A Phase I-II Study to Evaluate the Efficacy and Safety of Niraparib in Combination With Cabozantinib (XL184) in Patients With Advanced Urothelial Cancer After Failure to First-line Platinum-based Chemotherapy

Who is this study for? Adult patients with Advanced Urothelial Cancer
What treatments are being studied? Niraparib+Cabozantinib
Status: Active, not recruiting
Location: See all (10) locations...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 1/Phase 2

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor. Its primary targets are Hepatocyte growth factor receptor protein (MET), vascular endothelial growth factor receptor 1-3 (VEGFR1-3), RET, AXL, FLT3 and KIT. Cabozantinib has been approved by the FDA for clinical treatment of progressive, metastatic medullary thyroid cancer. Recently published trials have demonstrated activity for cabozantinib in patients with advanced renal cell carcinoma and metastatic castration-resistant prostate cancer (mCRPC). Furthermore, in preclinical models of urothelial carcinoma (UC) of the bladder, cabozantinib has demonstrated the ability to inhibit tumor xenograft growth. It has been suggested that levels of soluble Met ectodomain (sMet) can be measured in the urine as a useful biomarker to monitor the efficacy of c-Met therapy in bladder cancer patients. Moreover, cabozantinib has demonstrated activity in heavily pretreated, advanced bladder cancer patients, with a response rate of 19.5% and manageable toxicities. In the phase I of this study it is proposed to evaluate DLTs of niraparib and cabozantinib combination and determine maximum tolerated dose (MTD) in patients with advanced urothelial or renal cell carcinoma. In the phase II it is proposed to make a preliminary evaluation of the efficacy of this combination in patients with urothelial cell carcinoma. Efficacy results will be correlated with genomic alterations related to c-Met and Poly [ADP-ribose] polymerase (PARP) inhibitor activity.

Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: No

• Phase I study:

• Histologically confirmed UC of the urinary tract or renal cell carcinoma

• Advanced or metastatic disease that is not amenable to curative surgery or radiation

• Patients must be willing to provide a tumor specimen prior to enrollment

• Previous therapy:

• i.Renal cell carcinoma: Prior tyrosine kinase inhibitor (TKI) and mechanistic target of rapamycin (mTOR) therapies is allowed ii.UC of the urinary tract: ≤2 previous chemotherapy regimens (including a platinum-based regimen)

• Measurable disease will not be required

• The remaining inclusion/exclusion criteria will be identical to the phase II study

• Recovery to at least grade I from toxicities related to prior treatment unless non clinically significant or stable on supportive therapy

• Phase II study:

• Age ≥18 years

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1

• Histologically confirmed UC of the bladder, urethra, ureter or renal pelvis (patients with mixed histologies will be allowed if urothelial is the predominant component).

• Patients must have formalin-fixed paraffin-embedded (FFPE) tumor samples available from the primary or recurrent cancer or agree to undergo fresh biopsy prior to study treatment initiation

• Advanced or metastatic disease that is not amenable to curative surgery or radiation

• Prior treatment with one prior cytotoxic regimen of platinum-based chemotherapy. If the only prior cytotoxic therapy was administered in perioperative (ie, neoadjuvant or adjuvant) settings, the patient will be eligible provided the interval from end of therapy to the diagnosis of metastatic disease is less than one year.

• Confirmed progressive disease after treatment with platinum-based chemotherapy

• At least one measurable disease site that has not been previously irradiated

• No prior therapy with Poly(ADP-ribose) polymerase (PARP) or c-Met inhibitors.

• Prior anti programmed cell death protein 1 (PD1) and anti programmed death-ligand 1 (PD-L1) therapy is permitted

• Adequate bone marrow, liver and renal functions as assessed by the following:

• Hemoglobin ≥9 g/dL; absolute neutrophil count ≥1500 cells/µL; platelets ≥100,000 g/µL;

• Total bilirubin ≤1.5 times upper limit of normal (ULN) (≤2.0 in patients with known Gilberts syndrome); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times ULN unless liver metastases are present, in which case they must be ≤5x ULN.

• Serum creatinine ≤1.5x ULN or creatinine clearance ≥30 mL/min using Cockcroft-Gault formula

• Urine protein/creatinine ratio (UPCR) ≤1 mg/mg (113.2 mg/mmol) creatinine or 24-hr urine protein of <1 g

• Life expectancy greater than 3 months

• Patients must be able to take oral medications

• Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.

• Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

• Female participant has a negative serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of non-childbearing potential. Non-childbearing potential is defined as follows (by other than medical reasons):

• ≥45 years of age and has not had menses for >1 year

• Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation a. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

• Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.

• Male participant agrees to use an adequate method of contraception starting with the first dose of study treatment through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

• Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent

Other Locations
ICO Badalona
Hospital Clinic
Xarxa Assistencial Universitària de Manresa
ICO Girona
ICO L'Hospitalet
L'hospitalet De Llobregat
Hospital 12 de Octubre
Hospital Madrid Norte Sanchinarro
Hospital Ramon y Cajal
Hospital Marques de Valdecilla
Instituto Valenciano de Oncología
Time Frame
Start Date: October 14, 2019
Estimated Completion Date: October 2025
Target number of participants: 20
Experimental: Niraparib plus Cabozantinib
Patients will receive niraparib and cabozantinib p.o. once daily in 28-day cycles.~In phase I, patients will be accrued to each dose level in cohorts of 6 patients. Escalation will continue until a dose-limiting toxicity (DLT) is observed or the highest dose-level is reached.~In phase II study patients will receive niraparib p.o. once daily and cabozantinib p.o. once daily in 28-day cycles at doses recommended in the phase I study.~If niraparib or cabozantinib need to be interrupted due to toxicity, patient can continue only with the other drug.
Leads: Fundacion CRIS de Investigación para Vencer el Cáncer
Collaborators: Ipsen, GlaxoSmithKline, Apices Soluciones S.L.

This content was sourced from clinicaltrials.gov

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