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)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand the side effects of a new drug combination—ixazomib citrate (a proteasome inhibitor), gemcitabine hydrochloride, and doxorubicin hydrochloride—for treating advanced bladder cancer. These drugs work together to stop cancer growth by killing tumor cells or preventing their spread. The trial targets individuals whose bladder cancer has spread or cannot be surgically removed and who have already undergone at least one prior treatment. For those battling bladder cancer that has spread beyond the bladder and have not found success with other treatments, this trial might be suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a chance to be among the first to receive this new combination therapy.

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.

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

Researchers are investigating a combination of three drugs—ixazomib, gemcitabine, and doxorubicin—for treating bladder cancer. Ixazomib, already approved for other uses, suggests safety for patients. Studies have shown that ixazomib is usually well-tolerated.

Gemcitabine and doxorubicin, common chemotherapy drugs, have been used safely in many patients, though they can cause side effects like nausea and low blood counts. This combination treatment is still under testing to determine the optimal dose with the fewest side effects. Participation in this trial can help researchers learn more about the safety and effectiveness of this treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ixazomib, gemcitabine, and doxorubicin for bladder cancer because it introduces a novel way to tackle the disease. Unlike standard treatments that often focus solely on chemotherapy, ixazomib is a proteasome inhibitor, which works by blocking protein breakdown in cancer cells, potentially leading to increased cancer cell death. This combination approach not only targets cancer cells through multiple mechanisms but also allows for different administration methods, with ixazomib taken orally and the other drugs given intravenously. This could offer a more comprehensive attack on cancer cells compared to traditional chemotherapy alone.

What evidence suggests that this trial's treatments could be effective for bladder cancer?

In this trial, participants will receive a combination of ixazomib citrate, gemcitabine, and doxorubicin to treat bladder cancer. Research has shown that ixazomib citrate, when combined with gemcitabine and doxorubicin, may help treat certain cancers. Studies have found that ixazomib can stop tumors from growing by blocking enzymes that cancer cells need to multiply. Gemcitabine and doxorubicin are traditional chemotherapy drugs that kill cancer cells and prevent them from dividing or spreading. In past trials with similar drug combinations, patients experienced tumor shrinkage and slower disease progression. These results suggest that this drug combination could be effective for urothelial cancer, especially when the cancer has spread or cannot be surgically removed. ^{1 2 4 5 6}

Who Is on the Research Team?

Arlene O Siefker-Radtke

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

1. asco.org asco.org/abstracts-presentations/ABSTRACT241863

Phase II trial of ixazomib combined with gemcitabine and ... Phase II trial of ixazomib combined with gemcitabine and doxorubicin in patients with SMARCB1-deficient kidney malignancies. · Author Details · Pavlos Msaouel.

2. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/40/NCT02057640/Prot_SAP_001.pdf

A Phase I/II Study of MLN9708 (Ixazomib) in Combination ... The antitumor activity has been seen with single-agent MLN9708, when combined with established therapies, and across the malignancies studied (advanced solid ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5890941/

Tumor evolution and drug response in patient-derived ... In contrast, muscle invasive bladder cancers have a relatively poor prognosis (Kamat et al., 2016; Prasad et al., 2011). Treatment regimens for bladder cancer ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5480085/

Ritonavir and ixazomib kill bladder cancer cells by causing ... The overall survival for metastatic bladder cancer patients treated with a standard cisplatin–gemcitabine regimen was reported to be only 14.0 months.1 Clearly ...

5. go.drugbank.com go.drugbank.com/conditions/DBCOND0073677

Metastatic Urothelial Carcinoma (UC) (DBCOND0073677) Ixazomib Citrate With Gemcitabine Hydrochloride and Doxorubicin Hydrochloride in Treating Patients With Urothelial Cancer That is Metastatic or Cannot Be ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT02420847/ixazomib-citrate-with-gemcitabine-hydrochloride-and-doxorubicin-hydrochloride-in-treating-patients-with-urothelial-cancer-that-is-metastatic-or-cannot-be-removed-by-surgery

Ixazomib Citrate With Gemcitabine Hydrochloride and ... Giving ixazomib citrate together with gemcitabine hydrochloride and doxorubicin hydrochloride may be a better treatment for urothelial cancer. Read more ...