ZN-c3 + Gemcitabine for Pancreatic Cancer

Recruiting at 2 trial locations

Overseen By DFCI Clinical Trials Hotline

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brandon Huffman

Must not be taking: CYP3A4 inhibitors, P-gp inhibitors

Disqualifiers: WEE1 inhibitor, Gemcitabine, CNS disease, 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: 23

Duration: 18 months

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments: ZN-c3 (also known as Azenosertib, an experimental treatment) and Gemcitabine (also known as Gemzar, a chemotherapy drug). Researchers aim to determine if these drugs can safely and effectively treat pancreatic cancer. They seek to understand if the combination can manage cancer unresponsive to standard treatments. The trial seeks participants with advanced pancreatic cancer that current methods cannot cure and who have already tried but did not tolerate a platinum-based treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use certain drugs or supplements that strongly affect liver enzymes (CYP3A4) or P-gp inhibitors. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that the combination of ZN-c3 and Gemcitabine is likely to be safe for humans?

Research has shown that Gemcitabine, a key component of this treatment, is well-studied and frequently used for pancreatic cancer. Studies have proven that it helps patients live longer and respond better to treatment when combined with other drugs, indicating that Gemcitabine is generally well-tolerated by patients with pancreatic cancer.

While specific safety information for ZN-c3 (a drug targeting a specific protein) is not available in these sources, its combination with Gemcitabine in this study phase suggests that ZN-c3 has passed initial human safety tests. This indicates it is considered safe enough to evaluate its effectiveness with Gemcitabine.

Clinical trials are designed to closely monitor safety. Researchers will observe participants in this trial for any possible side effects to ensure the treatment remains as safe as possible. ^{1 2 3 4 5}

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

Researchers are excited about ZN-c3 combined with Gemcitabine for pancreatic cancer because it offers a fresh approach compared to the standard chemotherapy treatments. Most treatments for pancreatic cancer, like Gemcitabine alone, focus on stopping cancer cells from dividing. However, ZN-c3 is a WEE1 inhibitor that specifically targets and disrupts a critical cell cycle checkpoint, potentially making cancer cells more vulnerable to the effects of chemotherapy. This combination could enhance the treatment's effectiveness, offering new hope for better outcomes in a notoriously tough-to-treat cancer.

What evidence suggests that the combination of ZN-c3 and Gemcitabine could be an effective treatment for pancreatic cancer?

Research has shown that combining ZN-c3 with Gemcitabine may help treat pancreatic cancer. This trial will evaluate the effectiveness of this combination. Studies have found that pancreatic cancer is very sensitive to blocking a protein called WEE1, which ZN-c3 targets, especially when used with Gemcitabine. This combination works by preventing the cancer from repairing itself. Previous research with similar drug combinations showed response rates between 11.4% and 58%, with patients living between 7.4 to 10 months. These results suggest the treatment could be effective, but ongoing trials will provide more information. ^{1 2 3 4 6}

Who Is on the Research Team?

Brandon Huffman, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced pancreatic adenocarcinoma who've had no more than one prior platinum-based chemotherapy in the metastatic setting. They must have measurable disease, adequate organ function, and agree to use contraception. Excluded are those with previous WEE1 inhibitor treatment, certain CNS diseases, hypersensitivity to study drugs, recent major surgery or inability to swallow pills.

Inclusion Criteria

Patient has read and understands the informed consent form (ICF) and has been given written ICF prior to any study procedures which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

I had hepatitis C but am cured, or if currently treated, I have no detectable virus.

My pancreatic cancer cannot be cured with standard treatments.

Exclusion Criteria

Pregnant or lactating women are excluded from this study.

I received gemcitabine for pancreatic cancer or my condition worsened within 6 months after treatment.

I haven't taken any cancer drugs in the last 21 days or 5 half-lives, whichever is shorter.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ZN-c3 and Gemcitabine in a 21-day cycle with tumor assessments every 8 weeks

18 months

Cycle visits every 21 days, tumor assessments every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment with follow-up visits every 2 months

18 months

Follow-up visits every 2 months

What Are the Treatments Tested in This Trial?

Interventions

• Gemcitabine
• ZN-c3

Trial Overview The trial tests the combination of ZN-c3 (a WEE1 tyrosine kinase inhibitor) and Gemcitabine (a nucleoside metabolic inhibitor) for safety and effectiveness against pancreatic cancer. Participants will receive both medications under controlled conditions to evaluate how well they work together.

How Is the Trial Designed?

Group I: ZN-c3 + Gemcitabine Experimental Treatment 2 Interventions

Study procedures will be conducted as follows: * Cycle 1 - End of Treatment * Days 1 - 5 of 21-day cycle: Predetermined dose of ZN-c3 1x daily. * Days 8 - 12 of 21-day cycle: Predetermined dose of ZN-c3 1x daily. * Days 15 - 19 of 21-day cycle: Predetermined dose of ZN-c3 1x daily. * Day 1 and 8 of 21-day cycle: Predetermined dose of Gemcitabine 1x daily. * On-treatment tumor biopsy will be collected on either Cycle 1 Day 9 - 10 or Cycle 2 Day 9 - 10. * Tumor assessment by Computerized Tomography (CT) or Magnetic Resonance Imaging scan every 8 weeks while on treatment. * End of treatment visit with tumor assessment by CT or MRI and optional tumor biopsy. * Follow up visit every 2 months after treatment has ended.

Gemcitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Brandon Huffman

Lead Sponsor

Trials

1

Recruited

30+

Brandon Huffman, MD

Lead Sponsor

Trials

1

Recruited

30+

Lustgarten Foundation

Collaborator

Trials

27

Recruited

5,500+

K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

Industry Sponsor

Trials

8

Recruited

740+

Stand Up To Cancer

Collaborator

Trials

53

Recruited

40,100+

Published Research Related to This Trial

The combination of gemcitabine and irinotecan (IrinoGem) shows promising efficacy in treating advanced pancreatic cancer, with a 20% radiologic response rate and significant decreases in CA 19-9 levels in 32.5% of patients, based on a phase II trial of 45 patients.

The IrinoGem regimen demonstrated a higher maximum tolerated dose of irinotecan compared to previous trials, with manageable toxicity and no toxic deaths, indicating a potentially safer treatment option for patients with metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan/gemcitabine combination chemotherapy in pancreatic cancer. Rocha Lima, CM., Sherman, CA., Brescia, FJ., et al.[2022]

In a phase I/II study involving 34 Japanese patients with metastatic pancreatic cancer, the combination of nab-paclitaxel and gemcitabine demonstrated a high objective response rate of 58.8%, indicating promising efficacy for this treatment regimen.

The treatment was associated with manageable safety, with the most common severe adverse effects being neutropenia (70.6%) and leukopenia (55.9%), but no treatment-related deaths were reported, suggesting that the regimen can be safely administered with proper monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of nab-paclitaxel plus gemcitabine for chemotherapy-naive Japanese patients with metastatic pancreatic cancer. Ueno, H., Ikeda, M., Ueno, M., et al.[2022]

Gemcitabine has changed the perception of pancreatic cancer treatment, showing good tolerability and low side effects, making it a viable option for combination therapies with drugs like cisplatin and 5-fluorouracil.

Combination regimens with gemcitabine and cisplatin have shown response rates between 11.4% and 58% and median survival times of 7.4 to 10 months, while gemcitabine with 5-FU has lower response rates and survival times, indicating the need for further optimization of treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine-based combination treatment of pancreatic cancer. Heinemann, V.[2022]

Combining S-1 with gemcitabine (GEM) significantly improves overall survival (OS) and progression-free survival (PFS) in patients with advanced pancreatic cancer, based on a meta-analysis of five studies involving 917 patients.

However, this combination therapy also leads to higher rates of severe toxicities, including hematological issues like neutropenia and non-hematological effects such as diarrhea and nausea, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The addition of S-1 to gemcitabine-based chemotherapy improves survival with increased toxicity for patients with advanced pancreatic cancer: combined meta-analysis of efficacy and safety profile. Liu, Y., Huang, QK., Hong, WD., et al.[2022]

In a systematic review of 22 studies involving advanced pancreatic cancer, FOLFIRINOX was found to have an 83% probability of being the most effective treatment compared to other regimens, including gemcitabine and its combinations.

The analysis indicated that FOLFIRINOX may improve overall survival compared to G+ nab-paclitaxel, with no significant differences in toxicity, suggesting it could be a safer and more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer. Chan, K., Shah, K., Lien, K., et al.[2023]

Gemcitabine-loaded PEGylated liposomes (L-GEM) showed significantly greater antitumor activity against pancreatic cancer cell lines compared to free gemcitabine, with lower effective doses needed to reduce cell viability.

In vivo studies in mice demonstrated that L-GEM not only inhibited tumor growth more effectively than free gemcitabine but also improved survival rates without increasing toxicity, supporting its potential for clinical development in pancreatic cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer. Cosco, D., Bulotta, A., Ventura, M., et al.[2022]

In a phase III trial involving 214 patients with advanced pancreatic cancer, the combination of gemcitabine and capecitabine (GemCap) showed a trend towards improved overall survival (10.3 months) compared to gemcitabine alone (7.5 months), although this difference was not statistically significant (P=0.06).

GemCap significantly increased the overall response rate (43.7% vs 17.6%, P=0.001) compared to single-agent gemcitabine, while both treatment regimens had similar safety profiles, with neutropenia being the most common severe toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Lee, HS., Chung, MJ., Park, JY., et al.[2022]

In a pilot study involving 19 patients with locally advanced pancreatic cancer, the combination of gemcitabine, oxaliplatin, and bevacizumab showed a moderate toxicity profile but only an 11% response rate in primary tumors, which was lower than expected.

Despite the low response rate, 26% of patients were able to undergo surgery, and the one-year overall survival rate was 58%, indicating some potential benefit, although the overall clinical outcomes did not improve significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity study of gemcitabine, oxaliplatin, and bevacizumab, followed by 5-fluorouracil, oxaliplatin, bevacizumab, and radiotherapy, in patients with locally advanced pancreatic cancer. Sohal, DP., Metz, JM., Sun, W., et al.[2022]

In a phase II clinical trial involving patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), the combination of gemcitabine and dasatinib did not show a statistically significant improvement in overall survival compared to gemcitabine plus placebo.

The dasatinib treatment group experienced a higher burden of toxicity, indicating that while dasatinib was tested as a potential treatment, it did not provide additional benefits and may have increased side effects for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer. Evans, TRJ., Van Cutsem, E., Moore, MJ., et al.[2022]

Gemcitabine has been established as a new standard treatment for pancreatic cancer, showing improved clinical benefits, time to progression, and survival compared to older treatments like 5-fluorouracil.

Combining gemcitabine with cisplatin has shown better tumor response and time to progression than gemcitabine alone, although its impact on overall survival is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of randomized trials. Heinemann, V.[2022]

In a study of 41 patients with nonmetastatic pancreatic cancer, full-dose gemcitabine combined with radiation therapy was found to be well tolerated, with manageable side effects such as grade 3 neutropenia, nausea, and vomiting.

The treatment led to a significant reduction in CA 19-9 levels and a one-year survival rate of 73%, suggesting that this regimen could be effective and warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. Small, W., Berlin, J., Freedman, GM., et al.[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/NCT06015659

NCT06015659 | ZN-c3 + Gemcitabine in Pancreatic Cancer This study is being done to test the safety and effectiveness of combining ZN-c3 and Gemcitabine in participants with pancreatic cancer.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4211

Targeting replication stress in pancreatic cancer: A phase II ... It has been demonstrated that in vitro and in vivo PDAC models were exquisitely sensitive to WEE1 inhibition in combination with gemcitabine.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-09941

Azenosertib (ZN-c3) in Combination with Gemcitabine for ... This phase II trial evaluates the safety and effectiveness of azenosertib in combination with gemcitabine for the treatment of patients with pancreatic cancer.

4. onclive.com onclive.com/view/dr-huffman-on-the-investigation-of-azenosertib-plus-gemcitabine-in-advanced-pancreatic-cancer

Dr Huffman on the Investigation of Azenosertib Plus ... Brandon Huffman, MD, discusses an ongoing phase 2 trial evaluating azenosertib plus gemcitabine in advanced pancreatic cancer.

5. withpower.com withpower.com/trial/phase-2-adenocarcinoma-8-2023-d70ab

ZN-c3 + Gemcitabine for Pancreatic Cancer Combination regimens with gemcitabine and cisplatin have shown response rates between 11.4% and 58% and median survival times of 7.4 to 10 months, while ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06015659/zn-c3-gemcitabine-in-pancreatic-cancer?phase=-1&page=28&state=MA&city=Boston

ZN-c3 + Gemcitabine in Pancreatic Cancer This study is being done to test the safety and effectiveness of combining ZN-c3 and Gemcitabine in participants with pancreatic cancer.