Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Adenocarcinoma

Colorectal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Guadecitabine

Azacitidine

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antimetabolites

Enzyme Inhibitors

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.

Heinz-Josef Lenz, MD

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.

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.

Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer

A Phase Ib/II Study of Guadecitabine (SGI-110) Plus Nivolumab in Refractory CIMP+ Metastatic Colorectal Cancer

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.

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.

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.

National Cancer Institute (NCI)

Bristol-Myers Squibb

Astex Pharmaceuticals, Inc.

University of Southern California

Symptoms and General Pathology

Neoplasm Metastasis

Oxaliplatin

Capecitabine

Decitabine

Dose Escalation of Azacitidine + CAPOX (Capecitabine, Oxaliplatin)

Starting dose level 75 mg/m2/day subcutaneously on Days 1-5 of a 21 day cycle.

1500 mg/m2/day by mouth twice daily in divided doses on Days 1-14 of a 21 day cycle.

Starting dose level 90 mg/m2 by vein on Day 2 of a 21 day cycle.

Highest tolerable dose of combination azacitidine with CAPOX found in Phase I.

Azacitidine MTD

Michael Overman, MD

The goal of the Phase I portion of this study is to find the highest tolerable dose of azacitidine combined with capecitabine and oxaliplatin (CAPOX) that can be given to patients with metastatic colorectal cancer.

The goal of the Phase II portion of this study is to learn if azacitidine, given in combination with CAPOX, can help to control metastatic colorectal cancer. The safety of this drug combination will also be studied.

The Study Drugs:

Azacitidine is designed to block certain proteins in cancer cells whose job is to stop the function of the tumor-fighting proteins. By blocking the "bad" proteins, the tumor-fighting genes may be able to work better.

Capecitabine is designed to interfere with the growth of cancer cells.

Oxaliplatin is designed to keep new cancer cells from growing.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you joined this study. Up to 4 groups of up to 3-6 participants will be enrolled in the Phase I portion of the study, and up to 30 participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of azacitidine and oxaliplatin you receive will depend on when you joined this study. All participants will receive the same dose of capecitabine. The first group of participants will receive a low dose level of the combination. Each new group will receive a higher dose of the combination than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the combination of azacitidine, oxaliplatin, and capecitabine is found.

If you are enrolled in the Phase II portion, you will receive the combination of azacitidine, oxaliplatin, and capecitabine at the highest dose that was tolerated in the Phase I portion.

Central Venous Catheter (CVC):

Before you can begin to receive oxaliplatin on this study, you will have a CVC placed if you do not have one already. A CVC is a sterile, flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

Study Drug Administration:

A cycle of treatment is defined as 21 days.

Azacitidine will be injected under your skin on Days 1-5 of each cycle.

You will receive oxaliplatin by vein over 2 hours on Day 2 of each cycle.

You will take capecitabine by mouth 2 times each day on Days 1-14 of each cycle. Capecitabine tablets should be taken 12 hours apart, within 30 minutes after eating a meal.

Study Visits:

Up to 3 days before or on Day 1 of each cycle, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will have a neurosensory assessment.
* Your performance status will be recorded.
* You will be asked about any symptoms and/or side effects you may be experiencing and any drugs you may be taking.
* Blood (about 2 tablespoons) will be drawn for routine tests.

On Day 5 of Cycle 1 and Days 1 and 5 of Cycle 2, before you receive any of the study drugs, blood (about 2 teaspoons each time) will be drawn to test for CIMP, a chemical "marker" in the blood that may be related to how the drug may affect the cancer.

After every 3 cycles (Cycles 4, 7, 10 and so on), you will have a CT or MRI scan of the chest, abdomen, and/or pelvis to check the status of the disease.

Length of Study:

You may continue to take the study drugs for as long as you are benefitting. You will be taken off the study drugs if the disease gets worse, you experience any intolerable side effects, or if the study doctor thinks it is in your best interest to stop taking the study drugs.

If you chose to stop your participation in this study at any time, you should tell the study doctor or study staff right away. They will make sure that proper procedures are followed and a final visit is made for your safety.

End-of-Treatment Visit:

Within 10 days after your study treatment ends for any reason, you will return to the clinic and the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will have a neurosensory assessment.
* Your performance status will be recorded.
* You will have a CT scan or MRI scan of the chest, abdomen, and/or pelvis to check the status of the disease.
* You will be asked about any symptoms and/or side effects you may be experiencing and any drugs you may be taking.
* Blood (about 2 tablespoons) will be drawn for routine tests.

Follow-Up:

The study doctor and study staff will follow your health status for the first 30 days after you stop taking the study drugs to check if you are experiencing any treatment-related side effects. The follow-up will be done during your regularly scheduled routine clinic visits and/or by phone call, which should last about 5 minutes.

If you continue to experience any treatment-related side effects after the 30 days of follow-up, the study staff will continue to follow up with you during your regularly scheduled clinic visits until the side effects have gotten better or become stable.

Long-Term Follow-Up:

Every 3 months after the end-of-treatment visit, the study staff will contact you by phone or email to check on how you are doing. If you are contacted by phone, the call should last about 5 minutes. Your medical records may also be reviewed.

This is an investigational study. Azacitidine is FDA approved and commercially available for myelodysplastic syndrome (MDS - a blood disease that often leads to cancer). Its use in colorectal cancer is investigational.

Oxaliplatin and capecitabine are both FDA approved and commercially available as treatment for colorectal cancer.

The use of azacitidine, oxaliplatin, and capecitabine in combination is investigational.

Up to 54 patients will take part in this study. All will be enrolled at MD Anderson.

Azacitidine and CAPOX in Metastatic Colorectal Cancer

Phase I/II Study of Azacitidine and CAPOX (Capecitabine + Oxaliplatin) in Metastatic Colorectal Cancer Patients Enriched for Hypermethylation of CpG Promoter Islands

Dose just below the one at which ≥ 1/3 of subjects experience a dose limiting toxicity (DLT) considered the MTD.

Per Response Evaluation Criteria in solid Tumors Criteria (RECISTv1.0) for target lesions and assessed by CT or MRI: Partial Response (PR), \>= 30%decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither PD nor PR, the sum of the longest diameters no change or increase by \<20% from baseline or from nadir (smallest sum on treatment); Progressive Disease (PD), the sum of the longest diameters increases by\>= 20% from nadir (smallest sum on treatment). For non-target lesions assessed by CT or MRI: Stable Disease (SD), Persistence of \>=1 non-target lesion; Progressive Disease (PD), Enlargement of non-target lesions and/or appearance of new lesions.

Celgene

M.D. Anderson Cancer Center

Dose Escalation of Azacitidine + CAPOX (Capecitabine, Oxaliplatin)

Of 21 day cycle, starting dose Azacitidine 75 mg/m2/day subcutaneously on Days 1-5; Capecitabine 1500 mg/m2/day by mouth twice daily in divided doses on Days 1-14; and Oxaliplatin starting dose 90 mg/m2 by vein on Day 2.

Phase I: Starting Dose

Subcutaneous Azacitidine 75 mg/m2/day days 1 to 5, intravenous Oxaliplatin 110 mg/m2 day 2, and oral capecitabine 1500 mg/m2 divided twice daily for 2 weeks every three weeks

Phase I: Highest Dose Level

MTD of Azacitidine + CAPOX

Of a 21 day cycle, Azacitidine MTD (Highest tolerable dose of combination azacitidine with CAPOX found in Phase I); Capecitabine 1500 mg/m2/day by mouth twice daily in divided doses on Days 1-14; and Oxaliplatin starting dose 90 mg/m2 by vein on Day 2.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer	NCT03576963	Colorectal Aden... CpG Island Meth... Metastatic Micr... Refractory Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color... Stage IVC Color...	Guadecitabine Nivolumab	18 Years -	University of Southern California
Azacitidine and CAPOX in Metastatic Colorectal Cancer	NCT01193517	Colorectal Canc...	Azacitidine Capecitabine Oxaliplatin Azacitidine MTD	18 Years -	M.D. Anderson Cancer Center
Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer	NCT03576963	Colorectal Aden... CpG Island Meth... Metastatic Micr... Refractory Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color... Stage IVC Color...	Guadecitabine Nivolumab	18 Years -	University of Southern California

Spots Global Cancer Trial Database for cpg island methylator phenotype