A Phase II, Randomized, Trial of Niraparib Versus Best Supportive Care as Maintenance Treatment In Patients With Locally Advanced Or Metastatic Urothelial Cancer Whose Disease Did Not Progress After First-line Platinum-based Chemotherapy

University of Turin, Italy20 sites in 1 country58 target enrollmentAugust 27, 2019

ConditionsUrothelial Carcinoma

InterventionsNiraparib Best supportive care

Overview

Phase: Phase 2
Intervention: Niraparib
Conditions: Urothelial Carcinoma
Sponsor: University of Turin, Italy
Enrollment: 58
Locations: 20
Primary Endpoint: Progression-free survival (PFS)
Status: Completed
Last Updated: 3 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The primary objective of the trial is to evaluate the efficacy of niraparib plus Best Supportive Care (BSC) vs. BSC alone, as maintenance treatment, in terms of prolongation of progression-free survival (PFS), in patients with locally advanced or metastatic urothelial cancer that obtained disease control (objective response or stable disease) with first-line platinum-based chemotherapy.

Detailed Description

This is a 2-arm, prospective, randomized (2:1 ratio), open-label, multi-centre, phase II study conducted in patients affected by unresectable, locally advanced or metastatic urothelial cancer receiving niraparib plus best supportive care versus best supportive care as maintenance therapy after a first-line platinum-based chemotherapy. The primary objective of the trial is to evaluate the efficacy of niraparib plus Best Supportive Care (BSC) vs. BSC alone, as maintenance treatment, in terms of prolongation of progression-free survival (PFS), in patients with locally advanced or metastatic urothelial cancer that obtained disease control (objective response or stable disease) with first-line platinum-based chemotherapy. Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors sensitivity is based on the presence of truncating and missense mutations in genes associated with the homologous recombination pathways. In The Cancer Genome Atlas dataset approximately 34% of bladder urothelial carcinoma harbored these mutations. Furthermore, in this study we plan to select a population potentially sensible to niraparib, by enrolling patients responding to platinum, indeed we know that there is a cross-sensitivity and a cross-resistance between platinum drugs and PARP inhibitors in urothelial carcinoma. PFS is commonly adopted as primary endpoint in randomized phase II trials. Randomized design for phase II trials has been increasingly adopted in recent years, to allow a formal comparison between experimental and standard treatment. This should lead to a better interpretation of the results obtained with the experimental treatment, that are in most cases difficult to interpret in the absence of controls. The sample size of the study is calculated with "relaxed" statistical criteria. The study design will verify if the experimental treatment (Niraparib) is promising enough to warrant a phase 3 trial for efficacy compared to observation. A total of 65 PFS events are needed to provide 80% power to detect an hazard ratio (HR) of 0.57 (1.75), corresponding to a median increase in progression-free survival from 4 to 7 months, with one-tailed alpha 0.1. With an accrual duration of 24 months, and additional 6 months of follow up after the completion of recruitment, 77 patient need to be randomized (26 assigned to control arm and 51 assigned to experimental arm) to obtain the 65 events needed. Sample size of the phase II trial is too small to plan a formal analysis of interaction of treatment efficacy with type of response at first line treatment (i.e. objective response vs. stable disease). However, type of response to first line treatment will be among stratification factor for randomization, so the 2 treatment groups will be balanced. Exploratory subgroup analysis of treatment efficacy in patient who have obtained objective response with first line and in patients who have obtained stable disease with first line will be performed.

Registry

clinicaltrials.gov

Start Date

August 27, 2019

End Date

September 1, 2021

Last Updated

3 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

University of Turin, Italy

Responsible Party

Principal Investigator

Massimo Di Maio

Associate Professor of Medical Oncology, Department of Oncology

University of Turin, Italy

Eligibility Criteria

Inclusion Criteria

•Participant must have histologically/cytologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium (transitional cell carcinoma either pure or mixed histology)
•Measurable disease (per RECIST v1.1) prior to the start of first-line chemotherapy
•Prior first-line chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of platinum containing regimen (cisplatin or carboplatin)
•No evidence of progressive disease following completion of first-line chemotherapy (i.e., ongoing complete response (CR), partial response (PR), or stable disease (SD) per RECIST v1.1 guidelines )
•Patients must be enrolled within 4 weeks of scans demonstrating stable disease/partial-complete response and no more than 6 weeks after receiving the last standard chemotherapy dose
•Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
•Participant must be ≥ 18 years of age
•Participant must have adequate bone marrow and organ function, defined as follows:
•Absolute neutrophil count ≥ 1,500/µL
•Platelets ≥ 100,000/µL

Exclusion Criteria

•Participant must not be simultaneously enrolled in any interventional clinical trial
•Participant must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.
•Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
•Participant must not have received radiation therapy encompassing \>20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
•Participant must not have a known hypersensitivity to niraparib components or excipients.
•Participant must not have been treated previously with a known PARP inhibitor agent
•Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
•Participant must not have received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
•Participant must not have experienced any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted \> 4 weeks.
•Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

Arms & Interventions

Experimental Arm

Patients assigned to experimental arm will receive Niraparib 300 mg or 200 mg daily (based on weight and platelet count) plus best supportive care (BSC), in 28-day cycles, until disease progression or unacceptable toxicity or death.

Intervention: Niraparib

Experimental Arm

Intervention: Best supportive care

Control Arm

Patients assigned to control arm will receive best supportive care alone, until disease progression or death.

Intervention: Best supportive care

Outcomes

Primary Outcomes

Progression-free survival (PFS)

Time Frame: Up to 3 years

PFS is defined as the time from the date of randomization to the earlier date of assessment of progression, or death by any cause in the absence of progression. Progression will be assessed following Response Evaluation Criteria In Solid Tumors (RECIST) criteria ( v.1.1 ), using investigator's review.