Neoplasms

All Conditions

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Gland and Hormone Related Diseases

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Neoplasms by Histologic Type

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Gastrointestinal Diseases

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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Micronutrients

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Gemcitabine

Fluorouracil

Hydroxychloroquine

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Antiparasitic Agents

Enzyme Inhibitors

Antioxidants

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Alpha-lipoic Acid

Folate

Vitamin B9

Patients with colorectal cancer receive devimistat IV, 5-FU IV, plus HCQ PO on study. Patients also undergo CT and/or MRI and undergo blood specimen collection throughout the study.

Patients with pancreatic cancer receive devimistat IV, 5-FU IV, plus HCQ PO on study. Patients also undergo CT and/or MRI and undergo blood specimen collection throughout the study.

Patients with gastroesophageal cancer receive devimistat IV, 5-FU IV, plus HCQ PO on study. Patients with urothelial, ovarian, or non-small cell lung cancer receive devimistat IV, gemcitabine IV, plus HCQ PO on study. Patients with biliary tumors receive devimistat IV and gemcitabine IV or HCQ PO on study. Patients also undergo CT and/or MRI and undergo blood specimen collection throughout the study.

Biospecimen Collection

Computed Tomography

Devimistat

Gemcitabine Hydrochloride

Magnetic Resonance Imaging

Study Coordinator

Devalingam Mahalingam, MD, PhD

Devalingam Mahalingam

This phase II trial tests how well CPI-613 (devimistat) in combination with hydroxychloroquine (HCQ) and 5-fluorouracil (5-FU) or gemcitabine works in patients with solid tumors that may have spread from where they first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that have not responded to chemotherapy medications (chemorefractory). Metabolism is how the cells in the body use molecules (carbohydrates, fats, and proteins) from food to get the energy they need to grow, reproduce and stay healthy. Tumor cells, however, do this process differently as they use more molecules (glucose, a type of carbohydrate) to make the energy they need to grow and spread. CPI-613 works by blocking the creation of the energy that tumor cells need to survive, grow in the body and make more tumor cells. When the energy production they need is blocked, the tumor cells can no longer survive. Hydroxychloroquine is a drug used to treat malaria and rheumatoid arthritis and may also improve the immune system in a way that tumors may be better controlled. Fluorouracil is in a class of medications called antimetabolites. It works by killing fast-growing abnormal cells. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill tumor cells. CPI-613 (devimistat) in combination with hydroxychloroquine and 5-fluorouracil or gemcitabine may work to better treat advanced solid tumors.

PRIMARY OBJECTIVE:

I. The primary objective of this study will be to estimate the overall response rate (ORR) of treatment with devimistat (CPI-613) plus HCQ and, depending on the cohort and indication, either 5-FU or gemcitabine.

SECONDARY OBJECTIVES:

I. Evaluate progression-free survival (PFS) of patients with solid tumors that are treated with CPI-613 plus HCQ and, depending on the cohort and indication, either 5-FU or gemcitabine.

II. Determine overall survival (OS) of patients with solid tumors that are treated with CPI-613 plus HCQ and, depending on the cohort and indication, either 5-FU or gemcitabine.

III. Assess duration of response (DOR) of patients with solid tumors that are treated with CPI-613 plus HCQ and, depending on the cohort and indication, either 5-FU or gemcitabine.

IV. Assess safety and tolerability for patients with solid tumors treated with specified treatments.

EXPLORATORY OBJECTIVES:

I. Blood from patients in cohort 3 that consent will be collected at baseline, cycle 1, day 1 (C1D1), C1D15, C2D1, and at the time of treatment discontinuation for further molecular and metabolic analysis, possibly including but not limited to proteomic, metabolomic, and genetic/genomic analysis.

OUTLINE: Patients are assigned to 1 of 3 cohorts.

COHORT 1: Patients with colorectal cancer receive devimistat intravenously (IV), 5-FU IV, plus HCQ orally (PO) on study. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) and undergo blood specimen collection throughout the study.

COHORT 2: Patients with pancreatic cancer receive devimistat IV, 5-FU IV, plus HCQ PO on study. Patients also undergo CT and/or MRI and undergo blood specimen collection throughout the study.

COHORT 3: Patients with gastroesophageal cancer receive devimistat IV, 5-FU IV, plus HCQ PO on study. Patients with urothelial, ovarian, or non-small cell lung cancer receive devimistat IV, gemcitabine IV, plus HCQ PO on study. Patients with biliary tumors receive devimistat IV and gemcitabine IV or HCQ PO on study. Patients also undergo CT and/or MRI and undergo blood specimen collection throughout the study.

CPI-613 (Devimistat) in Combination With Hydroxychloroquine and 5-fluorouracil or Gemcitabine in Treating Patients With Advanced Chemorefractory Solid Tumors

Phase II Open-Label Multi-Cohort Study Evaluating CPI-613 (Devimistat) in Combination With Hydroxychloroquine and 5-fluorouracil or Gemcitabine in Patients With Advanced Chemorefractory Colorectal, Pancreatic, or Other Solid Cancers

Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in patients with solid tumors treated under this protocol. ORR is defined as the percentage of patients with documented complete response (CR) plus the percentage of patients with documented partial response (PR). ORR will be reported with the corresponding exact confidence intervals.

Will be assessed using Kaplan-Meier estimates. PFS for the main cohorts (cohort 1 and cohort 2) and exploratory cohort (cohort 3) will be analyzed and reported separately.

Will be assessed using Kaplan-Meier estimates. OS for the main cohort and exploratory cohort will be analyzed and reported separately.

Will be assessed using Kaplan-Meier estimates. DOR for the main cohorts and exploratory cohort will be analyzed and reported separately.

Will be assessed using the National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

National Cancer Institute (NCI)

Northwestern University

Cholangiocarcinoma

Bile Duct Cancer

Biliary Tract Cancer

Gallbladder Cancer

Patients with advanced and metastatic biliary tract adenocarcinoma (cholangiocarcinoma) who had been treated with and failed first-line chemotherapy will be treated with regorafenib (120 mg) (160 mg for second and subsequent treatment cycles) orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle

regorafenib (120 mg) (160 mg for second and subsequent treatment cycles)orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle.

Regorafenib

Nathan Bahary, MD, PhD

Based on the facts of multiple pathways involvement in cholangiocarcinoma tumor genesis, including EGFR, Ras, Raf, VEGFR, and PDGFR, with evidence of overexpression of these proteins associated with tumor stage, prognosis and response to therapy. Multikinase inhibitor targeting multiple tumor pathways agent as regorafenib should be the ideal candidate for evaluating the anti-cancer activity for the disease as cholangiocarcinoma. More importantly, regorafenib likely holds promise in this disease setting with known effectiveness either as a single agent or in combination with cytotoxic chemotherapy agents in multiple solid tumors as above and the toxicity profile.

Multiple pathways, including epidermal growth factor receptor (EGFR), Ras, Raf, Vascular Endothelial Growth Factor Receptors (VEGFR), and platelet-derived growth factor (PDGFR) appear to be involved in cholangiocarcinoma tumor genesis. Overexpression of these proteins has been shown to be associated with tumor stage, prognosis, and response to therapy. However, therapies targeting a single pathway have shown no clear benefit. A number of Phase 2 trials have been completed, or are underway, studying agents targeted to EGFR or VEGF - both as monotherapy and in combination with chemotherapy. These have shown varying increases in response rate, but have not found marked increases in progression-free or overall survival. This suggests that inhibition of multiple pathways simultaneously may be needed. Regorafenib, is an oral multikinase inhibitor targeting multiple tumor pathways, which has showed effectiveness as a single agent in multiple solid tumors.

Patients with advanced and metastatic biliary tract adenocarcinoma (cholangiocarcinoma) who had been treated with and failed first-line chemotherapy will be treated with regorafenib (120 mg) (160 mg for second and subsequent treatment cycles) orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle.

A Phase 2 Trial of Regorafenib as A Single Agent in Advanced and Metastatic Biliary Tract Carcinoma/Cholangiocarcinoma Patients Who Have Failed First-line Chemotherapy

Duration of time from start of treatment to time of progression or death, whichever occurs first. Per RECIST version 1.1, Progressive Disease (PD) is defined as: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

The number of patients who experienced a Partial Response (PR) + the number of patients who experienced a Complete Response (CR) / total number of response-evaluable patients. Per RECIST v1.1, Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

The length of time from the start of study treatment that patients remained alive.

Number of patients who achieved Complete Response (CR) + number of patients who achieved Partial Response (PR) + number of patients who achieved Stable Disease (SD) / total number of response-evaluable patients. Per RECIST v1.1, Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study treatment.

The difference between the levels of Cancer antigen 19-9 (CA19-9) prior to treatment compared to after treatment.

The difference between the levels of Carcinoembryonic antigen (CEA) prior to treatment compared to after treatment. ng/ml

Bayer

Nathan Bahary, MD

Associate Professor

Patients with advanced and metastatic biliary tract adenocarcinoma (cholangiocarcinoma) who had been treated with and failed first-line chemotherapy will be treated with regorafenib (120 mg) (160 mg for second and subsequent treatment cycles) orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle

regorafenib: (120 mg) (160 mg for second and subsequent treatment cycles)orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle.

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Patients who received at least one dose of regorafenib treatment.

Barbara Stadterman, Regulatory Supervisor

Patients who received at least one dose of regorafenib.

Progression-free Survival (PFS)

Patients who received two or more doses of regorafenib.

Progression-free Survival (PFS) - Two or More Doses

Patients who received at least one dose of regorafenib and were evaluable for response

Proportion of Participants With Overall Response (OR)

Overall Survival (OS)

Overall Survival (OS) - Two or More Doses

Disease Control Rate (DCR)

Before Treatment

After Treatment

Patients who received at least one dose of regorafenib and for which CA19-9 levels were obtainable.

Changes in Cancer Antigen 19-9 (CA19-9) Level

Change in Carcinoembryonic Antigen (CEA)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
CPI-613 (Devimistat) in Combination With Hydroxychloroquine and 5-fluorouracil or Gemcitabine in Treating Patients With Advanced Chemorefractory Solid Tumors	NCT05733000	Advanced Biliar... Advanced Colore... Advanced Gastro... Advanced Lung A... Advanced Malign... Advanced Ovaria... Advanced Pancre... Advanced Urothe... Clinical Stage ... Clinical Stage ... Metastatic Bili... Metastatic Colo... Metastatic Gast... Metastatic Lung... Metastatic Ovar... Metastatic Panc... Metastatic Urot... Refractory Bili... Refractory Colo... Refractory Gast... Refractory Lung... Refractory Ovar... Refractory Panc... Refractory Urot... Stage II Pancre... Stage III Color... Stage III Lung ... Stage III Ovari... Stage III Pancr... Stage IV Colore... Stage IV Lung C... Stage IV Ovaria... Stage IV Pancre...	Biospecimen Col... Computed Tomogr... Devimistat Fluorouracil Gemcitabine Hyd... Hydroxychloroqu... Magnetic Resona...	18 Years -	Northwestern University
A Phase 2 Trial of Regorafenib as A Single Agent in Advanced and Metastatic Biliary Tract Carcinoma/Cholangiocarcinoma Patients Who Have Failed First-line Chemotherapy	NCT02053376	Metastatic Bili...	Regorafenib	18 Years -	University of Pittsburgh

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