BAY 1895344 + Chemotherapy for Bladder Cancer

Not currently recruiting at 9 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Active malignancy, Peripheral neuropathy, others

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

Compensation: Varies

Number of Visits: 7

Duration: 18 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and potential effects of a new treatment, BAY 1895344, combined with chemotherapy for advanced cancers like bladder cancer. BAY 1895344 may inhibit tumor growth by blocking enzymes essential for cancer cell growth. Participants will receive a combination of this treatment and chemotherapy drugs such as cisplatin and gemcitabine to evaluate their combined effectiveness. Individuals with advanced solid tumors, including bladder cancer, who have previously undergone cisplatin-based treatment, may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding the treatment's effects in humans, offering participants the chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot participate if you are on certain medications that interact with the trial drugs. It's important to discuss your current medications with the trial team to see if any changes are needed.

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

Research has shown that the drug elimusertib (BAY 1895344), when used with cisplatin or with both cisplatin and gemcitabine, may help treat advanced tumors. However, some safety concerns exist. When combined with cisplatin, elimusertib has caused blood-related side effects in some patients. In such cases, doctors sometimes needed to lower the dose to manage these effects. Despite these issues, the treatment has shown potential in slowing tumor growth, especially when used with both cisplatin and gemcitabine.

These results come from early clinical studies. At this stage, researchers are working to find the best dose and understand all possible side effects. While the treatment is being tested, it is important to monitor how patients handle it and adjust the treatment if necessary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for bladder cancer because of the novel inclusion of elimusertib (BAY 1895344), a new active ingredient that targets the ATR (Ataxia Telangiectasia and Rad3-related) pathway. This is different from standard treatments like cisplatin and gemcitabine, which focus on damaging DNA and preventing cancer cells from dividing. Elimusertib enhances the effects of these traditional chemotherapies by disrupting the cancer cells' ability to repair DNA damage, potentially increasing their effectiveness. The combination of elimusertib with cisplatin and gemcitabine could offer a more powerful approach to tackling bladder cancer, making it a promising avenue for researchers looking for more effective treatments.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors, including urothelial cancer?

This trial studies BAY 1895344 in combination with chemotherapy drugs for bladder cancer. Previous studies have shown that BAY 1895344 blocks certain enzymes necessary for cancer cell growth. Participants in one arm of the trial will receive BAY 1895344 (elimusertib) combined with cisplatin, a chemotherapy drug, to increase cancer cells' sensitivity to the therapy. Another arm will study BAY 1895344 with both cisplatin and gemcitabine. Research has shown that changes in DNA repair genes, such as ATM deficiency, can enhance the response of cancers like bladder cancer to treatments like cisplatin. BAY 1895344, when combined with cisplatin and gemcitabine, may further enhance this effect, potentially improving outcomes for patients with advanced solid tumors. Overall, the combination treatment is under study for its potential to more effectively halt tumor growth. ^{2 3 6 7 8}

Who Is on the Research Team?

Mamta Parikh

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced solid tumors or urothelial cancer, including those HIV-positive on effective therapy, and those who've had certain prior treatments. Must have adequate organ function and not be pregnant or breastfeeding. Excludes individuals with significant neuropathy, hearing loss, recent chemotherapy/radiotherapy, other active cancers needing treatment (except some skin/prostate cancers), or psychiatric/social conditions affecting compliance.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

Your hemoglobin level is at least 9 grams per deciliter.

I have previously received immune checkpoint inhibitor therapy.

Exclusion Criteria

I am not on any strong medication that affects liver enzymes or can't switch to another.

I haven't had chemotherapy, radiotherapy, or targeted therapies like PARP inhibitors in the specified time before joining the study.

The doctor thinks you have less than 6 weeks to live.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cisplatin and elimusertib, or cisplatin, gemcitabine, and elimusertib in cycles

18 weeks

6 cycles, each 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 28 days after treatment completion

1 visit (in-person) at 30 days, then every 3 months

Long-term follow-up

Participants are monitored for progression-free survival and response rate

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• BAY 1895344
• Cisplatin
• Gemcitabine Hydrochloride

Trial Overview The trial is testing BAY 1895344 added to usual chemotherapy drugs Cisplatin or Cisplatin plus Gemcitabine for treating advanced solid tumors. It aims to find the best dose of BAY 1895344 and assess its benefits/side effects when combined with these chemotherapies.

How Is the Trial Designed?

Group I: Arm II (cisplatin, gemcitabine, elimusertib) Experimental Treatment 3 Interventions

Patients receive cisplatin IV over 1-2 hours on day 1 and 8, gemcitabine IV over 30 minutes on days 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (cisplatin, elimusertib) Experimental Treatment 2 Interventions

Patients receive cisplatin IV over 1-2 hours on day 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

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

In a study of 28 patients aged 65 and older with urothelial cancer, the combination of gemcitabine and cisplatin was found to be reasonably well-tolerated, with 57.1% receiving it in the neoadjuvant setting.

The study suggests that a lower dose of gemcitabine (1000 mg/m²) is better tolerated than the standard higher dose (1250 mg/m²), as higher doses led to more hematologic toxicity and treatment delays.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of Gemcitabine Plus Cisplatin for Treatment of Urothelial Cancer in the Elderly Population. Jan, AS., Dolan, DE., Lombardi, K., et al.[2022]

In a phase II study involving 27 patients with advanced transitional cell carcinoma, the sequential treatment of gemcitabine and carboplatin followed by paclitaxel resulted in an objective response rate of 40.7%, with one complete response and ten partial responses.

The treatment was generally safe, with hematologic toxicities being the most common, but the study concluded that while this sequential approach appears safer than triplet therapy, it did not significantly improve patient outcomes, indicating a need for further research with larger groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential therapy with gemcitabine and Carboplatin followed by Paclitaxel as first line treatment for advanced urothelial cancer. Kattan, JG., Boutros, CY., Farhat, FS., et al.[2021]

Cis-diamminedichloroplatinum (II) demonstrated significant efficacy as a single-agent treatment for advanced genitourinary tumors, achieving complete responses in 16.7% of testicular cancer patients and partial responses in 50% of the same group, based on a study of 112 patients with various genitourinary tumors.

The treatment was associated with common adverse reactions such as gastrointestinal issues, nephrotoxicity, and myelosuppression, but also included occasional ototoxicity and peripheral neuropathies, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase II study of cis-diamminedichloroplatinum (II) in genitourinary cancer]. [2013]

In a study of 11 patients with untreated metastatic bladder cancer, cis-diamminedichloroplatinum (CDDP) showed a partial response in 37.5% of patients, indicating some efficacy in this difficult-to-treat population.

While CDDP was generally tolerated, it caused moderate nausea and vomiting in some patients, and nephrotoxicity was a significant concern, leading to renal failure in 2 patients with ureteral obstruction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cis-diamminedichloroplatinum activity in bidimensionally measurable metastatic lesions of bladder carcinoma. De Lena, M., Lorusso, V., Iacobellis, U., et al.[2022]

Gemcitabine, a newer chemotherapy agent, has shown promising activity against bladder cancer, both as a single agent and in combination with cisplatin, offering a favorable toxicity profile compared to traditional treatments.

The standard treatment for advanced bladder cancer in the US remains the M-VAC regimen, but ongoing trials are exploring the effectiveness of gemcitabine combined with other agents, which may lead to improved treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in the treatment of bladder cancer. Ryan, CW., Vogelzang, NJ.[2022]

The current chemotherapy regimen for metastatic bladder cancer, which includes cisplatin, methotrexate, vinblastine, and doxorubicin, shows limited impact on survival and is associated with significant toxicity.

Gemcitabine, a novel nucleoside analogue, has demonstrated promising response rates of up to 33% in phase II studies and is well tolerated, suggesting it may be a safer and effective alternative for treating bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic bladder cancer: advances in treatment. Stadler, WM., Kuzel, TM., Raghavan, D., et al.[2022]

In a phase III trial with 405 patients, the gemcitabine/cisplatin (GC) regimen showed comparable effectiveness to the standard MVAC regimen for advanced bladder cancer, with similar response rates and overall survival.

The GC regimen demonstrated significantly better safety and tolerability, with much lower rates of severe side effects like mucositis and neutropenic fever, suggesting it should be preferred as the standard treatment for advanced bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in advanced bladder cancer. von der Maase, H.[2022]

The gemcitabine and cisplatin doublet regimen has shown a better efficacy-toxicity profile compared to the traditional MVAC chemotherapy for bladder cancer, making it a more suitable option for elderly patients with metastatic disease.

Ongoing phase II studies of triplet regimens combining gemcitabine, paclitaxel, and either cisplatin or carboplatin have demonstrated promising activity and improved median survival, particularly in patients with visceral disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of gemcitabine triplets in metastatic bladder cancer. de Wit, R., Bellmunt, J.[2022]

The combination of paclitaxel, cisplatin, and gemcitabine demonstrated a high overall response rate of 77.6% in 61 patients with advanced transitional-cell carcinoma, indicating strong antitumor activity.

The recommended doses for further studies were established as 80 mg/m² of paclitaxel and 1,000 mg/m² of gemcitabine, with manageable toxicity, although significant side effects like grade 3 neutropenia were observed in 55% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. Spanish Oncology Genitourinary Group. Bellmunt, J., Guillem, V., Paz-Ares, L., et al.[2022]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-05428

Testing the Addition of an Anti-cancer Drug, BAY 1895344, ... BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cisplatin and gemcitabine are chemotherapy drugs that ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10750798/

ATR Inhibition in Advanced Urothelial Carcinoma - PMC The 5-year relative survival rate for locally advanced or metastatic disease remains around 15% despite current systemic therapy regimens. The current standard ...

3. science.org science.org/doi/10.1126/sciadv.adg2263

ATM deficiency confers specific therapeutic vulnerabilities ... We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation.

4. dfhcc.harvard.edu dfhcc.harvard.edu/fileadmin/media/ETCTN/02_Developing_an_ETCTN_Study/PTMA_Requests/BAY_1895344_NSC_810486_PTMA.pdf

FOR CONDUCTING CLINICAL TRIALS USING BAY ... Luecking, et al. (2017). ATR inhibitor BAY 1895344 shows potent anti- tumor efficacy in monotherapy and strong combination potential with the targeted alpha ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10664985/

ATM deficiency confers specific therapeutic vulnerabilities in ... In bladder cancer, several studies have identified an association between alterations in DNA repair genes and improved response to cisplatin- ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41104717/

The ATR inhibitor Elimusertib in Combination with Cisplatin ... Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation.

7. researchgate.net researchgate.net/publication/367696256_A_phase_I_trial_of_elimusertib_in_combination_with_cisplatin_or_with_cisplatin_plus_gemcitabine_in_advanced_solid_tumors_with_an_emphasis_on_urothelial_carcinoma?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJzY2llbnRpZmljQ29udHJpYnV0aW9ucyIsInByZXZpb3VzUGFnZSI6bnVsbH19

A phase I trial of elimusertib in combination with cisplatin or ... Elimusertib is a potent, highly selective, and orally available ATR inhibitor that has shown promising activity in both in vitro and in vivo in ...

8. clinical-genitourinary-cancer.com clinical-genitourinary-cancer.com/article/S1558-7673(22)00223-3/fulltext

ATR Inhibition in Advanced Urothelial Carcinoma Both cisplatin and carboplatin exhibit strong synergism when combined with elimusertib in the control of bladder cancer cell growth (C and F).