Combination Therapy for Pancreatic Cancer

Not currently recruiting at 55 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, CYP3A4 inhibitors

Disqualifiers: CNS metastases, Active infection, Autoimmune, others

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

Compensation: Varies

Number of Visits: 29

Duration: Up to 17 cycles (approximately 12-16 months)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the safest dose and examine the side effects of a new treatment combination for advanced pancreatic cancer. It involves a mix of targeted therapy (Anetumab Ravtansine), immunotherapy (Ipilimumab, also known as Yervoy, and Nivolumab, also known as Opdivo), and chemotherapy (Gemcitabine Hydrochloride, also known as Gemzar). The goal is to determine if this combination can more effectively treat cancer that has spread beyond the pancreas. Individuals with advanced pancreatic cancer who have a specific protein marker (mesothelin positive) and have not responded well to other treatments might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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 take certain medications like strong CYP3A4 inhibitors or inducers, and you should avoid live vaccines and systemic immunosuppressive medications before and during the trial.

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

Research has shown that anetumab ravtansine, when used with nivolumab, is generally well-tolerated. Studies indicate that this combination has a manageable safety profile, with no severe or unexpected side effects. Common side effects may include tiredness or nausea, typical of cancer treatments.

When combined with nivolumab and ipilimumab, early findings suggest anetumab ravtansine remains fairly tolerable. Side effects related to the immune system, such as skin rashes or diarrhea, may occur due to ipilimumab, but these are usually manageable.

For the combination of anetumab ravtansine with nivolumab and gemcitabine, studies suggest similar mild to moderate side effects. Gemcitabine can lower blood counts, potentially leading to tiredness or a higher risk of infection, but these effects are common with chemotherapy.

Overall, these combinations have demonstrated a manageable safety profile in studies. Each drug has its own set of mild to moderate side effects, but they are generally predictable and manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pancreatic cancer because they combine cutting-edge approaches that are different from current standard therapies like FOLFIRINOX and gemcitabine with nab-paclitaxel. Anetumab ravtansine is a novel antibody-drug conjugate that targets mesothelin, a protein often overexpressed in pancreatic cancer cells, allowing for precise delivery of its toxic payload to cancer cells. Nivolumab and ipilimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells more effectively. Additionally, these combinations are designed to work synergistically, potentially enhancing the overall effectiveness against the cancer and offering new hope for more effective treatments.

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

Research suggests that combinations of treatments—anetumab ravtansine, nivolumab, ipilimumab, and gemcitabine—might improve outcomes for pancreatic cancer patients. In this trial, participants will be assigned to different treatment arms. Arm I includes anetumab ravtansine and nivolumab. Arm II adds ipilimumab to this combination. Arm III includes anetumab ravtansine, nivolumab, and gemcitabine. Early results are promising; in one study, all participants experienced stable disease. Anetumab ravtansine targets cancer cells directly, delivering a chemotherapy drug to destroy them. Nivolumab and ipilimumab are immunotherapy drugs that help the body's immune system fight cancer. Gemcitabine is another chemotherapy drug that prevents cancer cells from growing and spreading. Together, these treatments show potential for helping patients live longer and manage the disease better. ^{1 2 6 7 8}

Who Is on the Research Team?

Anna Spreafico, MD PhD

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with advanced pancreatic cancer that has spread and can't be removed by surgery. Participants must have tried at least one treatment before, have tumors expressing a protein called mesothelin, and be in good physical condition (ECOG score 0-1). They should not have untreated brain metastases or certain infections like HIV or hepatitis B/C. Women who can bear children and men with partners of childbearing potential must use effective contraception.

Inclusion Criteria

Your albumin levels in the blood need to be at least 2.5 mg/dL or higher.

Your hemoglobin level is 9 grams per deciliter or higher.

My cancer has grown in an area previously treated with radiation, and the growth can be measured.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I have a corneal condition or other eye issues as diagnosed by my eye doctor.

I am currently receiving or have received chemotherapy or biological therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive anetumab ravtansine with nivolumab, ipilimumab, or gemcitabine in cycles of 21 or 28 days for up to 17 cycles

Up to 17 cycles (approximately 12-16 months)

Visits every 21 or 28 days for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 100 days post treatment, then every 12 weeks

Follow-up every 8 weeks for up to 100 days, then every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Anetumab Ravtansine
• Gemcitabine Hydrochloride
• Ipilimumab
• Nivolumab

Trial Overview The study tests anetumab ravtansine combined with nivolumab, ipilimumab, or gemcitabine to see which works best against pancreatic cancer. Anetumab ravtansine targets cancer cells directly while the other drugs help the immune system fight the disease or stop tumor growth. The trial aims to find out the safest doses and how well these combinations work together.

How Is the Trial Designed?

Group I: Arm III (anetumab ravtansine, nivolumab, gemcitabine) Experimental Treatment 5 Interventions

Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive gemcitabine hydrochloride over 30-40 minutes on days 1 and 8. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.

Group II: Arm II (anetumab ravtansine, nivolumab, ipilimumab) Experimental Treatment 5 Interventions

Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive ipilimumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of cycles 2-4. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.

Group III: Arm I (anetumab ravtansine, nivolumab) Experimental Treatment 4 Interventions

Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Treatment repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Single-agent gemcitabine is still the standard treatment for advanced pancreatic cancer, but recent phase III trials have not shown improved survival with most combinations of gemcitabine and other chemotherapy drugs.

The combination of gemcitabine with erlotinib has been linked to a significant increase in survival, and ongoing trials are exploring the effectiveness of gemcitabine with bevacizumab and other biologic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent updates on the role of chemotherapy in pancreatic cancer. Burris, HA.[2022]

Fewer than 20% of pancreatic cancer patients have tumors confined to the pancreas, highlighting the need for effective treatment strategies for advanced disease, as about 40% present with locally advanced cancer.

Gemcitabine is established as the first-line treatment for pancreatic cancer, showing significant clinical benefits, and is being explored in combination with various other agents like 5-fluorouracil and irinotecan to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of pancreatic cancer. Haller, DG.[2022]

The combination of ipilimumab and gemcitabine was found to be safe and tolerable for treating advanced pancreatic ductal adenocarcinoma (PDAC), with a maximum tolerated dose established at ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2.

Despite the safety of the regimen, the overall response rate was only 14%, indicating that adding ipilimumab does not significantly enhance the effectiveness compared to gemcitabine alone in advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. Kamath, SD., Kalyan, A., Kircher, S., et al.[2022]

In a phase I trial involving 50 patients with advanced pancreatic cancer, the combination of nivolumab, nab-paclitaxel, and gemcitabine showed a manageable safety profile, with 48 patients experiencing grade 3/4 treatment-emergent adverse events, but only one dose-limiting toxicity reported.

The treatment resulted in a median overall survival of 9.9 months and an overall response rate of 18%, indicating limited efficacy, which led to the conclusion that further investigation of this combination is not supported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer. Wainberg, ZA., Hochster, HS., Kim, EJ., et al.[2022]

The combination of gemcitabine, capecitabine, bevacizumab, and erlotinib showed promising efficacy in treating advanced pancreatic cancer, with 10 partial responses observed among 20 patients and median overall survival of 12.5 months.

The maximum-tolerated dose of capecitabine was determined to be 1,660 mg/m², with a recommended dose of 1,440 mg/m² for further studies, while the treatment was generally well-tolerated with manageable side effects like diarrhea and skin rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose finding and early efficacy study of gemcitabine plus capecitabine in combination with bevacizumab plus erlotinib in advanced pancreatic cancer. Starling, N., Watkins, D., Cunningham, D., et al.[2022]

Itacitinib, a selective JAK1 inhibitor, combined with nab-paclitaxel and gemcitabine, showed an acceptable safety profile and clinical activity in patients with advanced solid tumors, including pancreatic cancer, with a 24% overall response rate across various doses.

The study indicated that while itacitinib was tolerated at lower doses, treatment-related toxicities such as neutropenia and fatigue were common, leading to dose adjustments; however, the study was terminated early due to negative results from a related phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. Beatty, GL., Shahda, S., Beck, T., 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]

Gemcitabine is now considered a standard treatment for advanced pancreatic cancer due to its effectiveness and favorable side-effect profile.

While combinations of gemcitabine with other antitumor drugs and biological agents have shown promise in phase II trials, none have yet been established as an evidence-based standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Present and future treatment of pancreatic cancer. Heinemann, V.[2022]

In a phase III trial involving 319 patients with advanced pancreatic cancer, the combination of gemcitabine and capecitabine (GemCap) did not significantly improve overall survival compared to gemcitabine alone, with median survival times of 8.4 months for GemCap and 7.2 months for Gem.

However, in patients with a good performance status (Karnofsky score of 90-100), GemCap showed a significant improvement in median overall survival (10.1 months vs. 7.4 months for Gem), suggesting it may be a beneficial alternative for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. Herrmann, R., Bodoky, G., Ruhstaller, T., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03816358

NCT03816358 | Testing the Combination of Anetumab ... Giving anetumab ravtansine together with nivolumab, ipilimumab, and gemcitabine hydrochloride may work better in treating patients with pancreatic cancer.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.4136

Phase Ib study of anetumab ravtansive in combination with ... Only G1 peripheral neuropathy was observed in 4/33 (12%) pts. Efficacy data is presented in the table. In ARM3, the range of tumor measurement ( ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0014299924001390?via%3Dihub

A new era of immune therapeutics for pancreatic cancer The results showed a median overall survival of 21.3 months for the combination group and 19.6 months for the mFFX group. Progression free ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9179513/

The Next Frontier in Pancreatic Cancer: Targeting ... National Cancer Institute (NCI) Testing the Combination of Anetumab Ravtansine with Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab ...

5. researchgate.net researchgate.net/publication/367695397_Phase_Ib_study_of_anetumab_ravtansive_in_combination_with_immunotherapy_or_immunotherapy_plus_chemotherapy_in_mesothelin-enriched_advanced_pancreatic_adenocarcinoma_NCI10208

Phase Ib study of anetumab ravtansive in combination with ... Early data is showing promising results for the AR combination, with all eight patients treated so far achieving stable disease [83] .

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03816358?intr=ly%20936558&aggFilters=studyType:int&viewType=Table&checkSpell=&rank=1

Testing the Combination of Anetumab Ravtansine With ... A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to ...

7. clinicaltrials.med.nyu.edu clinicaltrials.med.nyu.edu/cancer/clinicaltrial/1338/phase-i-study-anetumab/

Perlmutter Cancer Center - Clinical Research Studies The purpose of the study is to determine the side effects and best dose of anetumab ravtansine when given together with nivolumab, ipilimumab and gemcitabine ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10512125/

Anetumab ravtansine versus vinorelbine in patients with ... Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed ...