, cetuximab or panitumumab) but in a different order: STRATEGY A: FOLFIRI-cetuximab, followed by oxaliplatin-based chemotherapy with bevacizumab vs. STRATEGY B: OPTIMOX-bevacizumab, followed by irinotecan-based chemotherapy with bevacizumab, followed by anti-EGFR mab with or without irinotecan.

Official Title
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Multi-Line Therapy Trial in Unresectable Wild-Type RAS Metastatic Colorectal Cancer. A GERCOR Randomized Open-label Phase III Study.

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Biological: FOLFIRI-cetuximab
* Biological: mFOLFOX6-bevacizumab
* Biological: OPTIMOX-bevacizumab
* Biological: irinotecan-based chemo + bevacizumab
* Biological: Anti-EGFR agent (cetuximab +/- irinotecan or panitumumab)
* Biological: XELOX + bevacizumab


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, Wild-type RAS tumor no mutation in exon 2 [codon 12/13], exon 3 [codon 59/61] and exon 4 [codon 117/146] of both KRAS and NRAS genes (local assessment, performed either on primary tumor or metastasis), In exceptional circumstances, RAS mutational status (KRAS and NRAS) can be pending at time of randomization, provided it is obtained within the first two cycles of first line therapy Metastatic disease confirmed, No prior therapy for metastatic disease (in case of previous adjuvant therapy, interval from end of chemotherapy and relapse must be >6 months for fluoropyrimidine alone or >12 months for oxaliplatin-based, bevacizumab-based, or cetuximab-based therapy), Duly documented unresectable metastatic disease, ie not suitable for complete carcinological surgical resection at inclusion [NB: patients with unresectable disease at study entry but with any potential of salvage surgery after induction therapy are eligible], 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 ≤1.5 x upper normal limit (ULN), alkaline phosphatase <5xULN, Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour, Baseline evaluations performed before randomization when the KRAS WT status is known: clinical and blood evaluations no more than 2 weeks (14 days) prior to randomization, tumor assessment (CT-scan or MRI, evaluation of non-measurable lesions) no more than 3 weeks (21 days) prior to randomization, Female patients must commit to using reliable and appropriate methods of contraception during the trial and until at least six months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial and until at least 6 months after the end of the study treatment, Registration in a national health care system (CMU included for France). Exclusion Criteria: History or evidence upon physical examination of CNS metastasis (e.g. non irradiated CNS metastasis, seizure not controlled with standard medical therapy), unless adequately treated, 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), or history of hypertensive crisis, or hypertensive encephalopathy, Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy), Treatment with any investigational medicinal product within 28 days prior to study entry, Other serious and uncontrolled non-malignant disease, Gilbert's syndrome, 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, Major surgery (open biopsy, surgical resection, wound revision or any other major surgery involving entry into body cavity) or significant traumatic injury within the last 28 days prior to randomization, and/or minor surgical procedure including placement of a vascular device within 2 days of first study treatment, Pregnant or breastfeeding women, Patients with known allergy/hypersensitivity to any component of study drugs, History of arterial thrombo and/or embolic event (e.g. myocardial infarction, stroke,…) within 6 months prior to randomization, Chronic inflammatory bowel disease Total bowel obstruction, History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to randomization, Serious, non-healing wound, active ulcer or untreated bone fracture, History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding, Current or recent (within 10 days of randomization) use of aspirin (>325 mg/d), clopidogrel (>75 mg/d) or use of oral anticoagulants or thrombolytic agents. Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine Concomitant administration of prophylactic phenytoin. Treatment with sorivudine or its chemically related analogues, such as brivudine. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Concomitant use with St John's Wort Patients with interstitial pneumonitis or pulmonary fibrosis

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STRATEGY A<br>FOLFIRI-cetuximab, followed by oxaliplatin-based chemotherapy with bevacizumab | Biological: FOLFIRI-cetuximab<br> <br> Biological: mFOLFOX6-bevacizumab<br> <br> Biological: XELOX + bevacizumab<br> <br> |
| Experimental: STRATEGY B<br>OPTIMOX-bevacizumab, followed by irinotecan-based chemotherapy with bevacizumab, followed by anti-EGFR mab with or without irinotecan | Biological: OPTIMOX-bevacizumab<br> <br> Biological: irinotecan-based chemo + bevacizumab<br> <br> Biological: Anti-EGFR agent (cetuximab +/- irinotecan or panitumumab)<br> <br> Biological: XELOX + bevacizumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Disease Control (DDC) | DDC is defined as the sum of PFS of each active treatment course planned in the treatment strategy. DDC excludes 1) intervals between disease progression and re-initiation of treatment, and 2) PFS of inactive treatment if PD occurs at first evaluation after treatment re-initiation (either reintroduction in a stop-and-go strategy or subsequent course of treatment in a multi-line strategy). | From baseline until end of strategy; up to 80 months after the beginning of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Quality of life (QoL) | QoL will be considered to be improved if at least one time to QoL score deterioration (5 targeted dimensions) will be significantly longer without a significant shorter time to QoL score dimensions for other 4 targeted dimensions. | From baseline until end of strategy; up to 80 months after the beginning of the study | 
| Overall Survival (OS) | Time from randomization to the date of death from any cause | Up to 80 months after the beginning of the study | 
| Time to Failure of Strategy (TFS) | TFS is defined as beginning with the initiation of the strategy under investigation and ending with the first of the following events: 1) death, 2) disease progression on the last received planned sequence, 3) patient requires the addition of a new (unplanned) therapeutic agent, 4) patient experiences disease progression during a partial or complete break in therapy from initial treatment strategy and receives no further therapy within one month. | Up to 80 months after the beginning of the study | 
| Progression-free survival (PFS) per sequence of therapy | Time from randomization to the date of first documented disease progression or death from any cause, whichever occurs first. | Up to 80 months after the beginning of the study | 
| Tumor Response Rate (RR) | Tumor response will be assessed using RECIST version 1.1 per sequence of therapy | From baseline until end of strategy; up to 80 months after the beginning of the study | 
| Curative salvage surgery rate | The number of patient with R0 and R1 curative salvage surgery will be assessed globally (per arm) and per sequence of therapy | From baseline until end of strategy; up to 80 months after the beginning of the study | 
| Safety profile of each treatment sequence | The report will take into account all adverse events observed during and after drug administration, including any adverse events that may be related to the administration procedure itself. | From study entry to 1 month after last study drug administration; up to 80 months 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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wild-type RAS metastatic colorectal cancer