Bortezomib + Gemcitabine/Doxorubicin for Urothelial Cancer

Recruiting in Houston (>99 mi)

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Investigational drugs

Disqualifiers: Pregnancy, Brain metastases, Atherosclerotic disease, others

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

Compensation: Varies

Number of Visits: 6

Duration: 42 days

80 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to find the highest tolerable dose of Gemzar® (gemcitabine) and Adriamycin® (doxorubicin) that can be given together with Velcade® (bortezomib) in patients with urothelial cancer or other solid tumors.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot have received other investigational drugs within 14 days before joining the trial.

What data supports the effectiveness of the drug combination Bortezomib, Gemcitabine, and Doxorubicin for treating urothelial cancer?

The research indicates that Gemcitabine and Doxorubicin are part of standard treatments for advanced urothelial cancer, often used in combination with other drugs like cisplatin. New combinations involving Gemcitabine have shown promise, suggesting potential effectiveness when combined with other agents like Bortezomib. ^{1 2 3 4 5}

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

Gemcitabine has been studied for safety when used in the bladder and is generally well tolerated. Doxorubicin has been evaluated in combination with other drugs for urothelial cancer, but it is known to have significant toxicity. There is no specific safety data available for the combination of Bortezomib, Gemcitabine, and Doxorubicin together. ^{2 3 6 7 8}

How does the drug combination of Bortezomib, Doxorubicin, and Gemcitabine differ from other treatments for urothelial cancer?

This drug combination is unique because it includes Bortezomib, which is not part of the standard regimens like MVAC or Gemcitabine plus Cisplatin. Bortezomib works by inhibiting proteasomes (cellular complexes that break down proteins), potentially enhancing the effectiveness of chemotherapy in urothelial cancer. ^{1 5 9 10 11}

Research Team

Arlene Siefker-Radtke, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with urothelial cancer or other solid tumors without standard treatment options. Participants must have had prior therapy, be able to perform daily activities (Zubrod status ≤2), and not be pregnant or breastfeeding. They should have normal organ function and agree to use birth control. Those with severe heart disease, active second cancers, significant neuropathy, or allergies to the drugs are excluded.

Inclusion Criteria

Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

I am using or willing to use birth control during the study.

My cancer is confirmed by biopsy and has no standard treatment.

Exclusion Criteria

Your total bilirubin level is higher than 2.5 mg/dL.

I am allergic to bortezomib, boron, mannitol, gemcitabine, or doxorubicin, except for manageable gemcitabine skin rash.

Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Bortezomib, Gemcitabine, and Doxorubicin in cycles to determine the highest tolerable dose

42 days

Weekly visits for physical exams and blood tests

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Phone call every 6 months

Treatment Details

Interventions

• Bortezomib
• Doxorubicin
• Gemcitabine

Trial Overview Researchers are testing the highest dose of Gemzar (gemcitabine) and Adriamycin (doxorubicin) that can safely be given with Velcade (bortezomib). The study aims to determine tolerable levels for patients who've exhausted standard treatments for their advanced cancers.

Participant Groups

Group I: Bortezomib + Gemcitabine + Doxorubicin Experimental Treatment 3 Interventions

Starting dose of Bortezomib 0.8 mg/m\^2 IV Over 3-5 Seconds. Starting dose of Gemcitabine 225 mg/m\^2 IV Up to 90 Minutes. Starting dose of Doxorubicin 12.5 mg/m\^2 IV Over 15-30 minutes.

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

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Millennium Pharmaceuticals, Inc.

Industry Sponsor

Trials

406

Recruited

46,900+

Dr. Christophe Bianchi

Millennium Pharmaceuticals, Inc.

Chief Medical Officer since 2006

MD from University of Geneva

Dr. Deborah Dunsire

Millennium Pharmaceuticals, Inc.

Chief Executive Officer since 2005

MD from University of Witwatersrand

Findings from Research

The standard treatment for locally advanced and metastatic transitional cell carcinoma includes the four-drug combination MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the two-drug combination GC (gemcitabine and cisplatin).

New studies suggest that pemetrexed, either alone or in combination with gemcitabine, shows promise for improved efficacy and reduced toxicity, indicating a need for further research into these new treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in transitional cell carcinoma of the urothelium. 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 (Gem) shows a lower incidence of side effects like dysuria and hematuria compared to Bacille Calmette-Guérin (BCG) in treating non-muscle invasive bladder cancer, based on a meta-analysis of 386 subjects from 5 trials.

Both treatments have similar efficacy in terms of recurrence and progression rates, indicating that Gem could be a safer alternative to BCG, but further high-quality trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of intravesical gemcitabine vs Bacille Calmette-Guérin for adjuvant treatment of non-muscle invasive bladder cancer: a meta-analysis. Ye, Z., Chen, J., Hong, Y., 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]

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 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]

References

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

New chemotherapy combinations for advanced bladder cancer. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Paclitaxel plus doxorubicin chemotherapy as second-line therapy in patients with advanced urothelial carcinoma pretreated with platinum plus gemcitabine chemotherapy. [2022]

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

Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma. [2015]

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

Pemetrexed in transitional cell carcinoma of the urothelium. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Intravesical gemcitabine: a phase 1 and pharmacokinetic study. [2022]

7. 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]

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

The efficacy and safety of intravesical gemcitabine vs Bacille Calmette-Guérin for adjuvant treatment of non-muscle invasive bladder cancer: a meta-analysis. [2022]

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

Gemcitabine in the treatment of bladder cancer. [2022]

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

Gemcitabine in advanced bladder cancer. [2022]

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

Tolerability of Gemcitabine Plus Cisplatin for Treatment of Urothelial Cancer in the Elderly Population. [2022]