Clinical Trials /

Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer

NCT03576963

Description:

This phase Ib/II trial studies the side effects and best dose of guadecitabine when given together with nivolumab and to see how well they work in treating participants with colorectal cancer that does not respond to treatment and has spread to other places in the body. Drugs used in chemotherapy, such as guadecitabine, 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. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving guadecitabine and nivolumab may work better in treating participants with colorectal cancer.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer
  • Official Title: A Phase Ib/II Study of Guadecitabine (SGI-110) Plus Nivolumab in Refractory CIMP+ Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 3C-18-5
  • SECONDARY ID: NCI-2018-01072
  • SECONDARY ID: 3C-18-5
  • SECONDARY ID: P30CA014089
  • NCT ID: NCT03576963

Conditions

  • Colorectal Adenocarcinoma
  • CpG Island Methylator Phenotype
  • Metastatic Microsatellite Stable Colorectal Carcinoma
  • Refractory Colorectal Carcinoma
  • Stage IV Colorectal Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8

Interventions

DrugSynonymsArms
GuadecitabineDNMT inhibitor SGI-110, S110, SGI-110Treatment (guadecitabine, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (guadecitabine, nivolumab)

Purpose

This phase Ib/II trial studies the side effects and best dose of guadecitabine when given together with nivolumab and to see how well they work in treating participants with colorectal cancer that does not respond to treatment and has spread to other places in the body. Drugs used in chemotherapy, such as guadecitabine, 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. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving guadecitabine and nivolumab may work better in treating participants with colorectal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety, tolerability, maximum tolerated dose (MTD)/recommended phase 2
      dose (R2PD) of guadecitabine in combination with nivolumab in patients with refractory CpG
      island methylator phenotype (CIMP+) metastatic colorectal cancer. (Phase Ib Dose Escalation)
      II. To assess the overall response rate (ORR) in refractory CIMP+ metastatic colorectal
      cancer patients treated with guadecitabine and nivolumab. (Phase II Expansion)

      SECONDARY OBJECTIVES:

      I. To determine the incidence of adverse events (AEs) and serious adverse events (SAEs) of
      guadecitabine combined with nivolumab. (Phase Ib Dose Escalation) II. To assess
      progression-free (PFS) and overall survival (OS) in refractory CIMP+ metastatic colorectal
      cancer patients treated with guadecitabine and nivolumab. (Phase II Dose Expansion)

      EXPLORATORY OBJECTIVES:

      I. Characterize pre and post-treatment morphometric, proteomic and genomic profiles of
      circulating tumor cells using the high-definition single cell analysis (HD-SCA) platform.

      II. Determine associations between circulating cell-free tumor deoxyribonucleic acid (DNA),
      messenger ribonucleic acid (mRNA) expression, inflammatory T-cell and DNA methylation
      signatures, with response rate (RR), PFS, OS.

      III. Determine associations between tumor PD1/PDL1 expression with RR, PFS, OS.

      OUTLINE: This is a phase Ib, dose-escalation study of guadecitabine followed by a phase II
      study.

      Participants receive guadecitabine subcutaneously (SC) on days 1-5 and nivolumab
      intravenously (IV) over 2 hours on days 8 and 22. Cycles repeat every 28 days in the absence
      of disease progression or unaccepted toxicity.

      After completion of study treatment, participants are followed up at 30 days and then every 2
      months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (guadecitabine, nivolumab)ExperimentalThis study consists of an initial dose escalation followed by an expansion cohort. Dose escalation of guadecitabine starts from 30 mg/m^2 given SC on days 1-5 every 28 days in combination with fixed dose of nivolumab at 240 mg given IV on days 8 and 22 every 28 days. Dose escalation will continue until the maximum tolerated dose is reached or all planned doses are administered.
  • Guadecitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed microsatellite stable (MSS) metastatic colorectal
             adenocarcinoma with prior treatment or intolerance to a fluoropyrimidine, oxaliplatin,
             irinotecan, bevacizumab, and an anti-EGFR agent (in patients with RAS wildtype tumors)

          -  CIMP+ status: A tumor sample will be classified as CIMP+ if >= 3 of 5 CIMP reactions
             give a PMR (percent of methylated reference) >= 10, using the MethylLight assay and
             following CIMP-defining panel - CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1

          -  No limit to number of prior lines of therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets >= 100,000/mcl

          -  Serum total bilirubin =< 1.5 upper limit normal (ULN)

          -  Serum albumin >= 2.5 g/dL

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT])
             =< 3 X ULN, unless liver metastases are present or patient has known chronic liver
             disease, in which case AST and ALT must be =< 5 X ULN

          -  Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula (Cockcroft
             and Gault 1976) or by 24-hour urine collection for determination of creatinine
             clearance

          -  Women of childbearing potential (WOCBP) must agree to follow instructions for
             method(s) of contraception for the duration of study treatment with nivolumab and 5
             months after the last dose of study treatment (i.e. 30 days [duration of ovulatory
             cycle] plus the time required for the investigational drug to undergo approximately
             five half-lives). Males who are sexually active with WOCBP must agree to follow
             instructions for method(s) of contraception for the duration of study treatment with
             nivolumab and 7 months after the last dose of study treatment (i.e. 90 days [duration
             of sperm turnover] plus the time required for the investigational drug to undergo
             approximately five half-lives). Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she should inform her treating physician
             immediately

               -  A female of child-bearing potential is any woman (regardless of sexual
                  orientation, having undergone a tubal ligation, or remaining celibate by choice)
                  who meets the following criteria:

                    -  Has not undergone a hysterectomy or bilateral oophorectomy; or

                    -  Has not been naturally postmenopausal for at least 12 consecutive months
                       (i.e., has had menses at any time in the preceding 12 consecutive months)

          -  Ability to understand and the willingness to sign a written informed consent

          -  Patients with treated parenchymal brain metastases are eligible for study
             participation. Steroids, at stable dose for 2 weeks, not to exceed equivalent of
             prednisone 10 mg daily dose, are allowed. Anticonvulsants (at stable dose) are
             allowed. Treatment for brain metastases may be whole-brain radiotherapy, radiosurgery,
             neurosurgery, or a combination as deemed appropriate by the treating physician.
             Radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to
             randomization

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
             the study (or within 6 weeks for nitrosurea or mitomycin C) or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier

          -  Patients may not be receiving any other investigational agents

          -  Any previous treatment with a hypomethylating agent, or with an anti-PD1 or anti-PD-L1
             or anti-PD-L2 or anti-CTLA-4 inhibitor, including nivolumab (or any other antibody or
             drug specifically targeting T-cell co-stimulation or checkpoint pathways). Any
             immunomodulatory agent that is not described above should be cleared by the principal
             investigator (PI)

          -  Known hypersensitivity to any of the components of guadecitabine or nivolumab

          -  Receipt of live attenuated vaccination within 30 days prior to study entry

          -  History of leptomeningeal carcinomatosis or uncontrolled seizures

          -  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

          -  Malignancies other than colorectal adenocarcinoma within 5 years prior to treatment,
             except for adequately treated carcinoma in situ (e.g. of the cervix), non-melanoma
             skin cancer, T1a or T1b prostate cancer treated with curative intent at least 1 year
             prior to study entry with normal prostate specific antigen (PSA), and ductal carcinoma
             in situ treated surgically with curative intent. Other early stage cancers that have a
             minimal chance of recurrence (i.e. stage I endometrial cancer, cervical cancer, etc.)
             may be cleared and should be discussed with the PI

          -  Renal insufficiency requiring dialysis

          -  Known positivity for human immunodeficiency virus (HIV)

          -  Active hepatitis B, hepatitis C

          -  Surgery (including open biopsy), significant traumatic injury within 28 days prior to
             randomization, or anticipation of the need for major surgery during study treatment

          -  Active or prior documented autoimmune disease. Subjects with vitiligo, Graves disease,
             or psoriasis not requiring systemic treatment (within the past 2 years) are not
             excluded

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn?s disease,
             ulcerative colitis)

          -  History of allogeneic organ transplant

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of nivolumab, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid. Live attenuated vaccines within 30 days
             of nivolumab dosing (i.e. 30 days prior to the first dose, during treatment with
             nivolumab and for 30 days post discontinuation of nivolumab. Inactivated vaccines,
             such as the injectable influenza vaccine, are permitted

          -  Known history or ongoing diagnosis of pneumonitis

          -  Known history of previous clinical diagnosis of tuberculosis

          -  Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3
             electrocardiograms (ECGs) using Fridericia?s correction

          -  Patients must not be pregnant or nursing due to the potential for congenital
             abnormalities and the potential of this regimen to harm nursing infants
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of guadecitabine when given in combination with nivolumab
Time Frame:Up to 28 days
Safety Issue:
Description:MTD defined as the highest dose tested in which none or only one patient experienced dose limiting toxicity (DLT) attributable to the study drug(s), when 6 patients have been treated at that dose and are evaluable for toxicity. DLT defined as toxicity thought to be at least possibly related to study drug(s): Any grade 4 immune related adverse event (irAE); Any > or = grade 3 colitis; Any grade 3 or 4 noninfectious pneumonitis irrespective of duration; Any grade 2 pneumonitis that does not resolve to < or = to grade 1 within 3 days of the initiation of maximal supportive care; Any grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to grade 2 within 3 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to < or = grade 1 or baseline within 14 days.

Secondary Outcome Measures

Measure:Incidence and severity of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Will be assessed by Common Terminology Criteria for Adverse Events version 4.03. Will assess frequencies of adverse events (AEs), severe adverse events (SAEs), AEs leading to discontinuation, death, grade 3 and 4 AEs, and grade 3 and 4 laboratory abnormalities occurring up to 30 days after the last dose of study drug.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Southern California

Last Updated