Study to Evaluate the Safety and Tolerability of Andecaliximab as Monotherapy and in Combination With Chemotherapy in Participants With Advanced Solid Tumors

A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5745 as Monotherapy and in Combination With Chemotherapy in Subjects With Advanced Solid Tumors

The primary objective of the study is to determine the maximum tolerated dose of andecaliximab monotherapy and to evaluate the safety and tolerability of andecaliximab (formerly GS-5745) alone and in combination with chemotherapy.

The study consists of 2 parts (Parts A and B). Participants can only qualify for and participate in 1 part.

Part A is a sequential dose escalation to determine the maximum tolerated dose of andecaliximab in participants with advanced solid tumors that are refractory to or intolerant to standard therapy or for which no standard therapy exists. In Part A, participants will receive andecaliximab only.

Part B is a dose expansion to obtain additional safety and tolerability data for andecaliximab in participants with advanced pancreatic adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, esophagogastric adenocarcinoma, colorectal cancer, or breast cancer. In Part B, participants will receive andecaliximab in combination with standard-of-care chemotherapy.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Colorectal Cancer; Pancreatic Cancer; Non-small Cell Lung Cancer; Esophagogastric Cancer
• Intervention / Treatment: Drug: Andecaliximab; Drug: Gemcitabine; Drug: Nab-paclitaxel; Drug: Carboplatin; Drug: Pemetrexed; Drug: Paclitaxel; Drug: Leucovorin; Drug: Oxaliplatin; Drug: 5-FU; Drug: Bevacizumab; Drug: Irinotecan

• Study Type: Interventional
• Enrollment (Actual): 236
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35243
      • Alabama Oncology
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Pinnacle Oncology Hematology
  • California
    • Bakersfield, California, United States, 93309
      • Comprehensive Blood And Cancer Center
    • Encinitas, California, United States, 92024
      • San Diego Pacific Oncology and Hematology Associates, Inc.
    • Los Angeles, California, United States, 90033
      • University of Southern California (USC)
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
    • Santa Monica, California, United States, 90404
      • UCLA Medical Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Parkview Research Center
    • Goshen, Indiana, United States, 46526
      • Indiana University Health Goshen Center for Cancer Care
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10021
      • Cornell University
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Health System, Institute for Translational Oncology Research
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Part A: histologically or cytologically confirmed advanced malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available

• Part B: Pancreatic Adenocarcinoma

  • Presence of histologically confirmed inoperable locally advanced or metastatic pancreatic adenocarcinoma

• Part B: NSCLC

  • Stage IIIB with malignant pleural effusion/pleural seeding or stage IV histologically confirmed NSCLC
  • Absence of known epidermal growth factor receptor (EGFR) mutation
  • Absence of known translocation or inversion events involving the ALK gene locus (resulting in EML4-ALK fusion)

• Part B: Esophagogastric Adenocarcinoma:

  • Histologically confirmed inoperable advanced gastric adenocarcinoma (including adenocarcinoma of the gastrooesophageal junction) or relapsed gastric adenocarcinoma
  • Human epidermal growth factor receptor 2 (HER2)-negative tumor (primary tumor or metastatic lesion)

• Part B: First-Line Colorectal Cancer

  • Histologically confirmed inoperable advanced adenocarcinoma of the colon or rectum
  • Radiographically measureable disease
  • No prior cytotoxic chemotherapy to treat their metastatic disease

• Part B: Second-Line Colorectal Cancer

  • Histologically confirmed inoperable advanced adenocarcinoma of the colon or rectum
  • Radiographically measureable disease
  • Received first-line combination therapy containing oxaliplatin and fluoropyrimidine with or without bevacizumab for metastatic disease with documented evidence of disease progression during or after treatment completion

• Part B: Breast Cancer

  • Histologically or cytologically confirmed metastatic breast cancer
  • Radiographically measureable disease
  • Previous hormonal therapy for metastatic breast cancer or cytotoxic adjuvant chemotherapy is allowed
  • Treatment with weekly single-agent paclitaxel is appropriate in the opinion of the treating physician
  • HER-2 negative tumor (primary tumor or metastatic lesion)
• Adequate organ function

Key Exclusion Criteria:

• Pregnant or lactating
• Individuals with known central nervous system (CNS) metastases, unless metastases are treated and stable and the individual does not require systemic steroids
• Myocardial infarction, symptomatic congestive heart failure, unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months
• Anti-tumor therapy within 28 days of study drug dosing; concurrent use of hormone therapy for breast or prostate cancer is permitted

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: ADX 200 mg; Participants with advanced solid tumors who fail or are intolerant to standard therapy or for whom no standard therapy exists, will receive 200 mg ADX as monotherapy via IV infusion (approximately 30 minutes) every 2 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745
Experimental: Part A: ADX 600 mg; Participants with advanced solid tumors who fail or are intolerant to standard therapy or for whom no standard therapy exists, will receive 600 mg ADX as monotherapy via IV infusion (approximately 30 minutes) every 2 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745
Experimental: Part A: ADX 1800 mg; Participants with advanced solid tumors who fail or are intolerant to standard therapy or for whom no standard therapy exists, will receive 1800 mg ADX as monotherapy via IV infusion (approximately 30 minutes) every 2 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745
Experimental: Part B: PAC, ADX 800 mg; Participants with PAC will receive ADX 800 mg every 2 weeks via IV infusion in addition to the 28-day cycle chemotherapy (gemcitabine and nab paclitaxel, on Days 1, 8, and 15) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Gemcitabine; Administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle; Drug: Nab-paclitaxel; Administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle
Experimental: Part B: LAC, ADX 1200 mg; Participants with lung adenocarcinoma (LAC) will receive ADX 1200 mg every 3 weeks via IV infusion in addition to the 21-day cycle chemotherapy (carboplatin and pemetrexed, on Day 1) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Carboplatin; Administered intravenously on Day 1 of each 21-day treatment cycle; Drug: Pemetrexed; Administered intravenously on Day 1 of each 21-day treatment cycle
Experimental: Part B: LSC, ADX 1200 mg; Participants with lung squamous cell carcinoma (LSC) will receive ADX 1200 mg every 3 weeks via IV infusion in addition to the 21-day cycle chemotherapy (carboplatin and paclitaxel, on Day 1) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Carboplatin; Administered intravenously on Day 1 of each 21-day treatment cycle; Drug: Paclitaxel; Administered intravenously on Days 1, 8 and 15 of each 28-day treatment cycle (Breast cancer) or on Day 1 of each 21-day treatment cycle (NSCLC)
Experimental: Part B: EGC, ADX 800 mg; Participants with esophagogastric adenocarcinoma (EGC) will receive ADX 800 mg every 2 weeks via IV infusion in addition to the 28-day cycle chemotherapy (leucovorin+oxaliplatin+5-fluorouracil {5-FU} [mFOLFOX6], on Days 1 and 15) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Leucovorin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Oxaliplatin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: 5-FU; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle
Experimental: Part B: FL CRC, ADX 800 mg+BEV 5 mg/kg; Participants with colorectal cancer (CRC) will receive first-line (FL) treatment with ADX 800 mg every 2 weeks via IV infusion in addition to the 28-day cycle chemotherapy (mFOLFOX6 and bevacizumab 5 mg/kg, on Days 1 and 15) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Leucovorin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Oxaliplatin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: 5-FU; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Bevacizumab; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle
Experimental: Part B: FL CRC, ADX 800 mg+BEV 10 mg/kg; Participants with CRC will receive FL treatment with ADX 800 mg every 2 weeks via IV infusion in addition to the 28-day cycle chemotherapy (mFOLFOX6 and bevacizumab 10 mg/kg, on Days 1 and 15) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Leucovorin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Oxaliplatin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: 5-FU; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Bevacizumab; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle
Experimental: Part B: SL CRC, ADX 800 mg+BEV 5 mg/kg; Participants with CRC will receive second-line (SL) treatment with ADX 800 mg every 2 weeks via IV infusion in addition to the 28-day cycle chemotherapy (leucovorin+irinotecan+5-FU [FOLFIRI] and bevacizumab 5 mg/kg, on Days 1 and 15) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Leucovorin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: 5-FU; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Bevacizumab; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Irinotecan; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle
Experimental: Part B: SL CRC, ADX 800 mg+BEV 10 mg/kg; Participants with CRC will receive SL treatment with ADX 800 mg every 2 weeks via IV infusion in addition to the 28-day cycle chemotherapy (FOLFIRI and bevacizumab 10 mg/kg, on Days 1 and 15) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Leucovorin; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: 5-FU; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Bevacizumab; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle; Drug: Irinotecan; Administered intravenously on Days 1 and 15 of each 28-day treatment cycle
Experimental: Part B: BRCA, ADX 800 mg; Participants with breast cancer (BRCA) will receive ADX 800 mg every 2 weeks via IV infusion in addition to the 28-day cycle chemotherapy (paclitaxel, on Days 1, 8, and 15) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug.	Drug: Andecaliximab; Administered intravenous infusion; Other Names: GS-5745; Drug: Paclitaxel; Administered intravenously on Days 1, 8 and 15 of each 28-day treatment cycle (Breast cancer) or on Day 1 of each 21-day treatment cycle (NSCLC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Treatment-Emergent Adverse Events		Part A: First dose date up to 32 weeks plus 30 days; Part B: First dose date up to 181 weeks plus 30 days
Percentage of Participants Experiencing Laboratory Abnormalities	Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. Participants with any laboratory abnormality were reported.	Part A: First dose date up to 32 weeks plus 30 days; Part B: First dose date up to 181 weeks plus 30 days

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Shah MA, Starodub A, Sharma S, Berlin J, Patel M, Wainberg ZA, Chaves J, Gordon M, Windsor K, Brachmann CB, Huang X, Vosganian G, Maltzman JD, Smith V, Silverman JA, Lenz HJ, Bendell JC. Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study. Clin Cancer Res. 2018 Aug 15;24(16):3829-3837. doi: 10.1158/1078-0432.CCR-17-2469. Epub 2018 Apr 24.
• Lenz H, Park H, Shah MA, Berlin JD, Bruetman D, Chaves J, et al. Results of a phase I study of andecaliximab in combination with mFOLFOX6 and bevacizumab in patients with previously untreated metastatic colorectal cancer. Annals of Oncology (2018) 29 (suppl_8): viii150-viii204
• Wainberg Z, Bendell J, Lenz H, Baron A, Berlin J, Bessudo A, et al. Results from a phase I study of andecaliximab in combination with FOLFIRI and bevacizumab in patients with second line metastatic colorectal cancer. Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018) 3578-3578
• Bendell J, Patel M, Brachmann C, Huang X, Maltzman J, Smith V, et al. Updated results of a phase 1 study combining the matrix metalloproteinase 9 inhibitor GS-5745 with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer [Abstract 363] 2017 American Society of Clinical Oncology Gastrointestinal Cancers Symposium
• Brachmann C, Zhang Y, Zavodovskaya M, Hu J, Maltzman J, Smith V, et al. Evaluating collagen neoepitopes as pharmacodynamic biomarkers of GS-5745, an MMP9 inhibitor, in advanced gastric cancer [Abstract 58] 2017 American Society of Clinical Oncology Gastrointestinal Cancers Symposium
• Juric V, Mikels-Vigdal A, O'Sullivan C, Greenstein A, Stefanutti E, Barry-Hamilton V, et al. Inhibition of MMP9 improves anti-tumor immunity by changing the tumor microenvironment to promote T cell trafficking and activation. [Abstract 653/27]. 2017 American Association for Cancer Research Annual Meeting 110th Annual Meeting; 2017 01 April-05 April; Washington, DC
• Zavodovskaya M, Zhang Y, Xiao Y, Maltzman J, Smith V, Brachmann C, et al. Exploratory Serum Biomarker Analysis in Gastric Cancer Patients Treated with GS-5745, an MMP9 Inhibitor, in Combination with mFOLFOX6 [Abstract 4463/24]. 2017 American Association for Cancer Research Annual Meeting 110th Annual Meeting; 2017 01 April-05 April; Washington, DC
• Bendell J, Huang X, Smith V, Maltzman J, Starodub A. Results of a phase I study of GS-5745 in combination with gemcitabine and nab-paclitaxel in patients (pts) with advanced pancreatic cancer [abstract e15683] 2016. J Clin Oncol 34 supplemental
• Shah M, Starodub A, Wainberg Z, Smith V, Maltzman J, Bendell J. Results of a phase I study of GS-5745 in combination with mFOLFOX in patients with advanced unresectable gastric / GE junction tumors [Poster 4033]. American Society of Clinical Oncology (ASCO) 52nd Annual Meeting; 2016 03 June- 07 June; Chicago, IL
• Bendell J, Starodub A, Sharma S, Wainberg Z, Shah M, Thai D. Phase I Study of GS-5745 Alone and in Combination with Chemotherapy in Patients with Advanced Solid Tumors [Poster 4030]. American Society of Clinical Oncology (ASCO) 51st Annual Meeting; 2015 29 May-02 June; Chicago, IL
• Marshall DC, Lyman SK, McCauley S, Kovalenko M, Spangler R, Liu C, Lee M, O'Sullivan C, Barry-Hamilton V, Ghermazien H, Mikels-Vigdal A, Garcia CA, Jorgensen B, Velayo AC, Wang R, Adamkewicz JI, Smith V. Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer. PLoS One. 2015 May 11;10(5):e0127063. doi: 10.1371/journal.pone.0127063. eCollection 2015.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2013
• Primary Completion (Actual): April 23, 2019
• Study Completion (Actual): April 23, 2019

Study Registration Dates

• First Submitted: February 27, 2013
• First Submitted That Met QC Criteria: February 28, 2013
• First Posted (Estimate): March 4, 2013

Study Record Updates

• Last Update Posted (Actual): June 2, 2020
• Last Update Submitted That Met QC Criteria: May 20, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Solid Tumor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Folic Acid Antagonists; Gemcitabine; Carboplatin; Paclitaxel; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Albumin-Bound Paclitaxel; Pemetrexed
• Other Study ID Numbers: GS-US-296-0101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No