Futibatinib + Durvalumab for Bladder Cancer

Overseen By Rebecca Williams

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yuanquan Yang

Must not be taking: Anticancer therapy, Immunotherapy

Disqualifiers: Pregnancy, Upper tract carcinoma, Metastatic disease, Active cardiac disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 14

Duration: 12 weeks

24 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently on certain anticancer therapies or have used specific drugs that affect liver enzymes within 7 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 Durvalumab for bladder cancer?

Durvalumab, an immune checkpoint inhibitor, has shown promise in treating urothelial carcinoma, a common type of bladder cancer, especially in patients whose disease progressed after chemotherapy. It was recognized for its effectiveness in 2017, offering a new option for patients with advanced-stage disease. ^{1 2 3 4 5}

Is the combination of Futibatinib and Durvalumab safe for humans?

Durvalumab, also known as Imfinzi, has been used in treating bladder cancer and is generally well-tolerated, though it can cause immune-related side effects. While specific safety data for the combination with Futibatinib is not provided, Durvalumab alone has shown a good safety profile in other studies. ^{4 5 6 7 8}

What makes the drug combination of Futibatinib and Durvalumab unique for bladder cancer?

The combination of Futibatinib and Durvalumab is unique because it pairs a targeted therapy (Futibatinib) with an immune checkpoint inhibitor (Durvalumab), potentially offering a novel approach for treating bladder cancer, especially for patients who have limited options after standard chemotherapy. ^{5 8 9 10 11}

What is the purpose of this trial?

This phase II trial tests how well the combination of futibatinib and durvalumab given before cystectomy works in treating patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based therapy. Cisplatin-based therapy is the standard of care for patients with MIBC. However, many patients cannot receive standard therapy due to poor renal function, peripheral neuropathy, poor functional status, or clinically significant heart failure. Futibatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Radical cystectomy is a surgery to remove all of the bladder as well as nearby tissues and organs. Giving futibatinib in combination with durvalumab before surgery may be an effective treatment option for patients with MIBC who are ineligible for cisplatin-based therapy.

Research Team

Yuanquan Yang

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for muscle-invasive bladder cancer patients who can't have the standard cisplatin-based therapy due to issues like poor kidney function, nerve damage, weak physical condition, or serious heart failure. Participants will undergo surgery to remove the bladder and should not have had prior treatments that would affect their eligibility.

Inclusion Criteria

My bladder cancer has been confirmed by a tissue examination.

Able to provide written informed consent

Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy), Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy), Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 100 days after the last dose of study therapy. Female subjects, if sexually active, must agree to use dual methods of contraception during the study and for a minimum period of 100 days after the last dose of the study drug, Women participants without childbearing potential should refrain from donating oocytes from screening through 100 days after the last dose of the study drug, Hemoglobin >= 9.0 g/dL, Absolute neutrophil count (ANC) > 1500 per mm^3, Platelet count >= 100 x 10^9/L, International normalized ratio (INR) or activated partial thromboplastin time (aPTT) < 1.5 × upper limit of normal (ULN), unless the patient is receiving anticoagulation therapy provided INR or PTT is within the therapeutic range of the intended anticoagulant therapy, Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN), Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal, Measured creatinine clearance (CL) > 30 mL/min or calculated creatinine CL > 30 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance

Exclusion Criteria

Has active cardiac disease, defined as: Myocardial infarction or unstable angina pectoris within 3 months of the first date of study therapy, Unstable arrhythmias, Decompensated heart failure, Average QT corrected by the Fridericia formula (QTcF) > 470 msec (males and females) (Note: If the QTcF is > 470 msec in the first electrocardiography [ECG], a total of 3 ECGs separated by >= 5 minutes should be performed. If the average of these 3 consecutive results for QTcF is =< 470 msec, the subject meets eligibility in this regard.), Has any medical condition that may prevent the patient from undergoing radical cystectomy, Must be at least 2 weeks beyond high-dose systemic corticosteroids; chronic steroid use up to 10 mg daily prednisone (or equivalent) is permitted, Has active autoimmune disease requiring systemic treatment with steroids (> 10 mg daily doses of prednisone or equivalent) or other immunosuppressive agents or any condition that, in the investigator's judgment, precludes treatment with durvalumab, Has a history or evidence of interstitial lung disease (ILD) or non-infectious pneumonitis, Has a known history of HIV-1/2 with detectable viral load and/or CD4 count < 300/mL within the previous 3 months, Has detectable hepatitis B virus (HBV) or hepatitis C virus (HCV) viral load polymerase chain reaction (PCR) if there is a known history of active hepatitis B or hepatitis C, History and/or current evidence of significant ectopic mineralization/calcification including but not limited to the soft tissues, kidneys, intestines, myocardium, and lungs, except calcified lymph nodes and asymptomatic coronary calcification, Current evidence of corneal or retinal disorder/ keratopathy including but not limited to bullous/ band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivitis etc., confirmed by ophthalmologic examination, Have current evidence of endocrine alterations of calcium/phosphate homeostasis (e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis) unless well controlled, Have used drugs that are dual p-glycoprotein and strong CYP3A inducers or inhibitors within 7 days prior to the first dose of the study drug, Has other concurrent medical or psychiatric conditions that, in the investigator's opinion, may be likely to confound study interpretation or prevent completion of the study procedure and follow-up examinations

My cancer has spread and can be measured.

I am not currently undergoing any form of cancer treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive futibatinib orally once daily and durvalumab intravenously on day 1 of each cycle. Treatment repeats every 28 days for up to 3 cycles.

12 weeks

3 visits (in-person)

Surgery

Participants undergo radical cystectomy within 4-12 weeks after treatment.

4-12 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up at 30 days, and then every 3 months for 2 years.

2 years

9 visits (in-person)

Treatment Details

Interventions

• Durvalumab
• Futibatinib

Trial Overview The study tests a combination of two drugs, futibatinib and durvalumab, given before bladder removal surgery (radical cystectomy). Futibatinib blocks enzymes needed for tumor growth while durvalumab targets tumor cells' ability to spread. The aim is to see if this drug combo works well as an alternative treatment.

Participant Groups

Group I: Treatment (futibatinib, durvalumab, radical cystectomy) Experimental Treatment 6 Interventions

Patients receive futibatinib PO QD on days 1-28 and durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo radical cystectomy within 4-12 weeks. Patients also undergo CT and MRI during screening and on the trial and also undergo blood sample collection on the trial.

Futibatinib is already approved in United States for the following indications:

Approved in United States as Lytgobi for:

• Treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements

Who Is Running the Clinical Trial?

Yuanquan Yang

Lead Sponsor

Trials

2

Recruited

60+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Findings from Research

Recent advancements in the treatment of advanced-stage urothelial carcinoma, a common type of bladder cancer, include the FDA approval of several immune checkpoint inhibitors such as nivolumab, pembrolizumab, and atezolizumab.

Despite these promising new therapies, clinicians face challenges in selecting the most effective treatment options for patients, particularly in determining the best first-line or second-line therapies to improve overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Changing Treatment Landscape for Metastatic Urothelial Carcinoma. Flaig, TW.[2019]

In a phase 3 trial involving 608 patients with advanced urothelial carcinoma, enfortumab vedotin significantly improved overall survival compared to standard chemotherapy, with a median survival of 12.88 months versus 8.97 months.

The treatment also resulted in longer progression-free survival (5.55 months vs. 3.71 months) while showing a similar incidence of treatment-related adverse events compared to chemotherapy, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. Powles, T., Rosenberg, JE., Sonpavde, GP., et al.[2023]

Bladder cancer is a leading cause of cancer-related deaths, with around 150,000 fatalities annually, and treatment options have not significantly changed in the last 20 years, relying mainly on cisplatin-based chemotherapy.

Recent advancements in understanding the genetics of urothelial tumors have led to the development of promising targeted therapies, particularly immune checkpoint inhibitors and FGFR-targeted treatments, which may offer new hope for patients with invasive bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutic targets in advanced urothelial carcinoma. Rouanne, M., Loriot, Y., Lebret, T., et al.[2022]

In a study of 160 patients with urothelial carcinoma, those with squamous differentiation (UCS) showed significantly worse outcomes when treated with immune checkpoint inhibitors (ICIs) and Enfortumab vedotin (EV), with median progression-free survival (mPFS) of 1.9 months for UCS compared to 4.8 months for pure urothelial carcinoma (pUC).

UCS patients also had a lower objective response rate (ORR) of 17% with EV compared to 70% in pUC patients, indicating that UCS is associated with increased resistance to these newer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Squamous Histology on Clinical Outcomes and Molecular Profiling in Metastatic Urothelial Carcinoma Patients Treated With Immune Checkpoint Inhibitors or Enfortumab Vedotin. Jindal, T., Zhang, L., Deshmukh, P., et al.[2023]

Durvalumab, an immune checkpoint inhibitor targeting Programmed Death Ligand 1, has shown significant efficacy and safety in treating urothelial carcinoma (UC), particularly in patients with disease progression after platinum-based chemotherapy.

The FDA approved durvalumab based on promising results from a Phase I/II study, highlighting its potential as a breakthrough treatment for advanced UC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the management of urothelial carcinoma: a short review on the emerging data and therapeutic potential. Baldini, C., Champiat, S., Vuagnat, P., et al.[2020]

Immunotherapy, particularly immune checkpoint inhibitors like atezolizumab and nivolumab, has received accelerated FDA approval for treating metastatic urothelial carcinoma, showing promise in improving patient outcomes.

The use of immunotherapy can lead to unique immune-related adverse events and response patterns, such as pseudoprogression, highlighting the need for careful management and the potential for predictive biomarkers to identify patients who will benefit most from these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy in metastatic urothelial carcinoma: focus on immune checkpoint inhibition. Siefker-Radtke, A., Curti, B.[2021]

In a review of 8 studies involving 1,666 patients with platinum-resistant urothelial cancer, anti-PD-1 therapy showed a higher objective response rate (22%) compared to anti-PD-L1 therapy (15%), indicating better antitumor activity for anti-PD-1.

Both anti-PD-1 and anti-PD-L1 therapies had comparable safety profiles and survival outcomes, with similar rates of treatment-related adverse events and overall survival at 12 months (43% for anti-PD-1 vs. 42% for anti-PD-L1).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Activity of Programmed Cell Death 1 Versus Programmed Cell Death Ligand 1 Inhibitors for Platinum-Resistant Urothelial Cancer: A Meta-Analysis of Published Clinical Trials. Li, Z., Li, X., Lam, W., et al.[2022]

Durvalumab, an immune-checkpoint inhibitor, has shown to be well-tolerated and effective in producing significant and lasting responses in patients with advanced urothelial bladder cancer, addressing a critical need for better treatment options.

The potential for combining durvalumab with other therapies may enhance treatment strategies for urothelial carcinoma, but further research is necessary to identify biomarkers that can predict which patients will benefit most from these immune-oncology treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in urothelial cancers. Lavaud, P., Hamilou, Z., Loriot, Y., et al.[2018]

In a study of patients with metastatic urothelial carcinoma, treatment with durvalumab led to significant improvements in health-related quality of life (HRQOL) and disease-related symptoms, as measured by the FACT-Bl and EORTC QLQ-C30 questionnaires.

The improvements in patient-reported outcomes were correlated with better tumor shrinkage and reductions in inflammatory biomarkers, suggesting that durvalumab not only helps manage cancer symptoms but may also positively influence systemic inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and inflammatory biomarkers in patients with locally advanced/metastatic urothelial carcinoma treated with durvalumab in phase 1/2 dose-escalation study 1108. O'Donnell, PH., Arkenau, HT., Sridhar, SS., et al.[2021]

Neoadjuvant chemotherapy has been shown to improve overall survival in patients with locally advanced muscle-invasive bladder cancer, but its use in clinical practice remains low due to ongoing controversies regarding adjuvant chemotherapy.

Recent advancements include the approval of atezolizumab, a checkpoint inhibitor, for metastatic bladder cancer, alongside other promising therapies targeting mutational signatures, such as VEGF and HER2-directed agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises. Aragon-Ching, JB., Trump, DL.[2017]

In a study of 86 patients with advanced/metastatic urothelial carcinoma, the combination of nivolumab and ipilimumab showed improved response rates, particularly in first-line treatment, with an objective response rate (ORR) of 45% compared to 27% in later lines of therapy.

Starting treatment with nivolumab alone was found to be inadequate for the aggressive nature of metastatic urothelial carcinoma, suggesting that dual checkpoint inhibition may be necessary for better outcomes in first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma. Grimm, MO., Schmitz-Dräger, BJ., Zimmermann, U., et al.[2022]

References

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

The Changing Treatment Landscape for Metastatic Urothelial Carcinoma. [2019]

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

Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Novel therapeutic targets in advanced urothelial carcinoma. [2022]

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

Impact of Squamous Histology on Clinical Outcomes and Molecular Profiling in Metastatic Urothelial Carcinoma Patients Treated With Immune Checkpoint Inhibitors or Enfortumab Vedotin. [2023]

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

Durvalumab for the management of urothelial carcinoma: a short review on the emerging data and therapeutic potential. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Immunotherapy in metastatic urothelial carcinoma: focus on immune checkpoint inhibition. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Activity of Programmed Cell Death 1 Versus Programmed Cell Death Ligand 1 Inhibitors for Platinum-Resistant Urothelial Cancer: A Meta-Analysis of Published Clinical Trials. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Durvalumab in urothelial cancers. [2018]

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

Patient-reported outcomes and inflammatory biomarkers in patients with locally advanced/metastatic urothelial carcinoma treated with durvalumab in phase 1/2 dose-escalation study 1108. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises. [2017]

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

Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma. [2022]