Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03576963|
Recruitment Status : Recruiting
First Posted : July 5, 2018
Last Update Posted : March 27, 2020
|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Guadecitabine Biological: Nivolumab||Phase 1 Phase 2|
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)
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)
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase Ib/II Study of Guadecitabine (SGI-110) Plus Nivolumab in Refractory CIMP+ Metastatic Colorectal Cancer|
|Actual Study Start Date :||January 30, 2020|
|Estimated Primary Completion Date :||January 30, 2022|
|Estimated Study Completion Date :||January 30, 2023|
Experimental: Treatment (guadecitabine, nivolumab)
This 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.
- Maximum tolerated dose (MTD) of guadecitabine when given in combination with nivolumab [ Time Frame: Up to 28 days ]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.
- Recommended phase 2 dose (RP2D) of guadecitabine when given in combination with nivolumab [ Time Frame: Up to 28 days ]The MTD will be the RP2D, unless other safety considerations intervene. On occasion, the MTD will be expanded to confirm that the doses at the MTD are well tolerated in later courses; if not, a dose lower than the MTD will be selected as the RP2D.
- Incidence and severity of adverse events [ Time Frame: Up to 1 year ]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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03576963
|Contact: Dana Agafitei||323-865-0467||Raluca.Agafitei@med.usc.edu|
|United States, California|
|USC / Norris Comprehensive Cancer Center||Recruiting|
|Los Angeles, California, United States, 90033|
|Contact: Dana Agafitei 323-865-0467 Raluca.Agafitei@med.usc.edu|
|Principal Investigator: Heinz-Josef Lenz, MD|
|Hoag Memorial Hospital Presbyterian||Recruiting|
|Newport Beach, California, United States, 92658|
|Contact: Cristina DeLeon, RN 949-764-6755 Cristina.firstname.lastname@example.org|
|Principal Investigator: Diana Hanna, MD|
|Principal Investigator:||Heinz-Josef Lenz, MD||University of Southern California|