Futibatinib in Combination With Durvalumab Prior to Cystectomy for the Treatment of Muscle-Invasive Bladder Cancer Patients Who Are Ineligible for Cisplatin-based Therapy

Bladder Urothelial Carcinoma Clinical Trial

Official title:

A Phase II Trial of Futibatinib in Combination With Durvalumab Administered to Cisplatin-Ineligible Patients With Muscle-Invasive Bladder Cancer Before Cystectomy

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06263153
• Other study ID #: OSU-23329
• Secondary ID: NCI-2024-00002
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: June 1, 2024
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: Ohio State University Comprehensive Cancer Center
• Contact: The Ohio State Comprehensive Cancer Center
• Phone: 800-293-5066
• Email: OSUCCCClinicaltrials[@]osumc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

PRIMARY OBJECTIVE:

I. Determine the pathologic complete response rate of neoadjuvant futibatinib and durvalumab combination in patients with MIBC and fibroblast growth factor receptor (FGFR) overexpression.

SECONDARY OBJECTIVES:

I. Determine the safety of this neoadjuvant regimen. II. Assess the pathologic downstaging rate. III. Evaluate overall survival (OS) and progression free survival (PFS). IV. Evaluate delay in cystectomy.

EXPLORATORY OBJECTIVES:

I. Evaluate potential predictive biomarkers. II. Assess changes in the tumor microenvironment in pre- and post-treatment tumor samples in participants.

OUTLINE:

Patients receive futibatinib orally (PO) once daily (QD) on days 1-28 and durvalumab intravenously (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 computed tomography (CT) and magnetic resonance imaging (MRI) during screening and on the trial and also undergo blood sample collection on the trial.

After completion of study treatment, patients are followed up at 30 days, and then every 3 months for 2 years.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 24
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Able to provide written informed consent

• Female or male subjects >= 18 years old

• FGFR1, 2, or 3 overexpression as defined by a score of 3+ or 4+ on ribonucleic acid (RNA) in-situ hybridization (RNAScope assay)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Histologically confirmed urothelial carcinoma of the bladder

• Mixed histologies are permitted if urothelial carcinoma is the predominant histology ( >= 50%)

• Clinical stage T2-T4a, N0, M0 disease by trans urethral removal of bladder tumour (TURBT) and imaging studies (stage II-IIIA per American Joint Committee on Cancer [AJCC] 2018)

• Refuse or ineligible for cisplatin-based neoadjuvant chemotherapy as defined by any of the following:

• ECOG performance status (PS) > 1

• Creatinine clearance (calculated or measured) < 60 mL/min as measured by the Cockcroft-Gault formula

• Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0) grade >= 2 hearing loss

• CTCAE v 5.0 grade >= 2 neuropathy

• New York Heart Association (NYHA) class > II cardiac dysfunction

• Treatment with anti-PD-1/PD-L1 therapy for non-muscle invasive bladder cancer is permitted if it is completed > 3 months before registration

• Eligible for radical cystectomy by the following:

• Fit and planned for radical cystectomy according to local guidelines

• Archival tissue submission must be 30 unstained slides. If archival tissue is unavailable, the patient must undergo cystoscopy and biopsy. The tumor sample must contain at least 20% viable tumor

• 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:

• Women who are pregnant or breastfeeding

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks before the first dose of trial treatment

• Has upper tract urothelial carcinoma

• Has small-cell carcinoma component on histology

• Evidence of measurable nodal or metastatic disease

• Concurrent anticancer therapy (e.g., chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, intravesical therapy, or tumor embolization)

• Received prior systemic chemotherapy for muscle-invasive bladder cancer at any time in the patient's medical history

• Participation in any other study in which receipt of an investigational study drug or device occurred within 28 days or 5 half-lives (whichever is longer) before the first dose. For investigational agents with long half-lives (e.g., 5 days or more), enrollment before the fifth half-life requires medical monitor approval

• Has received anti-PD-1/PD-L1 therapy or FGFR inhibitor previously for MIBC, except if used in earlier stage urothelial carcinoma such as non-muscle invasive bladder cancer (NMIBC) and completed > 3 months prior to registration

• Underwent major surgery and has not recovered adequately from the intervention's toxicity and/or complications before starting therapy

• Has an active second malignancy except for low-risk localized prostate cancer on "watch and wait"

• Subjects with a history of malignancy that has been completely treated, with no evidence of active cancer for 2 years before enrollment, or subjects with surgically cured tumors with a low risk of recurrence are allowed to enroll at principal investigator (PI's) discretion

• 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

Related Conditions & MeSH terms

• Bladder Urothelial Carcinoma
• Carcinoma
• Muscle Invasive Bladder Carcinoma
• Stage II Bladder Cancer AJCC v8
• Stage IIIA Bladder Cancer AJCC v8
• Urinary Bladder Neoplasms

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT

Biological:
• Durvalumab
Given IV

Drug:
• Futibatinib
Given PO

Procedure:
• Magnetic Resonance Imaging
Undergo MRI
• Radical Cystectomy
Undergo radical cystectomy

Locations

Country	Name	City	State
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Yuanquan Yang	Gateway for Cancer Research

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete pathologic response rate	Will be defined by a percentage of participants with ypT0N0 by pathologic responses.	1 day (At the time of radical cystectomy)
Secondary	Incidence of adverse events (AEs)	Will be assessed by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V 5.0). The frequency and severity of AEs and the tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.	Up to 30 days after cystectomy/end of treatment
Secondary	Pathologic down-staging rate to non-muscle invasive disease	Will be define as residual ypT0/1/a/isN0 on radical cystectomy specimens.	1 day (At the time of radical cystectomy)
Secondary	Overall survival	The Kaplan-Meier method will be used for survival analysis with 95% confidence intervals.	Time from the start date of treatment to death on the study from any cause, assessed up to 2 years
Secondary	Progression free survival	The Kaplan-Meier method will be used for survival analysis with 95% confidence intervals.	Time from the start date of treatment to the first occurrence of disease progression or death on the study from any cause, whichever occurs earlier, assessed up to 2 years
Secondary	Frequency and severity of adverse events, including delay in cystectomy	Will assess the frequency and severity of AEs, including delay in cystectomy for > 8 weeks from the end of neoadjuvant treatment due to treatment-related AEs. AEs will be evaluated per CTCAE V 5.0 criteria and will be tabulated by preferred term and system organ class for all events.	Up to 60 days after cystectomy/end of treatment

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