Maintenance With Niraparib In Patients With Advanced Urothelial Cancer After 1st-line Platinum-based Chemotherapy

Urothelial Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03945084
• Other study ID #: Meet-URO 12
• Status: Completed
• Phase: Phase 2
• Start date: August 27, 2019
• Est. completion date: September 1, 2021

Study information

• Verified date: May 2022
• Source: University of Turin, Italy
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 58
• Est. completion date: September 1, 2021
• Est. primary completion date: September 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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)

2. Measurable disease (per RECIST v1.1) prior to the start of first-line chemotherapy

3. 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)

4. 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 )

5. 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

6. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

7. Participant must be = 18 years of age

8. Participant must have adequate bone marrow and organ function, defined as follows:

• Absolute neutrophil count = 1,500/µL
• Platelets = 100,000/µL
• Hemoglobin = 9 g/dL
• Serum creatinine = 1.5 x upper limit of normal (ULN) or calculated creatinine clearance = 30 mL/min using the Cockcroft-Gault equation
• Total bilirubin = 1.5 x ULN (=2.0 in patients with known Gilberts syndrome) OR direct bilirubin = 1 x ULN
• Aspartate aminotransferase and alanine aminotransferase = 2.5 x ULN unless liver metastases are present, in which case they must be = 5 x ULN

9. Participant receiving corticosteroids is eligible if their dose is stable for least 4 weeks prior to initiating protocol therapy.

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

11. Female participant has a negative urine or 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
• 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.

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

13. 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.

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

15. Blood sample availability, to determine germline BRCA mutation status

16. Archived tumor tissue sample availability to determine homologous recombination deficiency (HRD) status

Exclusion Criteria:

1. Participant must not be simultaneously enrolled in any interventional clinical trial

2. Participant must not have had major surgery = 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.

3. 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.

4. 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.

5. Participant must not have a known hypersensitivity to niraparib components or excipients.

6. Participant must not have been treated previously with a known PARP inhibitor agent

7. Participant must not have received a transfusion (platelets or red blood cells) = 4 weeks prior to initiating protocol therapy.

8. 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.

9. Participant must not have experienced any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks.

10. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

11. Participant must not have a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent

12. Participant must not have a diagnosis of any other malignancy within 2 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast or of the cervix, low grade prostate cancer on surveillance without any plans for treatment intervention, or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms.

13. Participant must not have history of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan. However treated, stable and asymptomatic brain metastases are allowed.

Related Conditions & MeSH terms

• Carcinoma, Transitional Cell
• Urothelial Carcinoma

Intervention

Drug:
• Niraparib
Niraparib will be administered as a flat-fixed, continuous daily dose: =77 kg and =150,000 µL: 300 mg (3 X 100 mg capsules) daily <77 kg or <150,000 µL: 200 mg (2 X 100 mg capsules) daily* * For patients whose starting dose is 2 capsules once daily, escalation to 3 capsules once daily will be permitted if no treatment interruption or discontinuation will be required during the first 2 cycles of therapy

Other:
• Best supportive care
In both treatment arms, Best Supportive Care (BSC) is defined as a comprehensive assessment of symptoms, with timely application of symptom control measures, in order to maximize patient's quality of life. BSC does not include any active antitumoral treatment, and will be given according to local guidelines and the normal practice of each participating institution. BSC will include use of opioid analgesics, other supportive drugs, radiotherapy, administered with the exclusive aim of improving tumor symptoms (e.g. pain, haematuria, etc.), according to Investigator's judgment.

Locations

Country	Name	City	State
Italy	Azienda Sanitaria Locale CN2 - Alba e Bra	Alba
Italy	Azienda USL Toscana Sud Est, Ospedale San Donato	Arezzo
Italy	Istituto Tumori Giovanni Paolo II - IRCCS	Bari
Italy	Presidio Ospedaliero Senatore A.Perrino	Brindisi
Italy	Azienda Ospedaliero-Universitaria	Cagliari
Italy	Azienda Ospedaliera Cannizzaro	Catania
Italy	Azienda Ospedaliero-Universitaria Careggi	Firenze
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS	Meldola
Italy	Istituto Nazionale Tumori IRCCS	Milano
Italy	Istituto Nazionale Tumori - Fondazione G.Pascale IRCCS	Napoli
Italy	Istituto Oncologico Veneto IRCCS	Padova
Italy	ASL Piacenza, Dipartimento Oncologico	Piacenza
Italy	Azienda Ospedaliero-Universitaria Pisana, Ospedale Santa Chiara	Pisa
Italy	Ausl - Irccs	Reggio Emilia
Italy	Irccs Crob	Rionero In Vulture
Italy	Azienda Ospedaliera San Camillo Forlanini	Roma
Italy	Campus Biomedico	Roma
Italy	SCDU Oncologia Medica, AO Ordine Mauriziano	Torino
Italy	Presidio Ospedaliero Santa Chiara - APSS	Trento
Italy	AOU Santa Maria della Misericordia	Udine

Sponsors (2)

Lead Sponsor	Collaborator
University of Turin, Italy	Tesaro, Inc.

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	BReast CAncer gene (BRCA) mutation status (exploratory)	The study will collect blood sample from archival material of each patient at screening to assess BRCA mutation status.	Assessed on blood sample collected at baseline
Other	Homologous Recombination Deficiency (HRD) status (exploratory)	The study will collect tumor tissue from archival material of each patient at screening to assess HRD status	Assessed on tumor tissue collected at baseline
Primary	Progression-free survival (PFS)	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.	Up to 3 years
Secondary	Objective response rate (ORR)	ORR is defined as the percentage of patients with complete response (CR) or partial response (PR), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (v.1.1)	Up to 3 years
Secondary	Duration of response (DoR)	DoR is defined as the time between the date of documented response and the date of first documented sign of clinical or radiological progression	Up to 3 years
Secondary	Overall survival (OS)	OS is defined as the time from the date of randomization to the date of death by any cause	Up to 3 years
Secondary	Progression-free survival at 6 months	Progression-free survival at 6 month is defined as the rate of patients who are progression-free 6 months after randomization	6 months
Secondary	Treatment-emergent adverse events (TEAEs)	The study will collect information about the incidence of treatment-emergent AEs (TEAEs), coded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03	Up to 3 years
Secondary	Health-related quality of life	The study will collect information about patient health-related quality of life using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30. Multi-item scales are computed by calculating the mean raw scores of single items and transforming them linearly so that all scales range from 0 to 100. For single items, only linear transformation is performed. For functioning scales (i.e. those exploring physical, role, emotional, cognitive and social functioning and global health status), the higher the value the better the level of function; for symptoms scales and items, the higher the value the worse the severity of symptoms.	Up to 3 years

External Links

•   Abstract presented at ASCO GU 2022
•   Description of the results presented at ASCO GU 2022