Multi-Line Therapy Trial in Unresectable Metastatic Colorectal Cancer (STRATEGIC-1)

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer Metastatic
• Intervention / Treatment: Biological: FOLFIRI-cetuximab; Biological: mFOLFOX6-bevacizumab; Biological: XELOX + bevacizumab; Biological: OPTIMOX-bevacizumab; Biological: irinotecan-based chemo + bevacizumab; Biological: Anti-EGFR agent (cetuximab +/- irinotecan or panitumumab)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 464
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Benoist Chibaudel, MD; Phone Number: +33(0)1 47 59 19 23

Study Locations

• France
  • Annecy, France
    • Centre Hospitalier Annecy Gennevois
  • Auxerre, France
    • Centre hospitalier Auxerre
  • Caen, France
    • Centre Francois Baclesse
  • Cannes, France, 06400
    • Centre Hospitalier
  • Chateauroux, France
    • Centre Hospitalier Chateauroux
  • Colmar, France
    • Hospices Civils de Colmar
  • Créteil, France
    • Hopital Henri Mondor
  • Dax, France, 40107
    • Centre Hospitalier
  • Dijon, France
    • centre Georges François Leclerc
  • Dijon, France
    • Centre d'oncologie et de radiothérapie du Parc
  • La Roche sur Yon, France
    • CHD Vendée
  • Le Coudray, France
    • Hôpital Louis Pasteur
  • Le Havre, France
    • Hôpital Privé de l'Estuaire
  • Le Mans, France
    • Clinique Victor Hugo
  • Levallois Perret, France
    • Institut Hospitalier Franco-Britannique
  • Levallois Perret, France
    • Institut d'oncoloige Hartmann
  • Lille, France
    • Centre Bourgogne
  • Lorient, France
    • Centre Hospitalier de Bretagne Sud
  • Lyon, France
    • Hopital Prive Jean Mermoz
  • Marseille, France
    • Hôpital Européen
  • Marseille, France
    • Hopital Nord
  • Mont de Marsan, France
    • Centre Hospitalier Layné
  • Nancy, France
    • Centre d'oncologie de Gentilly
  • Nantes, France
    • Centre Sainte Catherine de Sienne
  • Paris, France
    • Hôpital Pitié-Salpêtrière
  • Paris, France
    • Hopital Saint-Antoine
  • Paris, France
    • Institut Mutualiste Montsouris
  • Paris, France
    • Hopital Saint-Louis
  • Paris, France
    • Hopital Cochin
  • Paris, France
    • Hôpital Saint-Joseph
  • Paris, France
    • Hôpital Tenon
  • Périgueux, France
    • Hôpital Périgueux
  • Saint Cyr sur Loire, France
    • Clinique de l'Alliance
  • Saint Malo, France
    • Hôpital Broussais - CH Saint Malo
  • Saint Priest en Jarez, France
    • institut de cancérologie Lucien Neuwirth
  • Saint-Brieuc, France
    • Clinique Armoricaine de Radiologie
  • Senlis, France
    • CH de Senlis
  • Sens, France
    • Centre Hospitalier de Sens
  • Strasbourg, France
    • Clinique Sainte-Anne
  • Suresnes, France
    • Hopital Foch
  • Thonon Les Bains, France, 74200
    • Hôpitaux du Léman
  • Toulon, France
    • Hôpital Sainte Musse
  • Valence, France
    • Clinique Générale
  • Villeneuve-d'Ascq, France, 59657
    • Institut de Cancérologie
• Ireland
  • Cork, Ireland
    • Bon Secours Hospital
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland
    • Beaumont Hospital
  • Dublin, Ireland
    • Mater Misericordiae University Hospital
  • Dublin, Ireland
    • St. James's Hospital
  • Dublin, Ireland
    • St. Vincent's University Hospital
  • Dublin, Ireland
    • Mater Private Hospital
  • Dublin, Ireland
    • Adelaide & Meath Hospital Dublin ( AMNCH)
  • Galway, Ireland
    • University Hospital Galway
  • Waterford, Ireland
    • University Hospital Waterford
• Israel
  • Ramat Gan, Israel
    • Sheba Tel Hashomer
  • Zerifin, Israel
    • Assaf Harofeh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed and dated informed consent, and willing and able to comply with protocol requirements,
2. Histologically proven adenocarcinoma of the colon and/or rectum,
3. 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
4. Metastatic disease confirmed,
5. 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),
6. 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],
7. At least one measurable or evaluable lesion as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1,
8. Age ≥18 years,
9. ECOG Performance status (PS) 0-2,
10. Hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; haemoglobin ≥9g/dL,
11. Adequate renal function: serum creatinine level <150µM,
12. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase <5xULN,
13. Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour,
14. 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,
15. 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,
16. Registration in a national health care system (CMU included for France).

Exclusion Criteria:

1. 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,
2. Exclusive bone metastasis,
3. Uncontrolled hypercalcemia,
4. Pre-existing permanent neuropathy (NCI grade ≥2),
5. Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy,
6. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
7. Treatment with any investigational medicinal product within 28 days prior to study entry,
8. Other serious and uncontrolled non-malignant disease,
9. Gilbert's syndrome,
10. 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,
11. 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,
12. Pregnant or breastfeeding women,
13. Patients with known allergy/hypersensitivity to any component of study drugs,
14. History of arterial thrombo and/or embolic event (e.g. myocardial infarction, stroke,…) within 6 months prior to randomization,
15. Chronic inflammatory bowel disease
16. Total bowel obstruction,
17. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to randomization,
18. Serious, non-healing wound, active ulcer or untreated bone fracture,
19. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding,
20. 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.
21. Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine
22. Concomitant administration of prophylactic phenytoin.
23. Treatment with sorivudine or its chemically related analogues, such as brivudine.
24. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
25. Concomitant use with St John's Wort
26. Patients with interstitial pneumonitis or pulmonary fibrosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: GERCOR - Multidisciplinary Oncology Cooperative Group
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: Benoist Chibaudel, MD, Institut Hospitalier Franco-Britannique

Publications and helpful links

General Publications

• Chibaudel B, Bonnetain F, Tournigand C, de Larauze MH, de Gramont A, Laurent-Puig P, Paget J, Hadengue A, Notelet D, Benetkiewicz M, Andre T, de Gramont A. STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer. BMC Cancer. 2015 Jul 4;15:496. doi: 10.1186/s12885-015-1503-7.

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2013
• Primary Completion (Actual): July 13, 2023
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 23, 2013
• First Submitted That Met QC Criteria: July 25, 2013
• First Posted (Estimated): July 29, 2013

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: wild-type RAS metastatic colorectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Topoisomerase I Inhibitors; Bevacizumab; Irinotecan; Panitumumab; Cetuximab
• Other Study ID Numbers: STRATEGIC-1 C12- 2; 2013-001928-19 (EudraCT Number)