Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer

NCT02340949 | Completed Phase 2 Results

• 1 other identifier: GEMCAD-1402
• Study Type: interventional
• Target: 180
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Rectal Cancer

Outcome Measures

Primary Outcomes (1)

• Number of Patients Achieving Pathologic Complete Response (pCR).

  The number of patients achieving pCR after induction therapy with mFOLFOX6 +/- aflibercept followed by chemotherapy (CT)/radiotherapy (RT). pCR will be defined as the absence of viable tumor cells in the primary tumor and in the lymph nodes (T0N0)

  From baseline until 2 years and 2 months

Secondary Outcomes (5)

• Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate

  From baseline until 2 years and 2 months

• Number of Participants With Significant MRI Changes Post Intervention, as Defined by T Downstaging

  From baseline until 2 years and 2 months

• Number of Patients Reporting Adverse Events (AEs)

  From baseline until 2 years and 2 months

• Number of Patients Reporting Surgical Complications

  From surgical intervention up to 30 days post-surgery, within a general time frame of 2 years and 2 months per study protocol

• Disease Free Survival (DFS) Rate at 3 Years

  At 3 years after study treatment completion, within a general time frame of 5 years and two months

Study Arms (2)

mFOLFOX6 + Aflibercept

EXPERIMENTAL

\- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs.

Drug: Aflibercept; Drug: 5-Fluoruracil; Drug: Oxaliplatin; Drug: Leucovorin

mFOLFOX6

ACTIVE COMPARATOR

\- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs.

Drug: 5-Fluoruracil; Drug: Oxaliplatin; Drug: Leucovorin

Interventions

Aflibercept DRUG

Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml

Also known as: ZALTRAP

mFOLFOX6 + Aflibercept

5-Fluoruracil DRUG

Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2

Also known as: 5-FU

mFOLFOX6; mFOLFOX6 + Aflibercept

Oxaliplatin DRUG

Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU

Also known as: Any marketed

mFOLFOX6; mFOLFOX6 + Aflibercept

Leucovorin DRUG

Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU

Also known as: Any marketed

mFOLFOX6; mFOLFOX6 + Aflibercept

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed and dated informed consent, and willing and able to comply with protocol requirement;
• Male or female subjects with rectal cancer ≥18 and \<70 years of age;
• 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
• Extramural vascular invasion (EMVI) positive
• Extramural extension \> 5 mms into perirectal fat
• 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.
• Histologically confirmed adenocarcinoma of the rectum. All other histological types are excluded;

You may not qualify if:

• Prior treatment with aflibercept;
• History or evidence upon physical examination of 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 protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy);
• Treatment with any other investigational medicinal product within 28 days prior to study entry;
• 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;
• Pregnant or breastfeeding women;
• Patients with known allergy to any excipient to study drugs;
• 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.
• Bowel obstruction.

Sponsors & Collaborators

• Grupo Espanol Multidisciplinario del Cancer Digestivo: lead
• Pivotal S.L.: collaborator

Related Publications (1)

• 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.

  PMID: 31465088 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

aflibercept; Fluorouracil; Oxaliplatin; Leucovorin

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Coordination Complexes; Organic Chemicals; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Limitations and Caveats

There are no overall limitations and caveats. In detail: There were 6 patients that received treatment doses that did not matched protocol specifications. These were notified as protocol major deviations to the competent authorities and ethics committees. The effect of these deviations on results is not significant.

Results Point of Contact

• Title: Pau Doñate Macian
• Organization: MFAR Clinical Research

investigacion@mfar.net

0034934344412

Study Officials

• Carlos Fernández-Martos, MD

  Fundación Instituto Valenciano de Oncología

  STUDY DIRECTOR

• Antonieta Salud Salvia, MD

  Hospital Universitari Arnau de Vilanova de Lleida

  PRINCIPAL INVESTIGATOR

• Carles Pericay Pijaume, MD

  Hospital de Sabadell - Parc Taulí

  PRINCIPAL INVESTIGATOR

• Clara Montagut, MD

  Hospital del Mar

  PRINCIPAL INVESTIGATOR

• Joan Maurel Santasusana, MD

  Hospital Clinic i provincial de Barcelona

  PRINCIPAL INVESTIGATOR

• Vicente Alonso Orduña, MD

  Hospital Miguel Servet

  PRINCIPAL INVESTIGATOR

• Ruth Vera García, MD

  Complejo Hospitalario de Navarra

  PRINCIPAL INVESTIGATOR

• Javier Gallego Plazas, MD

  Hospital General Universitario de Elche

  PRINCIPAL INVESTIGATOR

• Núria Rodríguez Salas, MD

  Hospital Universitario La Paz

  PRINCIPAL INVESTIGATOR

• Antonio Cubillo, MD

  Hospital Universitario Madrid Sanchinarro (CIOCC)

  PRINCIPAL INVESTIGATOR

• Bertomeu Massuti, MD

  Hospital General Universitario de Alicante

  PRINCIPAL INVESTIGATOR

• Ferrán Losa, MD

  Hospital de Sant Joan Despí Moisés Broggi

  PRINCIPAL INVESTIGATOR

• Miguel Nogué, MD

  Hospital General de Granollers

  PRINCIPAL INVESTIGATOR

• Jaume Capdevila, MD

  Hospital Universitari Vall d'Hebrón

  PRINCIPAL INVESTIGATOR

• Isabel Busquier, MD

  Consorcio Hospitalario Provincial de Castellón

  PRINCIPAL INVESTIGATOR

• Inma Guash Jordan, MD

  Fundación Althaia Manresa

  PRINCIPAL INVESTIGATOR

• Laura Layos Romero, MD

  Hospital Universitari Germans Trias i Pujol de Badalona

  PRINCIPAL INVESTIGATOR

• Marta Martín-Richard, MD

  Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

  PRINCIPAL INVESTIGATOR

• Rocio García Carbonero, MD

  Hospital Universitario 12 de Octubre

  PRINCIPAL INVESTIGATOR

• Carlos López López, MD

  Hospital Universitario Marqués de Valdecilla

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2015
• First Posted: January 19, 2015
• Study Start: January 1, 2015
• Primary Completion: July 15, 2019
• Study Completion: February 4, 2020
• Last Updated: May 3, 2021
• Results First Posted: May 3, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share