Ixazomib + Gemcitabine + Doxorubicin for Bladder Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP inhibitors, CYP inducers

Disqualifiers: Low platelets, Low neutrophils, Pregnancy, Brain metastases, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Varies (Phase I and Phase II)

57 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of ixazomib citrate, gemcitabine hydrochloride, and doxorubicin hydrochloride when given together in treating patients with urothelial cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery. Ixazomib citrate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as gemcitabine hydrochloride and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ixazomib citrate together with gemcitabine hydrochloride and doxorubicin hydrochloride may be a better treatment for urothelial cancer.

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 strong inhibitors or inducers of specific liver enzymes (like some antibiotics and antifungals) within 14 days before starting the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Ixazomib, Gemcitabine, and Doxorubicin for bladder cancer?

Gemcitabine, one of the drugs in the combination, has shown promising results in treating advanced bladder cancer, with response rates of up to 57% when combined with cisplatin, and it is well-tolerated with fewer side effects compared to older treatments. ^{1 2 3 4 5}

Is the combination of Ixazomib, Gemcitabine, and Doxorubicin safe for humans?

Gemcitabine, when used alone or with other drugs like cisplatin, has shown a favorable safety profile with reduced side effects compared to older treatments for bladder cancer. Doxorubicin is part of standard regimens but can have significant side effects. There is no specific safety data available for the combination of Ixazomib, Gemcitabine, and Doxorubicin in humans. ^{1 4 5 6 7}

How is the drug Ixazomib + Gemcitabine + Doxorubicin unique for bladder cancer?

This drug combination is unique because it includes Ixazomib, a newer agent not typically used in standard bladder cancer treatments, alongside Gemcitabine and Doxorubicin, which are known for their effectiveness and relatively favorable safety profiles in treating advanced bladder cancer. ^{1 3 4 8 9}

Research Team

Arlene O Siefker-Radtke

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with urothelial cancer that has spread or can't be removed by surgery. They must have had at least one prior therapy, unless they cannot or refuse cisplatin-based therapy. Participants should not be pregnant, breastfeeding, or planning to become pregnant and must agree to use effective contraception. They need a certain level of heart, liver, and kidney function and cannot have severe heart disease, active infections like hepatitis B/C or HIV, unstable angina, significant neuropathy (nerve pain), recent major surgery or other clinical trials within the last month.

Inclusion Criteria

I haven't been treated with specific cancer drugs before for my condition.

My heart pumps well despite past heart issues or specific cancer treatment.

I am a male and agree to follow the birth control requirements.

Exclusion Criteria

I haven't had a heart attack in the last 6 months and don't have severe heart issues.

I am not on IV antibiotics for an infection.

I don't have GI issues that affect medicine absorption or swallowing.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ixazomib citrate orally, gemcitabine hydrochloride intravenously over 90 minutes, and doxorubicin hydrochloride intravenously over 15-30 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Varies (Phase I and Phase II)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Phase II Extension

Assess the efficacy of the combination therapy in metastatic, surgically unresectable urothelial cancer

Varies

Treatment Details

Interventions

• Doxorubicin Hydrochloride
• Gemcitabine Hydrochloride
• Ixazomib Citrate

Trial Overview The trial tests ixazomib citrate combined with chemotherapy drugs gemcitabine hydrochloride and doxorubicin hydrochloride on patients with advanced urothelial cancer. It aims to find the best dose while assessing how well this combination works in stopping tumor growth compared to current treatments.

Participant Groups

Group I: Treatment (ixazomib, gemcitabine, doxorubicin) Experimental Treatment 3 Interventions

Patients receive ixazomib citrate PO, gemcitabine hydrochloride IV over 90 minutes, and doxorubicin hydrochloride IV over 15-30 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Doxorubicin Hydrochloride is already approved in United States, European Union for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma

Approved in European Union as Doxorubicin Hydrochloride for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a phase I study involving 18 patients with bladder cancer resistant to BCG therapy, gemcitabine administered intravesically showed substantial activity, with 7 patients achieving a complete response.

The treatment was generally safe, with minimal severe toxicity observed; the recommended dose for further studies is 2,000 mg, despite some patients experiencing mild side effects like hematuria and myelosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of intravesical gemcitabine in bacillus Calmette-Guérin-refractory transitional-cell carcinoma of the bladder. Dalbagni, G., Russo, P., Sheinfeld, J., et al.[2022]

Intravesical gemcitabine and docetaxel therapy shows promising efficacy for high-risk nonmuscle invasive bladder cancer, with 1-year and 2-year recurrence-free survival rates of 86% and 84% in BCG-naive patients, and 80%, 66%, and 51% in BCG-unresponsive patients at 6 months, 1 year, and 2 years, respectively.

The treatment is generally well tolerated, with only 2.3% of patients unable to complete induction therapy and 6.9% experiencing delays or dose reductions due to adverse events, suggesting it could be a viable alternative to BCG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential intravesical gemcitabine and docetaxel therapy in patients with nonmuscle invasive bladder cancer: a systematic review and meta-analysis. Kawada, T., Yanagisawa, T., Araki, M., et al.[2023]

In a study of 109 patients with muscle-invasive bladder cancer, both gemcitabine and cisplatin (GC) and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) showed similar rates of pathologic complete response (pCR), with 25% for GC and 21% for ddMVAC, indicating that both regimens are equally effective as neoadjuvant chemotherapy.

Switching between GC and ddMVAC after 1 or 2 cycles may benefit patients with poor initial responses, as 4 out of 7 patients in the switch therapy group experienced downstaging, suggesting a potential strategy for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Downstaging of Muscle-Invasive Bladder Cancer Using Neoadjuvant Gemcitabine and Cisplatin or Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin as Single Regimens or as Switch Therapy Modalities. Ruplin, AT., Spengler, AMZ., Montgomery, RB., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Gemcitabine in the treatment of bladder cancer. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Systemic chemotherapy in locally advanced and/or metastatic bladder cancer. [2007]

3. England pubmed.ncbi.nlm.nih.gov

Metastatic bladder cancer: advances in treatment. [2022]

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

Gemcitabine in advanced bladder cancer. [2022]

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

Gemcitabine and other new chemotherapeutic agents for the treatment of metastatic bladder cancer. [2022]

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

Phase I trial of intravesical gemcitabine in bacillus Calmette-Guérin-refractory transitional-cell carcinoma of the bladder. [2022]

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

Sequential intravesical gemcitabine and docetaxel therapy in patients with nonmuscle invasive bladder cancer: a systematic review and meta-analysis. [2023]

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

Downstaging of Muscle-Invasive Bladder Cancer Using Neoadjuvant Gemcitabine and Cisplatin or Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin as Single Regimens or as Switch Therapy Modalities. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

[Gemcitabine and cisplatin therapy in advanced or metastatic urothelial cancer: comparison of side effect with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)]. [2022]