STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer

Primary Objective

The primary objective is to demonstrate a difference in terms of DDC between the two
treatment strategies: FOLFIRI-cetuximab followed by an oxaliplatin-based chemotherapy
(modified FOLFOX6 [mFOLFOX6] or modified XELOX [mXELOX]) with bevacizumab vs. OPTIMOX-bevacizumab
followed by an irinotecan-based chemotherapy (modified FOLFIRI3 or FOLFIRI1) with
bevacizumab followed by an anti-EGFR agent (cetuximab or panitumumab) with/without
irinotecan, in patients with unresectable wild-type RAS mCRC.

Secondary Objective

The secondary objectives is to evaluate health-related quality of life (HRQoL), OS,
TFS, PFS, and RR (RECIST v1.1) per sequence of therapy, DDC per drug, curative salvage
surgery rate (R0 or R1 resection, global and per sequence of therapy), and safety
profile of each treatment sequence.

Trial design

STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial
comparing two standard therapeutic strategies in patients with unresectable RAS wild-type
mCRC. A full list of the participating institutions is displayed in Additional file
1: Table S3.

Study schedule

The trial has started on August 2013. The estimated accrual duration is 48 months.
The estimated study completion date is December 2019 (final data collection date for
primary outcome measure). Survival status will be collected until the patient death.

Coordination

GERCOR (France) is responsible for the overall coordination and management (study
documents and data quality, statistical analyses). In countries other than France
registration, management, and monitoring of centers are delegated to a country coordinator.

Ethics and regulatory considerations

This study is to be conducted in accordance with globally accepted standards of the
Good Clinical Practice (International Conference of Harmonization [ICH]-E6), the European
Directive 2001/20/EC, the latest version of the Declaration of Helsinki, and in agreement
with the Coordinated System for gaining National Health Service Permission (NIHR CSP)
specific to France. The study protocol was approved for all participating centers
by the French health authorities (the Agence Nationale de Sécurité du Médicament et
des Produits de Santé [ANSM] on June 24, 2013 and the Independent Ethics Committee
“Ile de France Paris VI” La Pitié Salpêtrière on April 12, 2013) and was registered
on 25 April, 2013 at EudraCT database (EudraCT 2013-001928-19) and on 23 July, 2013
at Clinicaltrials.gov (NCT01910610). If there are any possible future substantial
amendments to the original approved protocol, these have to be approved by the competent
authorities. This research is part of the “Reference Methodology” (MR-001) dated January
5, 2006, relating to personal data protection. GERCOR signed a commitment to comply
with the “Reference Methodology” regarding biomedical research and contracted civil
liability insurance to provide patients with compensation for any injury associated
with administration of the study drugs and other aspects of the conduct of the trial.

Eligibility criteria

Inclusion criteria

Signed and dated informed consent,

Patients willing and able to comply with protocol requirements,

Age???18 years,

Histologically proven adenocarcinoma of the colon and/or rectum,

Wild-type KRAS and NRAS tumor (local assessment performed either on primary tumor
or metastasis). In exceptional circumstances, RAS (KRAS and NRAS) mutational status
may be pending consideration at randomization provided that it is obtained within
the first two cycles of first-line therapy,

Metastatic disease according to RECIST v1.1,

No prior therapy for metastatic disease (in case of previous adjuvant therapy, interval
between the end of chemotherapy and relapse must be??6 months for fluoropyrimidine
alone or??12 months for oxaliplatin-, bevacizumab-, or cetuximab-based therapy),

Duly documented unresectable metastatic disease, i.e., not suitable for complete
carcinological surgical resection at inclusion (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 computerized tomography
scan (CT-scan) or magnetic resonance imaging (MRI) according to RECIST v1.136],

ECOG Performance Status (ECOG PS) between 0 and 2,

Hematological status: neutrophils???1.5×10
⁹
/L; platelets???100×10
⁹
/L; and hemoglobin???9 g/dL,

Adequate renal function: serum creatinine level??150 ?M,

Adequate liver function: serum total bilirubin level???1.5x upper normal limit (UNL),
serum alkaline phosphatase [ALP] level??5xULN,

Proteinuria??2+ (dipstick urinalysis) or???1 g/24 h,

Baseline evaluations performed before randomization when wild-type RAS status is
known: clinical and blood evaluations no more than 14 days prior to randomization,
and tumor assessment (CT-scan or MRI, evaluation of non-measurable lesions) no more
than 21 days prior to randomization,

Reliable and appropriate methods of contraception in childbearing potential women
during the trial and???6 months after the end of study treatments (when applicable).
Male patients with childbearing potential partner must agree to use contraception
in addition to having their partner use another birth control method during the trial
and until???6 months after the end of study treatments,

Registration in France with the French National Health Care System (including couverture
maladie universelle [CMU]).

Exclusion criteria

Medical history or evidence of metastasis upon physical examination of central nervous
system (CNS; 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 (National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) grade???2),

Uncontrolled hypertension (defined as systolic blood pressure??150 mmHg and/or diastolic
blood pressure??100 mmHg), or medical history of hypertensive crisis, or hypertensive
encephalopathy,

Concomitant unplanned anti-tumor therapy (e.g., chemotherapy, molecular targeted
therapy, immunotherapy),

Treatment with any investigational drug within 28 days prior to study entry,

Other serious and uncontrolled non-malignant disease,

Gilbert’s syndrome,

Medical history of other concomitant or malignant disease, except for adequately
treated in-situ cervical carcinoma, basal or squamous cell carcinoma of the skin,
and cancer in complete remission for more than 5 years,

Major surgical procedures (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 the 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, gastrointestinal perforation, intra-abdominal abscess
or active gastrointestinal bleeding within 6 months prior to randomization,

Serious, non-healing wound, active ulcer or untreated bone fracture,

Medical 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), 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 deficiency,

Concomitant use of St John’s Wort,

Patients with interstitial pneumonitis or pulmonary fibrosis.

Each patient’s eligibility will be verified by use of the standardized electronic
case-report form (eCRF, LINCOLN Technologies, France).

Interventions

Patients are exposed to all validated and recognized as standards of care agents (Fig. 1), including successive treatment lines in the mCRC therapeutic armamentarium.

Fig. 1. STRATEGIC-1 trial schema

A sequence of therapy starts with full therapy and may include planned/unplanned partial
treatment breaks or treatment-free interval (i.e., complete stop of therapy), and
ends with one of the following events (whichever occurs first): disease progression
occurring on full therapy or during a partial or complete stop of therapy without
any possibility of resuming full therapy. In case of progression, if the patient is
not on full therapy sequence, it should be resumed in arm B (first-line oxaliplatin)
if tolerable, and authorized in arm A (first-line irinotecan). Patients being under
RAS mutational evaluation will not receive targeted therapy, whatever treatment arm,
i.e. without cetuximab in arm A (FOLFIRI alone) and without bevacizumab in arm B (mFOLFOX7
or mXELOX alone) for a maximum of 2 cycles.

Before switching to the planned subsequent line of therapy, the following criteria
must be fulfilled: at least one reason to discontinue previous line of therapy, patient
general conditions compatible with treatment continuation (at investigator’s discretion),
and acceptable residual toxicities from previous line of therapy.

Arm A (Figure 1, Table 1)

Table 1. Treatment regimens in Arm A