IRB Study Number 25-153
Status Recruiting
Phase Phase 2
Locations Fairview Hospital, Hillcrest Hospital, Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives
Determine the pCR rate of neoadjuvant futibatinib and durvalumab combination in patients with MIBC and FGFR overexpression.
Secondary Objectives
Determine the safety of this neoadjuvant regimen.
Assess the pathologic downstaging rate.
Evaluate OS and PFS.
Evaluate delay in cystectomy.
Inclusion Criteria
Able to provide signed informed consent
Female or male subjects ≥18 years old
Body weight >30 kg
FGFR1, 2, or 3 overexpression as defined by a score of 3+ or 4+ on RNA ISH (RNAScope assay)
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Histologically confirmed urothelial carcinoma of the bladder
o Mixed histologies are permitted if urothelial carcinoma is the predominant histology (≥50%).
Clinical stage T2-T4a, N0, M0 disease by TURBT and imaging studies (Stage II-IIIA per AJCC 2017)
Refuse or ineligible for cisplatin-based NAC as defined by any of the following:
o ECOG PS >1
o Creatinine clearance (calculated or measured) <60 mL/min as measured by the Cockcroft-Gault formula
o CTCAE v5.0 grade >2 hearing loss
o CTCAE v5.0 grade >2 neuropathy
o NYHA class >II cardiac dysfunction
Treatment with anti-PD-1/PD-L1 therapy for non-muscle invasive bladder cancer (NMIBC) is permitted if it is completed >3 months before registration.
Eligible for radical cystectomy by the following:
o Fit and planned for radical cystectomy according to local guidelines.
Archival TURBT 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. Refer to section 9.8 for the definition of post-menopause.
Female subjects of childbearing potential and male subjects must be willing to completely abstain or agree to use a highly effective method of contraception (i.e., less than 1% failure rate), from the time of signing informed consent and for the duration of study participation through 90 days following the last dose of study drug. Refer to section 9.8 for the contraception guidelines.
Adequate organ function laboratory values as defined below:
o Hemoglobin ≥9.0 g/dL
o Absolute neutrophil count (ANC) >1500 per mm3
o Platelet count ≥100 × 109/L
o International normalized ratio (INR) or activated partial thromboplastin time (aPTT) <1.5× ULN, unless the patient is receiving anticoagulation therapy provided INR or PTT is within the therapeutic range of the intended anticoagulant therapy
o Serum bilirubin ≤1.5× institutional upper limit of normal (ULN)
o AST (SGOT)/ALT (SGPT) ≤2.5× institutional upper limit of normal
o Phosphorus ≤ institutional upper limit of normal
o Measured creatinine 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:
Males: Creatinine CL = weight (kg) × (140 – age) (mL/min) 72 × serum creatinine (mg/dL)
Females: Creatinine CL (mL/min) = weight (kg) × (140 – age) 72 × serum creatinine (mg/dL)
Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
Must have a life expectancy of at least 12 weeks.
Exclusion Criteria
Women who are pregnant or breastfeeding
Male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy
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 MIBC at any time in the patient’s medical history
Has received anti-PD-1/PD-L1 therapy or FGFR inhibitor previously for MIBC, except if used in earlier stage urothelial carcinoma such as NMIBC and completed >3 months prior to registration
a. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
b. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
c. Must not have experienced a ≥grade 3 irAE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
d. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if rechallenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day.
Underwent major surgery within 28 days 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 PI’s discretion (e.g., adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease and effectively treated carcinoma in situ without evidence of disease).
Has active cardiac disease, defined as:
o Myocardial infarction or unstable angina pectoris within 3 months of the first date of study therapy
o Unstable arrhythmias
o Decompensated heart failure
o Uncontrolled hypertension and unstable angina pectoris
o Average QTcF ≥470 msec (males and females) (Note: If the QTcF is ≥470 msec in the first 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), intranasal, inhaled, topical steroids, local steroid injections (e.g., intra articular injection), steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are permitted.
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
o Patients with vitiligo or alopecia
o Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
o Any chronic skin condition that does not require systemic therapy
o Patients without active disease in the last 5 years may be included but only after consultation with the study physician
o Patients with celiac disease controlled by diet alone
Has a known history of HIV-1/2 with detectable viral load and/or CD4 count <300/mL within the previous 3 months or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
Has detectable HBV or HCV viral load 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. The examples of dual p-glycoprotein and strong CYP3A inducers or inhibitors are included but not limited to those listed in section 16.2.
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.
Known allergy or hypersensitivity to study drugs or any excipient.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine while receiving the investigational product (IP) and up to 90 days after the last dose of IP.
Has other uncontrolled illnesses, ongoing or active infection, or serious chronic gastrointestinal conditions associated with diarrhea
Any unresolved toxicity CTCAE grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
a. Patients with grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician
- History of allogenic organ transplantation.
