CPI-613 (Devimistat) In Combination With Hydroxychloroquine And 5-fluorouracil Or Gemcitabine In Treating Patients With Advanced Chemorefractory Solid Tumors

Study Overview

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

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.

Advanced Biliary Tract Carcinoma
Advanced Colorectal Carcinoma
Advanced Gastroesophageal Junction Adenocarcinoma
Advanced Lung Adenocarcinoma
Advanced Malignant Solid Neoplasm
Advanced Ovarian Carcinoma
Advanced Pancreatic Carcinoma
Advanced Urothelial Carcinoma
Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
Metastatic Biliary Tract Carcinoma
Metastatic Colorectal Carcinoma
Metastatic Gastroesophageal Junction Adenocarcinoma
Metastatic Lung Adenocarcinoma
Metastatic Ovarian Carcinoma
Metastatic Pancreatic Carcinoma
Metastatic Urothelial Carcinoma
Refractory Biliary Tract Carcinoma
Refractory Colorectal Carcinoma
Refractory Gastroesophageal Junction Adenocarcinoma
Refractory Lung Adenocarcinoma
Refractory Ovarian Carcinoma
Refractory Pancreatic Carcinoma
Refractory Urothelial Carcinoma
Stage II Pancreatic Cancer AJCC v8
Stage III Colorectal Cancer AJCC v8
Stage III Lung Cancer AJCC v8
Stage III Ovarian Cancer AJCC v8
Stage III Pancreatic Cancer AJCC v8
Stage IV Colorectal Cancer AJCC v8
Stage IV Lung Cancer AJCC v8
Stage IV Ovarian Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8

PROCEDURE: Biospecimen Collection
PROCEDURE: Computed Tomography
DRUG: Devimistat
DRUG: Fluorouracil
DRUG: Gemcitabine Hydrochloride
DRUG: Hydroxychloroquine
PROCEDURE: Magnetic Resonance Imaging

NU 22MH03
NCI-2023-00070 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
STU00218203 (OTHER Identifier) (OTHER: Northwestern IRB)
NU 22MH03 (OTHER Identifier) (OTHER: Northwestern University)
P30CA060553 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2023-01-24	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2023-03-08
First Submitted that Met QC Criteria 2023-02-06	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2023-03-10
First Posted (ACTUAL) 2023-02-17	Results First Posted N/A	Last Verified 2023-02

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: COHORT 1 (Devimistat, 5-FU, HCQ) 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.	PROCEDURE: Biospecimen Collection Undergo blood sample collection PROCEDURE: Computed Tomography Undergo CT DRUG: Devimistat Receive IV DRUG: Fluorouracil Receive IV DRUG: Hydroxychloroquine Receive PO PROCEDURE: Magnetic Resonance Imaging Undergo MRI
EXPERIMENTAL: COHORT 2 (Devimistat, 5-FU, HCQ) 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.	PROCEDURE: Biospecimen Collection Undergo blood sample collection PROCEDURE: Computed Tomography Undergo CT DRUG: Devimistat Receive IV DRUG: Fluorouracil Receive IV DRUG: Hydroxychloroquine Receive PO PROCEDURE: Magnetic Resonance Imaging Undergo MRI
EXPERIMENTAL: COHORT 3 (Devimistat, 5-FU, HCQ, Gemcitabine) 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	PROCEDURE: Biospecimen Collection Undergo blood sample collection PROCEDURE: Computed Tomography Undergo CT DRUG: Devimistat Receive IV DRUG: Fluorouracil Receive IV DRUG: Gemcitabine Hydrochloride Receive IV DRUG: Hydroxychloroquine Receive PO PROCEDURE: Magnetic Resonance Imaging Undergo MRI

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: COHORT 1 (Devimistat, 5-FU, HCQ)

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.

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

PROCEDURE: Computed Tomography

Undergo CT

DRUG: Devimistat

Receive IV

DRUG: Fluorouracil

Receive IV

DRUG: Hydroxychloroquine

Receive PO

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

EXPERIMENTAL: COHORT 2 (Devimistat, 5-FU, HCQ)

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.

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

PROCEDURE: Computed Tomography

Undergo CT

DRUG: Devimistat

Receive IV

DRUG: Fluorouracil

Receive IV

DRUG: Hydroxychloroquine

Receive PO

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

EXPERIMENTAL: COHORT 3 (Devimistat, 5-FU, HCQ, Gemcitabine)

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

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

PROCEDURE: Computed Tomography

Undergo CT

DRUG: Devimistat

Receive IV

DRUG: Fluorouracil

Receive IV

DRUG: Gemcitabine Hydrochloride

Receive IV

DRUG: Hydroxychloroquine

Receive PO

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

Primary Outcome Measures	Measure Description	Time Frame
Overall response rate (ORR)	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.	Time from baseline to disease progression, initiates subsequent anti-cancer therapy, or 24 months (whichever occurs first)

Secondary Outcome Measures	Measure Description	Time Frame
Progression free survival (PFS)	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.	Time that elapses between the day of subject registration and the earlier of the day of first documented disease progression by clinical or radiographic evaluation or death from any cause, assessed up to 24 months
Overall survival (OS)	Will be assessed using Kaplan-Meier estimates. OS for the main cohort and exploratory cohort will be analyzed and reported separately.	Time that elapses between the day of subject registration and death from any cause, assessed up to 24 months
Duration of response (DOR)	Will be assessed using Kaplan-Meier estimates. DOR for the main cohorts and exploratory cohort will be analyzed and reported separately.	Time elapsed from the day when CR or PR is first observed until the earlier of the day of first documented disease progression or death, assessed up to 24 months
Incidence of adverse events	Will be assessed using the National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.	Up to 30 days post treatment

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Study Coordinator

Phone Number: 3126953101

Email: cancer@northwestern.edu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Patients must have histologically confirmed cancer for which standard-of-care curative measures are no longer effective or be intolerant to those agents. Patients in cohort 1 must have colorectal cancer. Patients in cohort 2 must have pancreatic cancer. Patients in cohort 3 may have any of the following cancers:

Biliary
Gastroesophageal
Urothelial
Ovarian
Non-small cell lung (adenocarcinoma only)
Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 disease.
Patients must have radiographic documentation of metastatic disease with imaging within =< 6 weeks prior to registration.
Patients must be age >= 18 years.
Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Performance Status of 2 will be allowed with approval from principle investigator (PI) on a case-by case basis.

Note: Performance status of 2 will be allowed with approval from PI on a case-by case basis. Documentation of PI approval in these cases will be stored with inclusion/exclusion signed checklist for patient and/or in patient's shadow chart.
Patients must have exhausted all available molecularly targeted therapies (e.g., anti-PD-1/anti-PD-L1 agents where indicated).
Absolute neutrophil count (ANC) >= 1,500/mcL (within the last 14 days of screening)
Hemoglobin (Hgb) >= 9 g/dL (within the last 14 days of screening) (Transfusions permitted. Eligibility labs should be drawn >= 7 days from transfusion).
Platelets (PLT) >= 100,000/mcL (within the last 14 days of screening) (Transfusions permitted. Eligibility labs should be drawn >= 7 days from transfusion).
INR (international normalized ratio) =< 1.6 (within the last 14 days of screening) (unless receiving anticoagulation therapy) If receiving anticoagulant: INR =< 3.0 and no active bleeding, (i.e., no bleeding within 14 days prior to first dose of study therapy).
Total bilirubin =<1.5 x Institutional upper limit of normal (ULN) (within the last 14 days of screening)

Note: Patients with Gilbert's Syndrome are exempt. Patients with liver metastases with no significant bilirubin obstruction may have a total bilirubin level of =< 2.0 mg/dL.
Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) =< 2.5 x institutional ULN (within the last 14 days of screening)

Note: If liver metastases are present, then =< 5 x ULN is allowed.
Alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) =< 2.5 x institutional ULN (within the last 14 days of screening)

Note: If liver metastases are present, then =< 5 x ULN is allowed.
Serum albumin > 3.0 g/dL (within the last 14 days of screening)
Creatinine =< 1.5 x ULN OR glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (within the last 14 days of screening)

eGFR is estimated GFR calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation
The effects of combination treatment of CPI-613, 5-FU, gemcitabine, and HCQ on the developing human fetus are unknown. For this reason and because antineoplastic agents as well as other therapeutic agents used in this trial are known to be teratogenic, patients of child-bearing potential (POCBP) regardless of gender must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent, for the duration of study participation, and for 180 days following completion of therapy. Patients who can impregnate their partners regardless of gender must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent, for the duration of study participation, and for 180 days following completion of therapy. Should a patient become pregnant or suspect they are pregnant while they or their partner is participating in this study, they should inform their treating physician immediately.

Note: At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
Note: A POCBP is any person with an egg-producing reproductive tract (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
Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
POCBP must have a negative pregnancy test prior to registration on study.

Note: If negative pregnancy test result is >7 days from first dose of study treatment it must be repeated at time of first dose of study treatment (with any of the four drugs used in this study).
For patients with a known history of human immunodeficiency virus (HIV), infected patients on effective anti-retroviral therapy must have a viral load undetectable for 6 months prior to registration.
For patients with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment, must have an undetectable HCV viral load. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardio toxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. Patients must be class 2B or better.

Note: Patients with pacemakers where corrected QT interval (QTc) is not a reliable measure will require an evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study.
Patients must have the ability to understand and the willingness to sign a written informed consent document for the duration of the entirety of the study.
Patients must be reliable, willing to make themselves available for the duration of the entire study and willing to follow screening procedures.

Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1).

Note: Patients who experience adverse events of alopecia and peripheral neuropathy that have not recovered are eligible; patients with any lab abnormality that is above grade 1 related to previous therapy found to be not clinically significant will also be eligible.
Patients with symptomatic brain metastases currently using corticosteroids.

Note: Patients with brain metastases who are asymptomatic and off corticosteroids for at least one week are eligible.
Patients with severe obstructive pulmonary disease or interstitial lung disease.
Patients with a history of myocardial infarction that is <90 days prior to registration.
Patients using concomitant medications that prolong the QT/QTc intervals. For example, patients receiving amiodarone. Using amiodarone together with hydroxychloroquine can increase the risk of long QT syndrome that although rare, may be serious, and potentially life-threatening.
Patients with a history of additional risk factors for drug-induced QT prolongation or Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome).
Patients with major surgery or significant traumatic injury =< 21 days prior to registration.
Patients receiving treatment with low dose chemotherapy concurrent with radiation =< 21 days prior to registration.

Note: Palliative radiation before and during study participation is permissible providing it is not to a target lesion.

Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:
Ongoing or active infection requiring systemic treatment.
Clinically significant complications such as perforation, gastrointestinal bleeding, or diverticulitis within 42 days prior to registration.
Symptomatic congestive heart failure; symptomatic coronary artery disease, symptomatic angina pectoris, or symptomatic myocardial infarction.
Unstable angina pectoris.
Unstable cardiac arrhythmia.
Psychiatric illness/social situations that would limit compliance with study requirements.
Active substance abuse.
Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints.

Patients who are pregnant or nursing.
Patients with Fridericia-corrected QT interval (QTcF) > 470 msec (female) or > 450 (male), or history of congenital long QT syndrome. Any electrocardiogram (ECG) abnormality that in the opinion of the investigator would preclude safe participation in the study.
Patients who have pre-existing retinopathy of the eye.
Patients who are unable to swallow or retain and absorb oral medication
Patients with known hypersensitivity to any of the following: CPI or its inactive components, 4-aminoquinoline compounds, or quinine.
Patients with poorly controlled diabetes mellitus (glycosylated hemoglobin (HbA1c) of > 7%, pre-prandial capillary plasma glucose > 130mg/dl, and peak postprandial capillary plasma glucose of > 180mg/dl).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Devalingam Mahalingam, Northwestern University

Publications

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