Niraparib in Combination with Cabozantinib (XL184) in Patients with Advanced Urothelial Cancer (NICARAGUA)

NCT03425201 | Completed Phase 1

• 2 other identifiers: NICARAGUA2017-004367-12
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Urothelial Cancer

Outcome Measures

Primary Outcomes (2)

• Phase I: maximum tolerated dose

  Highest dose at which ≤1 out of 6 patients experience a DLT

  up to 1 month

• Phase II: progression free survival

  Time from the date of first dose of study treatment to the date of progression or death (from any cause).

  Up to 6 months

Secondary Outcomes (5)

• Incidence of Treatment-Emergent Adverse Events

  Up to 6 months

• Phase II: Objective Response Rate

  Up to 6 months

• Phase II: Disease Control Rate

  Up to 6 months

• Phase II: Duration of response

  Up to 6 months

• Phase II: Overall Survival

  Up to 6 months

Other Outcomes (1)

• Correlation of the activity of niraparib plus cabozantinib with the molecular profile of the tumor

  Up to 6 months

Study Arms (1)

Niraparib plus Cabozantinib

EXPERIMENTAL

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.

Drug: Niraparib plus Cabozantinib

Interventions

Niraparib plus Cabozantinib DRUG

Non-randomized trial will comprise 2 stages. A dose escalation phase will characterize the safety, tolerability, DLTs and MTD, of oral niraparib plus cabozantinib in patients with urothelial or renal cell carcinoma. Subsequently, the phase II will further evaluate the safety and antitumor activity of this combination in patients with urothelial carcinoma.

Niraparib plus Cabozantinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fundacion CRIS de Investigación para Vencer el Cáncer: lead
• Ipsen: collaborator
• GlaxoSmithKline: collaborator
• Apices Soluciones S.L.: collaborator

Study Sites (10)

Xarxa Assistencial Universitària de Manresa

Barcelona, Catalonia, Spain

Location

ICO Badalona

Badalona, Spain

Location

Hospital Clinic

Barcelona, Spain

Location

ICO Girona

Girona, Spain

Location

ICO L'Hospitalet

L'Hospitalet de Llobregat, Spain

Location

Hospital 12 de Octubre

Madrid, Spain

Location

Hospital Madrid Norte Sanchinarro

Madrid, Spain

Location

Hospital Ramon y Cajal

Madrid, Spain

Location

Hospital Marques de Valdecilla

Santander, Spain

Location

Instituto Valenciano de Oncología

Valencia, Spain

Location

MeSH Terms

Interventions

niraparib; cabozantinib

Study Officials

• Albert Font, MD

  ICO Badalona-Hospital Germans Trias i Pujol

  PRINCIPAL INVESTIGATOR

• Daniel Castellano, MD

  Hospital 12 de Octubre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open-label, multicenter, phase I/II dose-escalation study

Study Record Dates

• First Submitted: February 1, 2018
• First Posted: February 7, 2018
• Study Start: October 14, 2019
• Primary Completion: July 31, 2024
• Study Completion: July 31, 2024
• Last Updated: December 31, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

ES (10)