ZEN003694 + Chemotherapy for Cancer

Recruiting at 6 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticonvulsants, Anticoagulants, PPIs, others

Disqualifiers: CNS metastases, Cardiac issues, others

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 24 weeks

55 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial tests the safety, side effects, and best dose of a new combination of drugs, ZEN003694, cisplatin, and etoposide in treating patients with NUT carcinoma (phase I), and identifies whether this combination therapy works to shrink tumor in these patients (phase II). Another purpose of this study is to see whether there are any changes in patient's tumor or blood characteristics (e.g. genes, molecules, etc.) due to combination therapy. ZEN003694 inhibits the production of certain growth-promoting proteins and may prevent proliferation of tumor cells that use those proteins for their growth. Chemotherapy drugs, such as etoposide and cisplatin, work by stopping or slowing the growth of cancer cells. Combination therapy with ZEN003694, etoposide and cisplatin may be effective in treating patients with NUT carcinoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that strongly affect certain liver enzymes (CYP3A4) or proton pump inhibitors. It's best to discuss your current medications with the study team to ensure there are no interactions.

What data supports the effectiveness of the drug combination ZEN003694, cisplatin, and etoposide for cancer treatment?

Research shows that the combination of cisplatin and etoposide has been effective in treating non-small-cell lung cancer, with response rates of up to 38% and improved survival compared to cisplatin alone. Additionally, these drugs have shown a synergistic effect, meaning they work better together, in leukemia cell studies. ^{1 2 3 4 5}

What safety data exists for the combination of ZEN003694, Cisplatin, and Etoposide in cancer treatment?

The combination of Cisplatin and Etoposide has been studied in cancer treatments, showing some side effects like leukopenia (low white blood cell count), thrombocytopenia (low platelet count), and mild nausea and vomiting. Serious side effects like life-threatening leukopenia and acute renal failure were observed at higher doses, indicating the importance of careful dose management. ^{1 3 6 7 8}

What makes the drug ZEN003694 + Chemotherapy unique for cancer treatment?

The combination of ZEN003694 with chemotherapy drugs like cisplatin and etoposide is unique because it potentially enhances the antitumor effects, as seen in studies where cisplatin and etoposide together showed synergistic effects in gastric cancer cells. This combination may offer a novel approach by potentially improving the effectiveness of existing chemotherapy regimens. ^{5 6 8 9 10}

Research Team

Jia Luo

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Eligibility Criteria

Adults and children (12-17 years) with NUT carcinoma, a rare cancer type. Participants must be able to swallow pills, have certain blood counts within normal ranges, no severe liver or kidney issues, not on specific anticoagulants or other investigational drugs, and without untreated brain metastases. They should also not have gastrointestinal disorders affecting drug absorption.

Inclusion Criteria

Absolute neutrophil count >= 1.5 x 10^9/L

Albumin >= 2.5 g/dL

I am HIV positive, on effective treatment, and my viral load is undetectable.

Exclusion Criteria

I am not pregnant, as the study drug may harm my unborn baby.

I have brain metastases that have not been treated.

I am not taking strong medication that affects liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ZEN003694 orally once or twice daily, etoposide IV on days 1-3, and cisplatin IV on day 1 of each cycle. Cycles repeat every 21 days for up to 8 cycles.

Up to 24 weeks

Multiple visits per cycle for drug administration and evaluations

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with evaluations every 4 weeks for up to 2 years.

Up to 2 years

Follow-up visits every 4 weeks

Treatment Details

Interventions

• Cisplatin
• Etoposide
• ZEN003694

Trial Overview The trial is testing the safety and effectiveness of adding ZEN003694 to standard chemotherapy (etoposide and cisplatin). It aims to find the best dose that's safe in phase I and then see if this combination can shrink tumors in phase II. The study will also look at changes in tumor/blood characteristics due to treatment.

Participant Groups

Group I: Treatment (ZEN-3694, etoposide, cisplatin) Experimental Treatment 10 Interventions

Patients receive ZEN003694 PO once or twice daily on days 1-14 or days 1-21 of each cycle depending upon dosage assignment. Patients also receive etoposide IV over 60 minutes on days 1-3 for cycles 1-4 or up to 8 cycles, and cisplatin IV over 60 minutes on day 1 of cycles 1-4 or up to 8 cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo radiologic evaluation (chest x-ray, CT, PET-CT, MRI, and/or FDG-PET), blood and urine sample collection and biopsy throughout the study.

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

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Cisplatin-based regimens, particularly when combined with drugs like etoposide, vindesine, and mitomycin-C, have shown a reproducible response rate of 30% to 40% in patients with non-small-cell lung cancer.

Patients with good performance status should be encouraged to participate in clinical trials, as current therapies need improvement and may offer better options than standard chemotherapy, especially for those who are nonresponders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of non-small-cell lung cancer. Klastersky, J., Sculier, JP.[2018]

The combination of etoposide (VP 16) and cis-diamminedichloroplatinum (DDP) showed poor overall antitumor effects against Lewis lung carcinoma cell lines, with high acute toxicity observed.

Administering VP 16 before DDP resulted in a significant reduction in metastasis while maintaining acceptable levels of toxicity, suggesting a potential strategy for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide prior to cis-diamminedichloroplatinum in combination chemotherapy: in vitro and in vivo studies. Zupi, G., Greco, C., Sacchi, A., et al.[2019]

The combination of etoposide (VP-16) and cisplatin (DDP) showed significant synergistic cytotoxicity against the K562 leukemia cell line, enhancing cell apoptosis compared to either drug alone.

Cisplatin (DDP) enhances the effectiveness of etoposide (VP-16) by up-regulating the expression of topoisomerase II, which is a key target for VP-16, thereby improving its therapeutic action against leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Synergetic cytotoxicity of cisplatin and etoposide to leukemia cell line K562 and its mechanism]. Ma, WD., Yin, MY., Jiang, CW., et al.[2017]

In a study of 156 patients with advanced non-small-cell lung cancer (NSCLC), combination chemotherapy with cisplatin and etoposide resulted in a 30% response rate, significantly improving median survival to 35 weeks compared to 18 weeks with cisplatin alone.

The addition of mitomycin C to the cisplatin and etoposide regimen did not enhance the therapeutic response, and the main side effect observed was myelosuppression, particularly in the mitomycin C group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized trial fo three cisplatin-containing regimens in advanced non-small-cell lung cancer (NSCLC): a study of the Umbrian Lung Cancer Group. Crino, L., Tonato, M., Darwish, S., et al.[2019]

In a pilot phase II trial involving 31 high-risk patients with advanced non-small cell lung cancer (NSCLC), a novel metronomic regimen of weekly cisplatin and oral etoposide showed a promising objective response rate of 45.2%, indicating significant anti-tumor activity.

The treatment was generally well tolerated, although some patients experienced severe side effects like leukopenia and anemia, and three patients died from pulmonary embolism; however, the regimen demonstrated a mean survival time of 13 months, suggesting potential benefits even for patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel metronomic chemotherapy regimen of weekly platinum and daily oral etoposide in high-risk non-small cell lung cancer patients. Correale, P., Cerretani, D., Remondo, C., et al.[2022]

A Phase I study involving 27 patients tested the combination of etoposide and cisplatin, revealing that the optimal safe dosage for etoposide is 75 mg/m2/day and for cisplatin is 30 mg/m2/day when administered as a continuous infusion for 72 hours.

The study found significant dose-limiting toxicities, including life-threatening leukopenia and acute renal failure, particularly at higher doses, indicating the need for careful monitoring of patients receiving this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide admixed with cisplatin. Phase I clinical investigation of 72-hour infusion. Lokich, J., Anderson, N., Bern, M., et al.[2019]

In a study of 35 patients with non-small cell lung cancer, the DDP-VP16 chemotherapy regimen (cis-platinum and etoposide) showed a longer median time to disease progression (29 weeks) compared to the MACC regimen (11 weeks), suggesting it may be more effective.

While the DDP-VP16 regimen had a trend towards improved survival (30 weeks vs. 17 weeks for MACC), it was associated with higher toxicity, including severe vomiting in 47% of patients, indicating it may be less well tolerated despite its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MACC (methotrexate, doxorubicin, cyclophosphamide and lomustine) versus cis-platinum and etoposide in the treatment of advanced non-small cell lung cancer. Buccheri, G., Ferrigno, D., Curcio, A., et al.[2013]

A five-day continuous infusion of etoposide (VP-16) combined with cisplatin (CDDP) was tested in eight patients with advanced solid tumors, showing dose-limiting toxicities primarily as leukopenia and thrombocytopenia, but no significant renal, neurologic, or otologic side effects.

Despite the study not being designed as a phase II trial, three patients with advanced gastric adenocarcinoma experienced objective regressions, suggesting potential efficacy of this combination therapy in patients who had previously failed chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of a continuous five-day intravenous infusion of etoposide concomitant with cisplatin in selected patients with advanced cancer. Creagan, ET., Richardson, RL., Kovach, JS.[2017]

The combination of cisplatin (CDDP) and etoposide (VP-16) demonstrated synergistic antitumor effects in both an established gastric cancer cell line (KATO-III) and fresh tumor cells from 55 gastric cancer patients, indicating its potential effectiveness in treating this type of cancer.

The study found that the antitumor effects of CDDP were enhanced by early exposure to VP-16, particularly in poorly differentiated gastric cancer cells, suggesting that this combination therapy could be especially beneficial for patients with more aggressive cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide enhances the antitumor effects of cisplatin in gastric cancer cells. Hotta, T., Tanimura, H., Yamaue, H., et al.[2013]

In a phase II study involving 37 patients with ovarian cancer, intraperitoneal cisplatin and etoposide as salvage therapy resulted in 24 patients being clinically free of disease, with 9 achieving pathologic complete remission after treatment.

The treatment was generally well-tolerated, with myelosuppression being the main side effect, but no significant renal damage or other severe complications were observed, indicating a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of intraperitoneal cisplatin and etoposide as salvage treatment for minimal residual ovarian carcinoma. Kirmani, S., Lucas, WE., Kim, S., et al.[2017]

References

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

Chemotherapy of non-small-cell lung cancer. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Etoposide prior to cis-diamminedichloroplatinum in combination chemotherapy: in vitro and in vivo studies. [2019]

3. China pubmed.ncbi.nlm.nih.gov

[Synergetic cytotoxicity of cisplatin and etoposide to leukemia cell line K562 and its mechanism]. [2017]

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

A randomized trial fo three cisplatin-containing regimens in advanced non-small-cell lung cancer (NSCLC): a study of the Umbrian Lung Cancer Group. [2019]

5. Greece pubmed.ncbi.nlm.nih.gov

A novel metronomic chemotherapy regimen of weekly platinum and daily oral etoposide in high-risk non-small cell lung cancer patients. [2022]

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

Etoposide admixed with cisplatin. Phase I clinical investigation of 72-hour infusion. [2019]

7. Italy pubmed.ncbi.nlm.nih.gov

MACC (methotrexate, doxorubicin, cyclophosphamide and lomustine) versus cis-platinum and etoposide in the treatment of advanced non-small cell lung cancer. [2013]

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

Pilot study of a continuous five-day intravenous infusion of etoposide concomitant with cisplatin in selected patients with advanced cancer. [2017]

9. Greece pubmed.ncbi.nlm.nih.gov

Etoposide enhances the antitumor effects of cisplatin in gastric cancer cells. [2013]

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

A phase II trial of intraperitoneal cisplatin and etoposide as salvage treatment for minimal residual ovarian carcinoma. [2017]