4638 - Results of a phase I study of andecaliximab in combination with mFOLFOX6 and bevacizumab in patients with previously untreated metastatic colorectal cancer

Background

Matrix metalloproteinase-9 (MMP-9) is highly expressed in metastatic colorectal cancer (mCRC) and other advanced cancers and confers an adverse prognosis. In a preclinical CRC model, inhibition of MMP-9 was associated with reduced tumor growth. Andecaliximab (ADX) is a chimeric antibody directed against MMP-9, engineered to remove T cell epitopes and reduce risk of human anti-mouse antibodies. In this phase I multi-cohort study, we evaluated the combination of ADX with standard chemotherapy in patients with previously untreated mCRC. (Clinicaltrials.gov NCT# 01803282).

Methods

The study enrolled 45 eligible patients (19 female) with measurable disease and previously untreated mCRC. The median age was 62 years (range 34-78) and 18% (8/45) of patients had received prior adjuvant chemotherapy. Patients were treated with 800 mg ADX IV every two weeks plus standard doses mFOLFOX6 and bevacizumab. Safety and efficacy were assessed. Primary endpoints were safety and tolerability. Exploratory endpoints were investigator-assessed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Molecular analysis of archival tumor samples was performed.

Results

As of March 5, 2018, the median duration of ADX treatment was 8.8 months. Median PFS follow up time was 13.5 months. The most common adverse events were fatigue (78%), nausea (71%), diarrhea (56%), peripheral sensory neuropathy (49%), decreased appetite (40%), and neutropenia (40%). 38% of patients reported serious adverse events (SAEs). Acute respiratory failure and sepsis (both 4%) were the most common SAEs. Median PFS was 10 months (90% CI 9.0-12.0 months), median duration of response was 8.1 months (90% CI 6.1, 10.4). Overall response rate was 62% (90% CI 49 – 74%) with 4% complete response rate. The response rate was 50% for mutated BRAF, 67% for mutated RAS, 67% for right-sided disease. The median OS was not reached. Study treatment continues in 7% of patients.

Conclusions

Combination of ADX with mFOLFOX6 and bevacizumab was safe and shows response and PFS similar to historical data with FOLFOX-bevacizumab in first-line treatment of patients with previously untreated mCRC.

Clinical trial identification

NCT 01803282.

Legal entity responsible for the study

Gilead Sciences, Inc.

Funding

Gilead Sciences, Inc.

Editorial Acknowledgement

Disclosure

H.J. Lenz: Consulting/Advisory Role: Bristol Myers Squibb, Roche, Merck Serono, Bayer; Travel/Expenses: Bayer, Merck Serono; Honoraria: Bristol Myers Squibb, Roche, Merck Serono, Bayer, and Takeda. M. Shah: Research funding: Lilly/ImClone, Gilead Science, Merck, Sanofi/Regeneron, Boston Biomedical. J. Berlin: Research funding: Genetech/Roche, OncoMed, Novartis, Immunomedics, Abbvie, Gilead Science, Merrimack, Taiho Pharmaceuticals, Five Prime Theraputics, Loxo, Vertex, Bayer, Symphogen, Incyte, Pharmacyclics, Karyopharm Theraputics; Consulting/Advisory Role: Celegene, Symphogen, Genetech/Roche, EMD Serono, Aduro Biotech, Cornerstone Pharmaceuticals, Five Prime Theraputics, Opsona Theraputics, Pierre Fabre, Exelixis, Gritstone Oncology, Erytech Pharma, BeiGene, Karyopharm Theraputics; Travel/Expenses: Genetech/Roche, Celgene, Nestle Health Science, End Serene; Honoraria: Genetech, Nestle Health Science; Other: Symphogen, AstraZeneca. J. Chaves: Stock Ownership: Abbott Laboratories, Johnson & Johnson, Merck; Research Funding: Calithera Biosciences, Celgene, EMD Serono, Halozyme, Immune Design, Novartis, Pfizer. A. Starodub: Consultant/Advisor: Sandoz, Bayer; Speakers’ bureau: Bristol Myers Squibb; Travel/Expenses: Bayer, Bristol Myers Squibb, Sandoz. J. Liu, C. Brachmann, P. Bhargava: Employee and stock ownership: Gilead Science Inc. Z.A. Wainberg: Research funding: Novartis, Plexxikon, Pfizer, Merck; Consulting, Advisory role: Sirtex Medical, Amgen, Array BioPharma, Five Prime Therapeutics, Novartis, Lilly, Merck, Merck KGaA, Bristol-Myers Squibb, Aduro Biotech; Speakers’ bureau: Genentech; Travel expenses: Genentech. J. Bendell: Research funding: Lilly, Genetech/Roche, Incyte, Gilead Science, Bristol-Myers Squibb, Leap Theraputics, AstraZeneca/MedImmune, Boston Biomedical, GlaxoSmithKline, Novartis, Array BioPharma, Taiho Pharmaceutical, Celgene, Oncomed, Daiichi Sankyo, Bayer, Apexigen, Kolltan Pharmaceuticals, SynDevRX, Merck, Macrogenics, Five Prime Theraputics, EMD Serono, TG Theraputics, Boehringer Ingelheim, Forty Seven, Stem CentRx, Onyx, Sanofi, Takeda, Abbott/AbbVie, Eisai, Celldex, Agios, ARMO BioScience, CytomX Theraputics, Nektar, Ipsen, Merrimack, Tarveda Theraputics, Tyrogenex, Oncogenex, Marshall Edwars, Pieris Pharmaceuticals, Mersana, Calithera BioScience, Blueprint Medicines, Gritstone Oncology, Evelo Therapeutics, Forma Therapeutics, Forty Seven, EMD Serono, Merus. All other authors have declared no conflicts of interest.