Two urology surgeons working side by side in the operating room

Clinical Trial Offers Bladder-Saving Option with Novel Multi-Drug Therapy

May 20, 2021

Bladder cancer is the sixth most common cancer in the U.S., with nearly 84,000 new cases estimated this year. While advances in therapeutics for bladder cancer are emerging, the primary treatment for high-risk stage 1 disease has remained relatively unchanged for many years. 

A team in the Department of Urology at Columbia’s Vagelos College of Physicians and Surgeons and the Herbert Irving Comprehensive Cancer Center (HICCC) is enrolling a phase 2 clinical trial to test a novel combination chemotherapy regimen for direct bladder instillation in patients who have limited options after failing initial treatment. Phase 1 trial results demonstrated that the combination was safe, and indicated significant efficacy. This drug combination  is promising for  an entirely new, bladder-saving treatment option for patients. 

“People who come to us are often told by other hospitals that they’ve done everything they can and cannot save their bladder, yet the cancer has not spread or hasn’t gone out of control,” says James McKiernan, MD, chair of the Department of Urology, director of urologic oncology, and co-investigator in the clinical trial. 

“These patients are looking for hope, a chance, an opportunity to save their bladder. Historically, we haven’t had anything new to offer them beyond the standard of care, which is removing their bladder.” 

“Radical cystectomy, or bladder removal, certainly provides the best outcomes in terms of disease remission, but it is a highly complex and morbid surgery that not every patient can tolerate,” says G. Joel DeCastro, MD, assistant professor of urology at Columbia and the trial’s lead investigator. “This fact makes the need for effective alternatives to radical cystectomy all the more important. This trial shows great promise for this population of patients.”

The trial focuses on patients with non-muscle invasive bladder cancer (NMIBC), when the cancer involves the inner lining of the bladder but has not invaded into the surrounding muscle. Patients enrolled in the trial must have a history of recurrence with NMIBC after having received intravesical Bacillus Calmette-Guerin (BCG) – a first-line therapy that is considered standard of care. Patients in the trial must have either refused or been ineligible for radical cystectomy.

The phase 1 portion of the study involved 18 patients, and involved sequential intravesical instillation, or direct delivery, of three chemotherapy drugs agents: cabazitaxel, gemcitabine, and cisplatin (CGC). The results, published in 2020 in the Journal of Urology, demonstrated that the combination treatment is safe. In addition, 89% of patients had an initial complete response to the novel multi-drug treatment, and 83% were recurrence-free at one year. Cystectomy-free survival—or survival without having had to undergo radical surgery—at one and two years was 94% and  81%, respectively.

With intravesical therapy, patients receive the chemotherapy drugs via injection directly into the bladder through a catheter. The drug remains in the bladder for up two hours and only affects the cells lining the inside of the bladder, avoiding any damage to surrounding tissue. In phase 1, all patients underwent a 6-week induction regimen of CGC. Patients who had a complete or partial response continued with maintenance cabazitaxel and gemcitabine monthly for the first year and bimonthly for the second year of treatment.

The trial grew out of a long-standing research collaboration between lead investigators and Cory Abate-Shen, PhD, chair of the Columbia Department of Molecular Pharmacology and Therapeutics. Dr. Abate-Shen, a leader in the development of innovative mouse models for translational research in prostate and bladder cancers, worked with Dr. McKiernan to implement co-clinical studies to identify and evaluate the safety and toxicity of different combinations of chemotherapeutic agents using genetically-engineered mouse models. Such models, developed by the Abate-Shen lab, develop bladder cancers that resemble the human version. 

A co-clinical study of single and combination regimens of intravesical cisplatin, gemcitabine, and docetaxel showed that of the three single agents tested, gemcitabine was most effective for preventing the cancer from progressing or spreading. However, mouse models receiving any 2-drug combination had a statistically significant delay in disease progression or metastasis when compared to the single agent treatments. 

“Through our collaboration with our laboratory  research team we’ve developed a combination of drugs that has been highly effective on bladder cancer patients, exceeding our expectations,” adds Dr. McKiernan. “We hope to broaden the impact we’re having to the greater community so that more people can benefit from this promising new treatment.” 

The phase 2 CGC trial is presently enrolling and will further examine the safety and effectiveness of the combination therapy on a larger cohort of patients. 

“While the trial is still in its early phases, the results so far make us very optimistic,” says Dr. DeCastro. “We are hopeful about creating an effective treatment alternative for this risky disease that is notoriously difficult to treat.”