Bortezomib + Gemcitabine/Doxorubicin for Urothelial Cancer

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose combination of three drugs—bortezomib (Velcade), gemcitabine (Gemzar), and doxorubicin (Adriamycin)—for treating urothelial cancer and other solid tumors. Researchers seek to find the maximum dose patients can tolerate without significant side effects. This study suits patients with solid tumors that standard therapies cannot treat and who have already tried at least one other treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering patients a chance to contribute to groundbreaking research.

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.

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

Research shows that the safety of combining bortezomib, gemcitabine, and doxorubicin is still under investigation. Although specific safety data for this combination is not yet available, each drug has been tested individually or with other drugs.

Bortezomib is used in other cancer treatments and is generally well-tolerated, with common side effects such as tiredness and nausea. Gemcitabine and doxorubicin are also used in chemotherapy and are effective, but they can cause side effects like low blood counts and fatigue.

This is a Phase 1 trial, marking the first step in testing this combination. The primary goal is to determine the highest dose patients can tolerate without serious side effects. While the safety of each drug individually is known, their combined effects are less certain. Phase 1 trials are crucial for understanding how these drugs interact in the body. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for urothelial cancer because it combines bortezomib, a proteasome inhibitor, with traditional chemotherapy agents, gemcitabine and doxorubicin. Bortezomib works by disrupting the protein degradation process in cancer cells, leading to cell death, which is a different approach compared to most standard treatments that primarily target DNA replication or cell division. This novel mechanism offers the potential to enhance the efficacy of existing chemotherapy, possibly improving outcomes for patients who may not respond well to current options like cisplatin-based therapies. By integrating bortezomib, researchers hope to provide a more effective strategy against resistant cancer cells.

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

In this trial, participants will receive a combination of bortezomib, gemcitabine, and doxorubicin. Research has shown that bortezomib and gemcitabine together can effectively halt tumor growth, slowing the progression of cancer cells. Gemcitabine, when combined with other drugs, has proven effective as an initial cancer therapy. Doxorubicin, also included in this trial, has been used with other medicines to treat urothelial cancer. This suggests that combining gemcitabine, doxorubicin, and bortezomib could be effective against this type of cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Arlene Siefker-Radtke, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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.

I have severe heart or blood vessel problems, including recent heart attacks or strokes.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

Citations

1. sites.withpower.com sites.withpower.com/trial/phase-1-urethral-neoplasms-8-2006-5fe5d

Bortezomib + Gemcitabine/Doxorubicin for Urothelial Cancer 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00479128?tab=results

No Study Results Posted | Bortezomib With Gemcitabine ... It identifies the role of the intervention that participants receive. Types of arms include experimental arm, active comparator arm, placebo comparator arm, ...

3. clinconnect.io clinconnect.io/trials/NCT00479128?queryID=709ae8b37b8bc0d515e9&apos=8403

Bortezomib With Gemcitabine/Doxorubicin in Patients With This clinical trial is testing a combination of three medications: Velcade® (bortezomib), Gemzar® (gemcitabine), and Adriamycin® (doxorubicin) in patients with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4792756/

Front-line Treatment with Gemcitabine, Paclitaxel and ... Median overall survival was 14.4 months. Conclusions. The combination of gemcitabine, paclitaxel, and doxorubicin is effective first-line chemotherapy for ...

5. aacrjournals.org aacrjournals.org/mct/article/3/3/279/234355/The-proteasome-inhibitor-bortezomib-synergizes

The proteasome inhibitor bortezomib synergizes with ... However, combination therapy with bortezomib plus gemcitabine produced synergistic tumor growth inhibition associated with strong suppression of tumor cell ...

6. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)41853-X/fulltext

Phase II study of bortezomib in patients with previously ... While combination chemotherapy for advanced urothelial cancer has led to improved outcomes, the overwhelming majority of patients with metastatic disease will ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S092375341941853X

Phase II study of bortezomib in patients with previously ... While combination chemotherapy for advanced urothelial cancer has led to improved outcomes, the overwhelming majority of patients with metastatic disease will ...

8. mayoclinicproceedings.org mayoclinicproceedings.org/article/S0025-6196(17)30568-2/fulltext

Management of Muscle-Invasive Urothelial Cancer and the ... This review highlights the landmark clinical trials of chemotherapy in both the neoadjuvant and advanced or metastatic urothelial carcinoma settings.