Devimistat + Chemoradiation for Pancreatic Cancer

No longer recruiting at 1 trial location

Overseen By Medical College of Wisconsin Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Medical College of Wisconsin

Must not be taking: Antiarrhythmics, Antivirals, Antifungals, others

Disqualifiers: Prior invasive malignancy, Major surgery, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 614

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, CPI-613® (also known as Devimistat), to determine its safety and optimal dose when combined with chemoradiation for pancreatic cancer that cannot be surgically removed. The trial seeks to identify the highest dose patients can tolerate without severe side effects. Individuals diagnosed with inoperable pancreatic cancer and advised to undergo chemoradiation may be suitable candidates for this study. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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 be on other anticancer treatments or certain medications for infections, so it's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CPI-613® (also known as devimistat) has been tested for safety when combined with other cancer treatments. One study found that CPI-613 can be safely combined with chemotherapy drugs like gemcitabine and nab-paclitaxel at doses up to 1,500 mg/m², indicating it is generally well-tolerated at these levels. Another study examined CPI-613 with a different chemotherapy regimen and assessed its safety in various locations. These studies provide evidence that CPI-613 has a strong safety record when used with other cancer therapies. However, side effects can still occur, and the treatment's safety is always closely monitored. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for pancreatic cancer?

Researchers are excited about CPI-613® (devimistat) because it targets cancer cells differently from standard treatments like FOLFIRINOX or gemcitabine with nab-paclitaxel. Unlike these traditional chemotherapies, which attack fast-growing cells indiscriminately, CPI-613® disrupts the energy production in cancer cells, making it harder for them to survive and multiply. This novel mechanism, combined with its use alongside established chemoradiation techniques, offers a promising new approach for tackling pancreatic cancer. Additionally, the use of a Bayesian optimal interval design to optimize dosing ensures a tailored and potentially more effective treatment strategy.

What evidence suggests that this trial's treatments could be effective for pancreatic cancer?

Research has shown that CPI-613, also known as devimistat, might aid in treating cancer by affecting the Krebs cycle, a process that produces energy in cells and is often more active in cancer cells. One study found that when CPI-613 was combined with chemotherapy, about half of the patients experienced tumor shrinkage or stability. However, another study showed that CPI-613 did not improve outcomes when paired with chemotherapy for advanced pancreatic cancer. This trial will test various doses of CPI-613 in combination with chemotherapy and Intensity-modulated radiation therapy (IMRT) to determine if these treatments together can be more effective for pancreatic cancer. IMRT is known to be effective for pancreatic cancer and can cause fewer side effects than older radiation methods. ^{2 3 5 6 7}

Who Is on the Research Team?

Mandana Kamgar, MD, MPH

Principal Investigator

Medical College of Wisconsin

Are You a Good Fit for This Trial?

This trial is for adults with confirmed pancreatic adenocarcinoma who cannot undergo surgery. They should have adequate blood cell counts, not be on hemodialysis, and have liver function within acceptable limits. Women of childbearing potential and men must agree to use effective contraception. Those with severe illnesses or conditions that could interfere with the study are excluded.

Inclusion Criteria

I've had the required scans and blood tests within the last 30 days.

I've had a check-up, including weight and vital signs, within the last 30 days.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

I have not had major surgery in the last 28 days.

Life expectancy less than two months

I haven't had any other cancer besides skin cancer in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CPI-613® in combination with gemcitabine and radiation therapy to determine the maximum tolerated dose and safety profile

6 weeks

Weekly visits for CPI-613® infusion and radiation therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• CPI-613®
• Intensity-modulated Radiation Therapy

Trial Overview The trial is testing various doses of CPI-613 (Devimistat) in combination with chemoradiation to find the highest dose patients can tolerate without severe side effects. It's an early-phase study focusing on safety and determining the right dosage for further research.

How Is the Trial Designed?

Group I: CPI-613® Maximum Tolerated Dose (MTD) Experimental Treatment 7 Interventions

MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.

Group II: CPI-613® (Dose level 3.0 1,500 mg/m^2) Experimental Treatment 3 Interventions

Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.

Group III: CPI-613® (Dose level 2.0 1,000 mg/m^2) Experimental Treatment 3 Interventions

Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.

Group IV: CPI-613® (Dose level 1.0 500 mg/m^2) Experimental Treatment 3 Interventions

Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.

Group V: CPI-613® (Dose level -1.0 250 mg/m^2) Experimental Treatment 3 Interventions

Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.

CPI-613® 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 (AML), myelodysplastic syndromes (MDS), peripheral T-cell lymphoma, and Burkitt's lymphoma

Approved in European Union as Devimistat for:

• Orphan drug designation for Burkitt’s lymphoma

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Barbara Ann Karmanos Cancer Institute

Collaborator

Trials

166

Recruited

9,300+

Cornerstone Pharmaceuticals

Industry Sponsor

Trials

15

Recruited

840+

Published Research Related to This Trial

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 of 20 patients with metastatic pancreatic cancer treated with CPI-613 and FOLFIRINOX, the overall survival (OS) and progression-free survival (PFS) were comparable to those of 60 patients with borderline-resectable pancreatic cancer who underwent curative surgery, indicating that CPI-613 may be a viable treatment option.

Despite the lack of significant differences in survival outcomes between the CPI-613 cohort and the surgical cohort, the results suggest potential benefits of adding CPI-613 to treatment regimens for patients with potentially resectable pancreatic adenocarcinoma, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of survival for metastatic pancreatic cancer patients treated with CPI-613 versus resected borderline-resectable pancreatic cancer patients. Mangieri, CW., Valenzuela, CD., Solsky, IB., et al.[2023]

The maximum tolerated dose of CPI-613, a novel anticancer agent, was established at 500 mg/m2 when combined with modified FOLFIRINOX chemotherapy in a trial involving 20 patients with metastatic pancreatic cancer.

At this maximum tolerated dose, 61% of patients achieved an objective response, indicating potential efficacy, while the treatment was associated with manageable adverse effects, including hyperglycemia and sensory neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Alistar, A., Morris, BB., Desnoyer, R., et al.[2021]

The combination of CPI-613 (devimistat) with radiation therapy significantly inhibits the growth of pancreatic ductal adenocarcinoma (PDAC) cells compared to radiation alone, suggesting enhanced efficacy in treating this aggressive cancer.

CPI-613 alters cancer cell metabolism and increases cell death when used with radiation, indicating its potential to sensitize PDAC cells to treatment, which is being further explored in a phase 1 clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Cellular Metabolism With CPI-613 Sensitizes Pancreatic Cancer Cells to Radiation Therapy. Khan, HY., Kamgar, M., Aboukameel, A., 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]

CPI-613 (Devimistat) shows promising anticancer activity in pancreatic cancer by inducing apoptosis through reactive oxygen species (ROS) and inhibiting lipid metabolism via the AMPK signaling pathway, based on studies conducted on pancreatic cancer cells in both 2D and 3D cultures.

The study identifies the enzyme ACC as a key target of CPI-613, where its inactivation leads to increased apoptosis, highlighting the importance of lipid metabolism in the effectiveness of CPI-613 as a treatment for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling. Gao, L., Xu, Z., Huang, Z., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39088774/

The Phase III AVENGER 500 Study Conclusion: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05325281

Study Details | NCT05325281 | CPI-613 (Devimistat) in ... This is a single-center, open-label, phase I study designed to determine the maximum tolerated dose (MTD) and safety profile of CPI-613® when used concomitantly ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT308251

A single-arm, open-label, phase I study of CPI-613 ... 1 patient achieved CR, 9 PR, 8 stable disease and 1 progressive disease for an objective response rate of 50% with a CR rate of 5.5%. Conclusions: The results ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.4023

Phase 3, multicenter, randomized study of CPI-613 with ... In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted ...

5. aacrjournals.org aacrjournals.org/cancerres/article/84/7_Supplement/CT080/742557/Abstract-CT080-A-phase-I-study-of-CPI-613

Abstract CT080: A phase I study of CPI-613 (devimistat) in ... CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28495639/

Safety and tolerability of the first-in-class agent CPI-613 in ... Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31512497/

A Phase III open-label trial to evaluate efficacy and safety of ... Devimistat (CPI-613®) is a novel lipoate analog that inhibits the tricarboxcylic acid cycle at two key carbon entry points. Through its inhibition of pyruvate ...