FOLFOX +/- Ziv-Aflibercept for Esophageal and Gastric Cancer

NCT01747551 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 12-401
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 2

Brief Summary

Anti-angiogenic therapy is a proven therapeutic target in refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) chemotherapy in metastatic esophagogastric adenocarcinoma. In this study (ZAMEGA), patients with treatment-naïve esophagogastric adenocarcinoma were randomly assigned 2:1 in a multicenter, placebo-controlled double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept 4mg/kg every 2 weeks. Randomization was stratified by ECOG performance status (0-1 vs. 2) and primary site of disease (esophagus or GE junction vs stomach).

Conditions

Esophageal Cancer; Gastric Cancer

Keywords

Advanced

Outcome Measures

Primary Outcomes (1)

• 6-month Progression-free Survival (PFS)

  6-month PFS is the percent probability of patients remaining alive and progression-free at 6-months from randomization estimated using Kaplan-Meier methods. PFS was measured as the time from randomization to 1st documented disease progression (PD) or death. Patients alive without PD were censored at the earliest of the date of last progression-free disease assessment or start of non-protocol therapy. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

  Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patient follow-up was 6 months.

Secondary Outcomes (3)

• Grade 4 Treatment-Related Toxicity Rate

  Adverse events were collected each cycle on treatment. Patients received a median (range) treatment duration (months) of 6.9 (0-23.3) and 6.4 (0-43.9) for mFOLFOX6/ziv-aflibercept and mFOLFOX6/placebo, respectively.

• Objective Response Rate (ORR)

  Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patients received a median (range) treatment duration (m) of 6.9 (0-23.3) and 6.4 (0-43.9) for mFOLFOX6/ziv-aflibercept and mFOLFOX6/placebo, respectively.

• Duration of Objective Response

  Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patient follow-up (months) median (range) was 14.5 (1.1-49.8) and 18.8 (0.6-49.8) for mFOLFOX6/ziv-aflibercept and mFOLFOX6/placebo, respectively.

Study Arms (2)

mFOLFOX6 + Ziv-aflibercept

ACTIVE COMPARATOR

Patients received mFOLFOX6 and ziv-aflibercept every 2 weeks. Ziv-aflibercept 4mg/kg was given via intravenous (IV) infusion over 1 hour. Immediately following this was administration of mFOLFOX6: oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV were given concurrently over 120 minutes, followed by fluorouracil 400 mg/m2 IV bolus injection and then fluorouracil 2,400 mg/m2 IV infusion over 46 hours. Patients continued on treatment until radiological or clinical progression, unacceptable toxicity, or death.

Drug: Oxaliplatin; Drug: Leucovorin; Drug: Fluorouracil; Drug: Ziv-aflibercept

mFOLFOX6 + Placebo

ACTIVE COMPARATOR

Patients received mFOLFOX6 and placebo every 2 weeks. Placebo was given via intravenous (IV) infusion over 1 hour. Immediately following this was administration of mFOLFOX6: oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV were given concurrently over 120 minutes, followed by fluorouracil 400 mg/m2 IV bolus injection and then fluorouracil 2,400 mg/m2 IV infusion over 46 hours. Patients continued on treatment until radiological or clinical progression, unacceptable toxicity, or death.

Drug: Oxaliplatin; Drug: Leucovorin; Drug: Fluorouracil

Interventions

Oxaliplatin DRUG

Also known as: Eloxatin

mFOLFOX6 + Placebo; mFOLFOX6 + Ziv-aflibercept

Leucovorin DRUG

Also known as: Folinic Acid

mFOLFOX6 + Placebo; mFOLFOX6 + Ziv-aflibercept

Fluorouracil DRUG

Also known as: 5-FU

mFOLFOX6 + Placebo; mFOLFOX6 + Ziv-aflibercept

Ziv-aflibercept DRUG

Also known as: ZALTRAP, Eylea

mFOLFOX6 + Ziv-aflibercept

Eligibility Criteria

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

You may qualify if:

• Confirmed adenocarcinoma of esophagus, GE junction or gastric origin
• Disease is not amenable to curative resection and is unresectable, locally advanced or metastatic
• Have not received any prior chemotherapy, investigative or biologic agents for esophagogastric cancer except in the neoadjuvant or adjuvant setting
• Any major surgery must be completed at least 4 weeks prior to study entry, minor procedures must be completed at least 2 weeks prior to study entry
• Vascular access device insertion should be performed at least 1 week prior to study entry. A central line is recommended for all participants
• Willing to use adequate contraception prior to study entry, for the duration of study participation and for 3 months after the last dose of Ziv-aflibercept/placebo

You may not qualify if:

• History of hypertension unless adequately controlled
• Evidence of active bleeding from primary tumor at time of study entry
• Pregnant or breastfeeding
• Squamous cell carcinoma histology
• Prior treatment for advanced or metastatic disease
• Palliative radiation to \< 25% of bone marrow must have been completed 2 weeks prior to study entry, palliative RT to \> 25% must have been completed 4 weeks prior to study entry
• Known allergy to study agents
• Known dihydropyrimidine dehydrogenase deficiency or thymidylate kinase gene polymorphism predisposing participant to 5-FU toxicity
• History of symptomatic congestive heart failure
• Clinically significant peripheral arterial disease
• Grade 2 or higher sensory or motor neuropathy
• Serious unhealed wound, ulcers or bone fractures
• History of HIV positivity or hepatitis B or C
• History of abdominal fistula, wound dehiscence, GI perforation, intra abdominal abscess, uncontrolled GI bleeding or diverticulitis that required hospitalization within 6 months of study entry
• History of arterial thrombotic events

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02214, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Esophageal Neoplasms; Stomach Neoplasms

Interventions

Oxaliplatin; Leucovorin; Fluorouracil; aflibercept

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Peter Enzinger
• Organization: Dana-Farber Cancer Institute

617-632-3029

Study Officials

• Peter Enzinger, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 5, 2012
• First Posted: December 11, 2012
• Study Start: January 1, 2013
• Primary Completion: November 29, 2016
• Study Completion: July 26, 2017
• Last Updated: February 10, 2020
• Results First Posted: May 8, 2018

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)