Devimistat Combo for Advanced Cancers

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: Corticosteroids, Amiodarone

Disqualifiers: Brain metastases, Pulmonary disease, Myocardial infarction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

94 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of three drugs to treat patients with advanced solid tumors that have spread or are resistant to previous treatments. The drugs work together to block energy production in tumor cells, boost the immune system, and kill fast-growing tumor cells. The goal is to see how well this combination works and how safe it is for patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are using medications that prolong the QT/QTc intervals, like amiodarone, due to potential serious heart risks when combined with hydroxychloroquine.

What data supports the effectiveness of the drug combination used in the Devimistat Combo for Advanced Cancers trial?

Research shows that 5-Fluorouracil (5-FU), a component of the Devimistat Combo, is effective in treating advanced gastric and colorectal cancers, often improving survival and quality of life when used in combination with other drugs. Additionally, Gemcitabine, another component, has been shown to improve survival in advanced pancreatic cancer when combined with other agents. ^{1 2 3 4 5}

What safety data exists for the treatment Devimistat Combo for Advanced Cancers?

The research articles reviewed do not provide specific safety data for the Devimistat Combo treatment. However, they do mention the evaluation of 5-Fluorouracil (5-FU) in various combinations, which is part of the treatment, indicating that 5-FU has been studied for its side effects and maximum-tolerated dose in other contexts. ^{6 7 8 9 10}

What makes the drug Devimistat Combo unique for treating advanced cancers?

Devimistat Combo is unique because it targets the energy production process in cancer cells by inhibiting key enzymes in the tricarboxylic acid cycle, which is crucial for the survival and growth of certain cancers like pancreatic cancer. This approach is different from traditional chemotherapy, which often targets DNA replication or cell division. ^{4 6 11 12 13}

Research Team

Devalingam Mahalingam, MBBChBAO

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for adults with advanced solid tumors like colorectal, pancreatic, biliary, gastroesophageal, urothelial, ovarian or lung cancer (adenocarcinoma only) that haven't responded to standard treatments. Participants must have good physical function and meet specific blood count and organ function criteria. They should not be pregnant/nursing and must agree to use contraception if applicable.

Inclusion Criteria

My kidney function meets the required levels.

Patients must have a measurable tumor according to specific guidelines.

I am 18 years old or older.

Exclusion Criteria

I cannot swallow or properly absorb pills.

My diabetes is not well-managed.

I have a pre-existing eye condition affecting my retina.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

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

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall survival assessments.

24 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if beneficial.

Treatment Details

Interventions

• CPI-613 (Devimistat)
• Fluorouracil
• Gemcitabine Hydrochloride
• Hydroxychloroquine

Trial Overview The trial tests CPI-613 (devimistat) combined with hydroxychloroquine and either 5-fluorouracil or gemcitabine against advanced chemorefractory solid tumors. Devimistat targets the energy production of tumor cells while hydroxychloroquine may enhance immune response; both fluorouracil and gemcitabine are chemotherapy drugs aiming to kill fast-growing abnormal cells.

Participant Groups

Group I: COHORT 3 (Devimistat, 5-FU, HCQ, Gemcitabine) Experimental Treatment 7 Interventions

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.

Group II: COHORT 2 (Devimistat, 5-FU, HCQ) Experimental Treatment 6 Interventions

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.

Group III: COHORT 1 (Devimistat, 5-FU, HCQ) Experimental Treatment 6 Interventions

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.

CPI-613 (Devimistat) is already approved in United States, European Union for the following indications:

Approved in United States as Devimistat for:

• Orphan drug designation for pancreatic cancer
• Acute myeloid leukemia
• Myelodysplastic syndromes
• Peripheral T-cell lymphoma
• Burkitt's lymphoma
• Biliary tract cancer
• Soft tissue sarcoma

Approved in European Union as Devimistat for:

• Orphan drug designation for Burkitt's lymphoma

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 200 patients with untreated advanced gastric carcinoma, the PELF treatment regimen showed a significantly higher complete response rate (13%) compared to the FAMTX regimen (2%), indicating greater efficacy in treating this type of cancer.

The objective response rates were also better for PELF (39%) versus FAMTX (22%), suggesting that PELF is a more effective treatment option, although the survival rate differences were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Cocconi, G., Carlini, P., Gamboni, A., et al.[2022]

A study of 5465 patients with advanced pancreatic cancer in Ontario showed that the introduction of new chemotherapy regimens, GEMNAB and FOLFIRINOX, significantly improved overall survival rates over time, with median survival increasing from 5.6 months to 7.6 months between 2008 and 2018.

FOLFIRINOX was found to provide better overall survival compared to GEMNAB, particularly in younger and healthier patients, while GEMNAB still showed improved survival compared to the older standard treatment, gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. Raphael, MJ., Raskin, W., Habbous, S., et al.[2023]

Chemotherapy significantly increases survival and improves quality of life in patients with advanced gastric carcinoma compared to supportive measures alone.

Current standard treatments include infusional 5-FU combined with cisplatin or ECF, while newer third-generation combinations with taxanes and irinotecan show similar effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Patient with stomach cancer with metastases. What is the value of chemotherapy?]. Wilke, H., Stahl, M., Vanhoefer, U.[2013]

The FEMTX-P regimen, which includes methotrexate, 5-fluorouracil, epirubicin, and cisplatin, showed a total response rate of 47% in 50 patients with advanced gastric cancer, with 11% achieving complete responses and 36% partial responses.

Despite some significant side effects, such as grade 4 leukopenia in 18% of patients, the regimen demonstrated an acceptable safety profile and a median survival of 10 months, indicating its potential effectiveness in treating this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of sequential high-dose methotrexate (MTX) and 5-fluorouracil (F) alternated with epirubicin (E) and cisplatin (P) [FEMTX-P] in advanced gastric cancer. Roelofs, EJ., Wagener, DJ., Conroy, T., et al.[2020]

The FOLFIRI-2 regimen, which combines leucovorin, fluorouracil, irinotecan, and hydroxyurea, showed a 17% objective response rate and 52% disease stabilization in 29 heavily pretreated patients with advanced colorectal cancer resistant to standard treatments.

Despite significant toxicities, including high rates of neutropenia (52%) and diarrhea (31%), the median progression-free survival was 4.1 months and median overall survival was 9.7 months, indicating that FOLFIRI-2 can be an effective option for difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bimonthly leucovorin, infusion 5-fluorouracil, hydroxyurea, and irinotecan (FOLFIRI-2) for pretreated metastatic colorectal cancer. Mabro, M., Louvet, C., André, T., et al.[2018]

In a study of 119 patients with advanced gastric cancer, the FTQ chemotherapy regimen showed a significantly higher overall response rate of 28.3% compared to 4.1% in the control group, indicating its effectiveness in treating this condition.

The FTQ regimen was generally well-tolerated, with similar rates of bone marrow toxicities (leucopenia and thrombocytopenia) compared to the control group, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Curative effects of FTQ combined with cisplatin in treatment of advanced gastric cancer: a multicenter study]. Yang, JL., Jiao, SC., Dai, GH., et al.[2013]

The combination therapy using a controlled molar ratio of 5-fluorouracil and vorinostat (Co-SMND) demonstrated a maximal synergistic effect, enhancing its antitumor efficacy in a mouse model.

The optimized Co-SMND showed improved safety and selective accumulation in tumors, indicating its potential for effective and targeted chemotherapy in future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unified D-α-Tocopherol 5-Fu/SAHA bioconjugates self-assemble as complex nanodrug for optimized combination therapy. Han, L., Wang, T., Mu, S., et al.[2018]

The combination of paclitaxel and doxifluridine showed a promising overall response rate of 33.3% in patients with advanced/recurrent gastric cancer, with a median overall survival of 287 days.

This treatment regimen was well-tolerated, allowing for outpatient administration, with manageable side effects such as leukopenia and fatigue occurring in a minority of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of weekly paclitaxel and doxifluridine combination chemotherapy for advanced/recurrent gastric cancer. Takeyoshi, I., Makita, F., Tanahashi, Y., et al.[2015]

FTC-092, a fluorinated pyrimidine derivative, demonstrated superior effectiveness against transplantable tumors in mice compared to other antitumor fluorinated pyrimidines, with an ED50 of 13.3 mg/kg daily for inhibiting sarcoma 180 growth.

Unlike its parent compound CF3dUrd, FTC-092 is not active on its own but is converted in the body to CF3dUrd over time, leading to sustained levels of the active drug in the bloodstream, which may enhance its clinical application while minimizing gastrointestinal exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of FTC-092, a masked 5-trifluoromethyl-2'-deoxyuridine derivative. Takeda, S., Yamashita, J., Saito, H., et al.[2019]

The maximum-tolerated dose (MTD) of S-1 for patients with advanced solid tumors was determined to be 40 mg/m², with diarrhea identified as the main dose-limiting toxicity, especially in patients with extensive prior chemotherapy.

S-1 demonstrated a linear pharmacokinetic profile for 5-FU, with some patients experiencing significant tumor reduction, indicating potential efficacy in treating certain cancers, warranting further Phase II trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. van Groeningen, CJ., Peters, GJ., Schornagel, JH., et al.[2022]

Devimistat (CPI-613) is a novel treatment that works by inhibiting key enzymes in the tricarboxylic acid cycle, which is crucial for the energy metabolism of pancreatic cancer cells.

In a Phase I study, devimistat combined with modified FOLFIRINOX showed a promising 61% objective response rate in metastatic pancreatic cancer patients, including a 17% complete response rate, leading to the initiation of a Phase III trial to further evaluate its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase III open-label trial to evaluate efficacy and safety of CPI-613 plus modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas. Philip, PA., Buyse, ME., Alistar, AT., et al.[2021]

Devimistat (CPI-613) shows promise as a treatment for advanced biliary tract cancer (BTC), demonstrating a 45% overall response rate and a median progression-free survival of 10 months in a phase Ib trial with 20 patients.

The combination of devimistat with gemcitabine and cisplatin was well tolerated, with manageable side effects, and the recommended phase II dose was established at 2,000 mg/m2, indicating its potential for further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04). Mohan, A., Griffith, KA., Wuchu, F., et al.[2023]

In a study involving 17 patients, the combination of JM-216 and UFT was found to have manageable toxicity, with nausea and vomiting being the main side effects at the highest tested dose of JM-216 (20 mg/day).

No significant neurotoxicity or nephrotoxicity was observed, suggesting that this combination therapy may be safer than higher doses of the individual drugs, indicating potential for further exploration of shorter administration schedules to enhance efficacy while reducing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of oral uracil/ftorafur (UFT) plus leucovorin and bis-acetato-ammine-dichloro-cyclohexylamine-platinum IV (JM-216) each given over 14 days every 28 days. DeMario, MD., Ratain, MJ., Vogelzang, NJ., et al.[2014]

References

1. England pubmed.ncbi.nlm.nih.gov

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

[Patient with stomach cancer with metastases. What is the value of chemotherapy?]. [2013]

4. England pubmed.ncbi.nlm.nih.gov

Phase II study of sequential high-dose methotrexate (MTX) and 5-fluorouracil (F) alternated with epirubicin (E) and cisplatin (P) [FEMTX-P] in advanced gastric cancer. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Bimonthly leucovorin, infusion 5-fluorouracil, hydroxyurea, and irinotecan (FOLFIRI-2) for pretreated metastatic colorectal cancer. [2018]

6. China pubmed.ncbi.nlm.nih.gov

[Curative effects of FTQ combined with cisplatin in treatment of advanced gastric cancer: a multicenter study]. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Unified D-α-Tocopherol 5-Fu/SAHA bioconjugates self-assemble as complex nanodrug for optimized combination therapy. [2018]

8. Greece pubmed.ncbi.nlm.nih.gov

A phase II study of weekly paclitaxel and doxifluridine combination chemotherapy for advanced/recurrent gastric cancer. [2015]

9. Germany pubmed.ncbi.nlm.nih.gov

Antitumor activity of FTC-092, a masked 5-trifluoromethyl-2'-deoxyuridine derivative. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. [2022]

11. England pubmed.ncbi.nlm.nih.gov

A Phase III open-label trial to evaluate efficacy and safety of CPI-613 plus modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04). [2023]

13. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of oral uracil/ftorafur (UFT) plus leucovorin and bis-acetato-ammine-dichloro-cyclohexylamine-platinum IV (JM-216) each given over 14 days every 28 days. [2014]