DNA Methyltransferase Inhibitor SGI-110, Donor GVAX and Cyclophosphamide in Treating Patients with Metastatic Colorectal Cancer

Status: Active


This randomized pilot phase I trial studies deoxyribonucleic acid (DNA) methyltransferase inhibitor SGI-110, donor autologous granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting lethally irradiated colorectal cancer cell vaccine (GVAX), and cyclophosphamide in treating patients with colorectal cancer that has spread to other places in the body. GVAX vaccine consists of two parts that are mixed together. One part of the vaccine is made from other patient's colon cancer cells and the other part is made from leukemia cells. The leukemia cells have been genetically changed, meaning that a certain gene was put into the DNA of those cells. A gene is a piece of DNA that carries a message that tells cells to make something, such as GM-CSF, a protein that has been shown to stimulate the immune response. DNA methyltransferase inhibitor SGI-110 may block abnormal cells or tumor cells from growing by blocking some of the enzymes needed for tumor growth. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cyclophosphamide may also help the immune system respond better to treatment with the vaccine. Giving DNA methyltransferase inhibitor SGI-110 and / or cyclophosphamide together with GVAX may be a safe and successful treatment for patients with metastatic colorectal cancer.

Eligibility Criteria

Inclusion Criteria

  • Have histologically proven adenocarcinoma of the colon or rectum
  • Metastatic colorectal cancer patients * Patient must have received a minimum of 1 systemic therapy in the metastatic setting
  • Patients must have at least one lesion which can be biopsied with acceptable clinical risk as judged by the clinical services who perform the biopsy
  • Patients must agree to have a biopsy at baseline and on treatment
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Life expectancy of greater than 4 months
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Lymphocytes >= 500/mcL
  • Platelets >= 90,000/mcL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal < 5 x upper limit of normal (ULN) if patient has liver metastases
  • Creatinine =< 1.5 x institutional upper limit of normal or creatinine clearance >= 50 mL/min/1.73 m^2
  • Total bilirubin =< 1.5 x ULN (patient with diagnosed Gilbert’s syndrome and normal direct bilirubin will be allowed)
  • Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * Male patients must agree to use an adequate method of contraception prior to study entry and for the duration of study participation as well
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Patient with a known history or evidence of brain metastases
  • Patient who has had prior treatment with demethylating agents
  • Patient who has had chemotherapy, radiation, hormonal, or biological cancer therapy < 4 weeks prior to the first dose of study drug
  • Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 28 days of the first dose of study drug
  • Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study
  • Patients who have had surgery within 4 weeks of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc), celiac plexus block, and biliary stent placement
  • Patients with a known or suspected hypersensitivity to GM-CSF (sargramostim), Cytoxan, pentastarch or hetastarch, corn, or dimethyl sulfoxide (DMSO)
  • Patients who have received any of the following concomitant therapy: interleukin (IL)-2, interferon or other non-study immunotherapy regimens; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses) within 28 days prior to first dose
  • Patients receiving growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin, etc. within 28 days of study drug administration; use of such agents while on study is also prohibited
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis, multiple sclerosis); history of Grave’s disease on stable thyroid hormone replacement for at least 1 year is allowed
  • Patients with a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection
  • Women who are pregnant or breastfeeding
  • Sexually active fertile men not using effective birth control if their partners are women of child-bearing potential (WOCBP)
  • Patients is unwilling or unable to comply with study procedures

Locations & Contacts


Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Nilofer Saba Azad
Phone: 410-614-9169
Email: nazad2@jhmi.edu

Trial Objectives and Outline


I. To evaluate changes in cluster of differentiation (CD)45RO positive tumor infiltrating lymphocytes (TILs) by histology in pre and post-treatment tumor specimens in metastatic colorectal cancer (mCRC) patients treated with SGI-110 (DNA methyltransferase inhibitor SGI-110) and cyclophosphamide (CY)/GVAX.

II. To determine the safety and feasibility of administering SGI-110 and CY/GVAX combinatorial therapy to mCRC patients.


I. To determine the optimal sequence of SGI-110 and CY/GVAX combination therapy using biological changes in immune endpoints.

II. To estimate overall survival (OS), time to progression (TTP), and progression-free survival (PFS) in mCRC patients treated with SGI-110 and CY/GVAX.


I. To analyze baseline and post-treatment tumor specimens for immune endpoints such as immune infiltrates and tumor associated antigen (TAA) expression as potential predictors of treatment benefit.

II. To assess post-treatment pharmacodynamic (PD) changes in gene expression and methylation in tumor biopsies to demonstrate proof of concept and assess for post-treatment predictive biomarkers.

III. To collect peripheral blood mononuclear cells (PBMCs) and serum to explore potential therapeutic targets, biomarkers, and predictors of treatment response.

IV. To collect pre and post-treatment whole blood to evaluate germline mutations in circulating DNA that may correlate with clinical benefit.

OUTLINE: Patients are randomized to 1 of 4 treatment cohorts.


COHORT I: Patients receive DNA methyltransferase inhibitor SGI-110 subcutaneously (SC) on days 1-5, cyclophosphamide intravenously (IV) over 30 minutes on day 1, and GVAX intradermally (ID) on day 2.

COHORT II: Patients receive DNA methyltransferase inhibitor SGI-110 as in Cohort I and cyclophosphamide IV over 30 minutes on day 8 and GVAX ID on day 9.

STAGE II (Conducted on the condition that the immune effect is successfully seen in Stage I):

COHORT III: Patients receive cyclophosphamide IV over 30 minutes on day 1 and GVAX ID on day 2.

COHORT IV: Patients receive DNA methyltransferase inhibitor SGI-110 SC on days 1-5.

In all cohorts, treatment repeats every 28 days for up to 4 courses.

In all cohorts, patients who show evidence of response or stabilization of disease after course 4 receive DNA methyltransferase inhibitor SGI-110 SC every 28 days and/or cyclophosphamide IV/GVAX ID every 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 3 months for 5 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type


Lead Organization

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Nilofer Saba Azad

Trial IDs

Primary ID J13138, NA_00087578
Secondary IDs NCI-2014-00919, J13138, NA_00087578
Clinicaltrials.gov ID NCT01966289