Ivaltinostat + Capecitabine for Pancreatic Cancer

Recruiting at 21 trial locations

Overseen By Glenn C. Michelson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: CG Pharmaceuticals, Inc

Must be taking: Fluoropyrimidine chemotherapy

Must not be taking: HDAC inhibitors

Disqualifiers: Radiographic progression, Prior HDAC inhibitors, others

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

Compensation: Varies

Number of Visits: 2

70 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days before starting the trial. You can continue a stable dose of bisphosphonates or RANKL therapy for bone metastases if started at least 2 weeks before the study.

What data supports the effectiveness of the drug combination Ivaltinostat and Capecitabine for pancreatic cancer?

Research shows that Ivaltinostat, when combined with other drugs like gemcitabine and erlotinib, has shown potential as a treatment option for advanced pancreatic cancer, with some patients experiencing disease control and extended survival. Additionally, Capecitabine is widely used to treat various solid tumors, suggesting its potential effectiveness in combination therapies. ^{1 2 3 4 5}

What safety information is available for the combination of Ivaltinostat and Capecitabine in treating pancreatic cancer?

Capecitabine, also known as Xeloda, has been studied in various trials for pancreatic cancer, showing some common side effects like hand-foot syndrome (skin reaction on palms and soles), low red blood cell count, and high bilirubin levels (a liver-related issue). These studies help understand its safety profile, even though Ivaltinostat-specific safety data is not provided. ^{3 5 6 7 8}

How is the drug Ivaltinostat + Capecitabine unique for treating pancreatic cancer?

The combination of Ivaltinostat and Capecitabine is unique because it pairs a novel drug, Ivaltinostat, with Capecitabine, an oral drug that is activated in tumors to become 5-fluorouracil, potentially enhancing its effectiveness against pancreatic cancer, which is known to be highly resistant to treatment. ^{3 6 9 10 11}

What is the purpose of this trial?

This trial tests ivaltinostat with capecitabine in patients with advanced pancreatic cancer who have not worsened after initial treatment. The goal is to find a safe and effective dose and to see if this combination can better control the cancer. Capecitabine is a medication that is converted into another drug in the body, showing better selectivity and tolerability in tumor tissues.

Research Team

Andrew H Ko, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

Adults with metastatic pancreatic adenocarcinoma who responded well to initial FOLFIRINOX chemotherapy without disease progression are eligible. They must have adequate organ function, good performance status (ECOG 0-1), and can join within 6 weeks of their last chemo dose. Prior treatments for other cancers or radiation therapy are okay if enough time has passed.

Inclusion Criteria

My cancer can be measured by standard health scans.

I've been treated with FOLFIRINOX for pancreatic cancer for at least 16 weeks without the cancer getting worse.

I have pancreatic cancer that has spread, and I've had at least one treatment before.

Exclusion Criteria

I have never been treated with a HDAC inhibitor, including ivaltinostat.

I have had more than one treatment for my advanced pancreatic cancer.

My pancreatic cancer has worsened after starting FOLFIRINOX chemotherapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Phase 1b Treatment

Dose-escalation study of ivaltinostat in combination with capecitabine to determine the RP2D

21-day cycles

Clinic visits on Days 1, 2, 3, 5, 8, and 15 in Cycle 1; weekly visits thereafter

Phase 2 Treatment

Randomized study of ivaltinostat plus capecitabine versus capecitabine monotherapy

21-day cycles

Weekly clinic visits for treatment and assessments on Days 1, 8, and 15

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 6 weeks until disease progression, then every 8 weeks for survival

Treatment Details

Interventions

• Capecitabine
• Ivaltinostat

Trial Overview The trial is testing ivaltinostat combined with capecitabine versus capecitabine alone in patients whose cancer hasn't worsened after first-line chemotherapy. It's a two-phase study: the first determines the best dose of ivaltinostat, and the second compares both treatment methods.

Participant Groups

Group I: Ivaltinostat plus Capecitabine Experimental Treatment 2 Interventions

Ivaltinostat plus Capecitabine

Group II: Capecitabine Monotherapy Active Control 1 Intervention

Capecitabine Monotherapy

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

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

CG Pharmaceuticals, Inc

Lead Sponsor

Trials

1

Recruited

70+

Findings from Research

In a phase I/II study involving patients with advanced pancreatic ductal adenocarcinoma (PDAC), the combination of the HDAC inhibitor ivaltinostat with gemcitabine and erlotinib showed a promising objective response rate (ORR) of 25% and a disease control rate (DCR) of 93.8%.

The maximum tolerable dose of ivaltinostat was determined to be 250 mg/m2, and the median overall survival (OS) was 8.6 months, indicating that this treatment combination may be a viable option for patients with unresectable PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma. Jo, JH., Jung, DE., Lee, HS., et al.[2023]

The combination of mocetinostat and capecitabine significantly reduced cell migration and increased apoptosis in 4T1 breast cancer cells, indicating a potent therapeutic effect when used together.

Lower concentrations of the combined drugs were more effective than higher doses of either drug alone, suggesting that this combination therapy could minimize side effects while maximizing treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro anti-proliferative effect of capecitabine (Xeloda) combined with mocetinostat (MGCD0103) in 4T1 breast cancer cell line by immunoblotting. Kaya Çakir, H., Eroglu, O.[2022]

The maximum tolerated dose (MTD) of vorinostat in combination with capecitabine and radiation for non-metastatic pancreatic cancer was determined to be 400 mg daily, with manageable side effects including lymphopenia and nausea.

Nineteen out of twenty-one patients (90%) experienced stable disease, and the treatment regimen led to a median overall survival of 1.1 years, indicating promising efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Chan, E., Arlinghaus, LR., Cardin, DB., et al.[2018]

In a Phase I/II study involving 48 patients with solid tumors, mocetinostat combined with gemcitabine showed significant treatment-related toxicities, with 81% of patients experiencing grade ≥3 adverse events, primarily fatigue and thrombocytopenia.

The overall response rate (ORR) was only 11% in the Phase I study, with no responses observed in the Phase II cohort, leading to the conclusion that the combination treatment was not effective enough to continue testing in advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors. Chan, E., Chiorean, EG., O'Dwyer, PJ., et al.[2022]

In a study of 31 patients with previously treated metastatic pancreatic adenocarcinoma, the combination of docetaxel and capecitabine resulted in a disease control rate of 32.3%, with partial responses in 9.7% of patients and stable disease in 22.6%.

The treatment was associated with a median overall survival of 6.3 months and manageable side effects, including grade III/IV neutropenia in 32.2% of patients, suggesting that this combination may improve quality of life as a second-line chemotherapy option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. Katopodis, O., Polyzos, A., Kentepozidis, N., et al.[2018]

In a study of 42 patients with metastatic or locally advanced pancreatic cancer, capecitabine demonstrated a clinical benefit response in 24% of patients, improving pain intensity and overall performance status.

Capecitabine was generally well tolerated, with a 9.5% objective response rate, suggesting it may be a viable treatment option for further evaluation in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. Cartwright, TH., Cohn, A., Varkey, JA., et al.[2022]

In a phase I study involving 25 patients with localized, inoperable pancreatic adenocarcinoma, capecitabine was found to be well tolerated when given concurrently with radiotherapy, with a recommended dose of 825 mg/m².

The study identified only mild dose-limiting toxicities, such as grade 3 vomiting and fatigue, and no significant hematological toxicities, indicating a favorable safety profile for this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I and pharmacokinetic study of capecitabine in combination with radiotherapy in patients with localised inoperable pancreatic cancer. Roxburgh, P., Lumsden, GR., Paul, J., et al.[2022]

Capecitabine (Xeloda) is an effective treatment for advanced/metastatic breast cancer, showing a response rate of 20% in a phase 2 trial with a median survival time of 452 days for patients who were resistant to previous therapies.

The most common side effects reported were hand-foot syndrome and various blood-related issues, indicating that while Capecitabine can be beneficial, it also carries a risk of significant adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological and clinical properties of Xeloda (Capecitabine), a new oral active derivative of fluoropyrimidine. Nishida, M.[2018]

A retrospective study of 12 patients with severe renal impairment (GFR <30 mL/min) showed that capecitabine can be safely administered with close monitoring and dose adjustments, despite previous contraindications from the manufacturer based on a small Phase II trial.

Most patients experienced only mild to moderate adverse effects, and some showed a positive response to treatment, indicating that capecitabine may still be effective in this population when managed carefully.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR Jhaveri, KD., Flombaum, C., Shah, M., et al.[2022]

In a study of 19 colorectal cancer patients, capecitabine was shown to preferentially convert to 5-fluorouracil (5-FU) in tumor tissues, with 5-FU concentrations in tumors being 3.2 times higher than in adjacent healthy tissues, indicating effective targeting of the drug.

The enzyme thymidine phosphorylase (TP) plays a crucial role in this preferential activation, being significantly more active in colorectal tumors compared to healthy tissue, which helps explain the enhanced efficacy of capecitabine in treating colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Schüller, J., Cassidy, J., Dumont, E., et al.[2022]

Capecitabine, when combined with gemcitabine, shows potential benefits for patients with advanced pancreatic cancer, particularly in those with a good performance status (KPS ≥90), where it improved median survival from 7.5 months to 10.1 months.

While the combination did not significantly improve overall survival compared to gemcitabine alone in the broader patient population, preliminary data suggests it may enhance response rates and survival, indicating a need for further research to fully understand its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine: an evidence-based review of its effectiveness in the treatment of carcinoma of the pancreas. Smith, DB., Neoptolemos, JP.[2021]

References

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

A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma. [2023]

2. Iran pubmed.ncbi.nlm.nih.gov

In vitro anti-proliferative effect of capecitabine (Xeloda) combined with mocetinostat (MGCD0103) in 4T1 breast cancer cell line by immunoblotting. [2022]

3. Ireland pubmed.ncbi.nlm.nih.gov

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. [2018]

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

Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

A phase I and pharmacokinetic study of capecitabine in combination with radiotherapy in patients with localised inoperable pancreatic cancer. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

Pharmacological and clinical properties of Xeloda (Capecitabine), a new oral active derivative of fluoropyrimidine. [2018]

9. England pubmed.ncbi.nlm.nih.gov

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Capecitabine: an evidence-based review of its effectiveness in the treatment of carcinoma of the pancreas. [2021]