Clinical trial NCT02340949: Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer
Official title: Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer. Phase II Randomized, Multicenter, Open Label Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rectal Cancer
Lead sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo
Sponsor class: OTHER
Collaborators: name: Pivotal S.L.
First posted: 2015-01-19
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial compares induction treatment with FOLFOX with or without aflibercept in a high risk population selected by MRI, prior to receiving standard chemoradiation (capecitabine combined with 50.4 Gy in 28 days) and surgery, in order to evaluate the efficacy in terms of pathologic complete response (pCR).

Detailed description: This is a randomized trial comparing induction treatment with FOLFOX with or without aflibercept in a high risk population selected by MRI, prior to receiving standard chemoradiation (capecitabine combined with 50.4 Gy in 28 days) and surgery. Once it is confirmed that the subjects fulfill the eligibility criteria (MRI-defined high risk RC), and have signed the informed consent, a central review will be requested to confirm clinical stage, and then they will be randomized to receive mFOLFOX6 + Aflibercept or mFOLFOX6 (without Aflibercept).

Random assignment of treatment will be stratified by T3 versus T4 stage. All the patients enrolled in the study will receive one cycle of study medication (mFOLFOX6 with or without aflibercept) every 14 days for six cycles, unless unacceptable toxicity or progression is detected. After this treatment, patients will receive standard chemo-radiotherapy (CT/RT) (capecitabine 825 mg/m2 twice daily combined with a total dose of 50.4 Gy in 28 days) followed by surgery, provided they have not progressed.

Patients with progression disease during the treatment phase will be withdrawn from the study and will receive their treatment according to the investigator's judgment. If a patient withdraws consent and refuses to receive further treatment, the patient must be followed up for 3 years from randomization or until progression, to evaluate disease-free survival. If a patient withdraws consent and refuses to continue in the study, the follow-up evaluations must be discontinued.

Eligibility criteria: Inclusion Criteria:

1. Signed and dated informed consent, and willing and able to comply with protocol requirement;
2. Male or female subjects with rectal cancer ≥18 and \<70 years of age;
3. High risk MRI-defined operable rectal cancer (with an inferior margin no more than 12 cm above the anal verge as assessed by MRI). Presence of at least 1 of the following on high resolution, thin-slice MRI (3 mm):

   Middle Third Tumors
   * mr T3

     1. Extramural vascular invasion (EMVI) positive
     2. Extramural extension \> 5 mms into perirectal fat
     3. Mesorectal fascia (MRF) threatened or involved\*
   * mr T4\*\*\*

   Distal Third Tumors (≤5 cm from anal verge)
   * mr T3 tumor at or below levators
   * T4 as above N2\*\*

     * tumor or lymph node \< 1 mm from the mesorectal fascia \*\*≥4 lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. ≥4 nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient.

       * T4a: overgrowth to an adjacent organ or structure or T4b: peritoneal involvement.
4. Histologically confirmed adenocarcinoma of the rectum. All other histological types are excluded;
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1;
6. Hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; hemoglobin ≥9g/dL;
7. Adequate renal function: serum creatinine level \<1.5 x upper limit of normality (ULN);
8. Adequate liver function: serum bilirubin ≤1.5 x ULN, alkaline phosphatase \<5x ULN, AST/ALT \< 3 x ULN;
9. Proteinuria \<2+ (dipstick urinalysis) or ≤1g/24hour;
10. Regular follow-up feasible;
11. For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior to starting study treatment;
12. Female patients must commit to using reliable and appropriate methods of contraception until at least three 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.

Exclusion Criteria:

1. Prior treatment with aflibercept;
2. History or evidence upon physical examination of 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 protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy);
7. Treatment with any other investigational medicinal product within 28 days prior to study entry;
8. 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;
9. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days;
10. Pregnant or breastfeeding women;
11. Patients with known allergy to any excipient to study drugs;
12. History of myocardial infarction and/or stroke within 6 months prior to randomization; Previous history of stable angina, uncontrolled arrhythmia, and acute coronary syndrome even if controlled with medication or with myocardial infarction within the last 12 months.
13. Bowel obstruction.

Primary outcomes:
measure: Number of Patients Achieving Pathologic Complete Response (pCR).
timeFrame: From baseline until 2 years and 2 months
Secondary outcomes:
measure: Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate
timeFrame: From baseline until 2 years and 2 months
measure: Number of Participants With Significant MRI Changes Post Intervention, as Defined by T Downstaging
timeFrame: From baseline until 2 years and 2 months
measure: Number of Patients Reporting Adverse Events (AEs)
timeFrame: From baseline until 2 years and 2 months
measure: Number of Patients Reporting Surgical Complications
timeFrame: From surgical intervention up to 30 days post-surgery, within a general time frame of 2 years and 2 months per study protocol
measure: Disease Free Survival (DFS) Rate at 3 Years
timeFrame: At 3 years after study treatment completion, within a general time frame of 5 years and two months
Other outcomes:
Locations:
Study officials:
affiliation: Fundación Instituto Valenciano de Oncología
name: Carlos Fernández-Martos, MD
role: STUDY_DIRECTOR
affiliation: Hospital Universitari Arnau de Vilanova de Lleida
name: Antonieta Salud Salvia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Sabadell - Parc Taulí
name: Carles Pericay Pijaume, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital del Mar
name: Clara Montagut, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clinic i provincial de Barcelona
name: Joan Maurel Santasusana, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Miguel Servet
name: Vicente Alonso Orduña, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Complejo Hospitalario de Navarra
name: Ruth Vera García, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General Universitario de Elche
name: Javier Gallego Plazas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Paz
name: Núria Rodríguez Salas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Madrid Sanchinarro (CIOCC)
name: Antonio Cubillo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General Universitario de Alicante
name: Bertomeu Massuti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Sant Joan Despí Moisés Broggi
name: Ferrán Losa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General de Granollers
name: Miguel Nogué, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitari Vall d'Hebrón
name: Jaume Capdevila, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Consorcio Hospitalario Provincial de Castellón
name: Isabel Busquier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundación Althaia Manresa
name: Inma Guash Jordan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitari Germans Trias i Pujol de Badalona
name: Laura Layos Romero, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
name: Marta Martín-Richard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario 12 de Octubre
name: Rocio García Carbonero, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Marqués de Valdecilla
name: Carlos López López, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fernandez-Martos C, Pericay C, Losa F, Garcia-Carbonero R, Layos L, Rodriguez-Salas N, Martin-Richard M, Alonso-Orduna V, Vera R, Gallego J, Capdevila J, Salud A, Nogue M, Maurel J, Guash I, Montagut C, Lopez C, Macias I, Jain RK, Garcia-Albeniz X. Effect of Aflibercept Plus Modified FOLFOX6 Induction Chemotherapy Before Standard Chemoradiotherapy and Surgery in Patients With High-Risk Rectal Adenocarcinoma: The GEMCAD 1402 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1566-1573. doi: 10.1001/jamaoncol.2019.2294.