LEGEND Study: EG-70 in NMIBC Patients BCG-Unresponsive and High-Risk NMIBC Incompletely Treated With BCG or BCG-Naïve

Официальное название

A Phase 1/2 Study of EG-70 as an Intravesical Administration to Patients With BCG Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) and High-Risk NMIBC Patients Who Are BCG Naïve or Received Incomplete BCG Treatment

Обзор

This study will evaluate the safety and efficacy of intravesical administration of detalimogene (EG-70) in the bladder and its effect on bladder tumors in patients with NMIBC. This study study consists of two phases; a Phase 1 dose-escalation to establish safety and recommended the phase 2 dose, followed by a Phase 2 study to establish how effective the treatment is. The Study will include patients with: NMIBC with CIS for whom BCG therapy is unresponsive, and other high risk patients with NMIBC. A Substudy will include a surfactant bladder rinse prior to the instillation of detalimogene in patients with NMIBC with CIS for whom BCG therapy is unresponsive.

Подробное описание

EG-70 is a novel non-viral gene therapy. EG-70 is designed to elicit a local immune response following delivery of the study gene therapy to the bladder urothelium. This approach of local administration through bladder instillation has the potential to induce a potent immune response exclusively at the site of the tumor, resulting in greater therapeutic benefit while reducing undesirable systemic toxicity.

Eligible BCG-unresponsive NMIBC with CIS patients will be enrolled in Phase 1, and Cohort 1 of Phase 2. Eligible high-risk NMIBC patients will be enrolled in Phase 2 into separate cohorts include: BCG-naïve patients or BCG-exposed (incompletely treated) patients with Carcinoma in situ (CIS), and BCG-unresponsive HG Ta/T1 papillary disease without CIS.

Patients will be treated for up to four 12-week cycles of study drug instillation doses and assessments with follow up assessments. Patients with complete response following four treatment cycles will enter up to 8 maintenance treatment cycles.

Вмешательства

• Препарат EG-70 (phase 1)
  Patients will receive up to four cycles of EG-70 administered as a bladder instillation of a 50 mL volume of study drug via catheter with a targeted retention time of 60 minutes.One cycle lasts approximately 12 weeks and consists of either a 2-dose (Day 1 and Day 8) or 4-dose (Day 1, Day 8, Day 29 and Day 36) regimen.
• Препарат EG-70 (phase 2) Master Protocol
  Under the Treatment Period, patients will receive 4 instillations per cycle for up to 4 cycles, of EG-70 at the RP2D defined in Phase 1, administered as a bladder instillation of a 50 mL volume of study drug via catheter with a targeted retention time of 60 minutes. One cycle lasts approximately 12 weeks. For Maintenance treatment 2 doses of EG-70 will be administered as a bladder instillation per 12-week cycle.
• Препарат Surfactant Bladder Pre-Rinse and EG-70 (Substudy)
  Patients will receive via catheter a 50 mL volume of a 5-minute bladder rinse immediately prior to administration of 50 mL of detalimogene voraplasmid (EG-70) at the RP2D for 30 minutes. During the Treatment Period, patients will receive 4 instillations per cycle for up to 4 cycles of the sudy intervention. One cycle lasts approximately 12 weeks. For Maintenance treatment, 2 doses of the study intervention will be administered as a bladder instillation per 12-week cycle.

Первичные конечные точки

• Phase 1: Nature, incidence, relatedness, and severity of all AEs and SAEs according to the CTCAE v5.0. [Срок оценки: Approximately 2 years]
• Phase 2: Percentage of patients with cystoscopic CR at any time, based on exam, urine cytology and appropriate biopsies. [Срок оценки: Approximately 24 weeks]
• Phase 2: Nature, incidence, relatedness, and severity of treatment emergent adverse events (as assessed by CTCAE v5.0) [Срок оценки: Approximately 3 years]

Вторичные конечные точки (6)

• Phase 1: The number of patients who experience a DLT through the end of Cycle 1 [Срок оценки: Approximately 12 Weeks]
• Phase 1: CR rate to EG-70 by cystoscopy at approximately 12 weeks. [Срок оценки: Approximately 12 weeks]
• Phase 2: Duration of response of the responding patients [Срок оценки: Approximately 3 years]
• Phase 2: Progression-free survival (PFS) [Срок оценки: Approximately 3 years]
• Phase 2: CR rate at 12, 24, 36, and 96 weeks [Срок оценки: Approximately 12, 24, 36, and 96 weeks]
• Phase 2: Quality of Life Assessment [Срок оценки: 24 weeks]

Критерии участия

Критерии включения

BCG-unresponsive Patients:

• BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without coexisting papillary Ta/T1 tumors who are ineligible for or have elected not to undergo cystectomy, and have experienced CIS disease within 12 months of treatment where: adequate BCG regimen consists of at least 2 courses of BCG where the first course (induction) must have included at least 5 or 6 doses and the second course may have included a re-induction (at least 2 treatments) or maintenance (at least 2 doses), and Cis must be documented or indicated by pathology

Phase 2 Only:

• BCG-Naïve or BCG-incompletely treated Patients with CIS or BCG-unresponsive, HG Ta/T1 papillary disease without CIS:

-NMIBC with current Cis of the bladder, with or without coexisting papillary Ta/T1 NMIBC tumor(s), who are ineligible for or have elected not to undergo cystectomy, where: either: cohort 2a) no treatment with BCG but may have previously been treated with at least 1 dose of intravesical chemotherapy following transurethral resection of bladder tumor (TURBT) and Cis must be documented or cohort 2b) indicated by pathology incomplete BCG treatment (at least 1 dose and less than the 5+2 doses required for adequate dosing per Cohort 1) or cohort 3) patients who are BCG-unresponsive following adequate treatment, with HG Ta/T1 papillary disease without CIS.

All Patients with High Grade NMIBC:

• Patients who have previously been treated with a checkpoint inhibitor and failed treatment are eligible for inclusion 30 days post-treatment (Phase 1) or 3 months post-treatment (Phase 2).
• Male or non-pregnant, non-lactating female, 18 years or older.
• Women of childbearing potential must have a negative pregnancy test at Screening.
• Female patients of childbearing potential must be willing to consent to using highly effective birth control methods; Male patients are required to utilize a condom for the duration of the study treatment through 3 months post-dose.
• In Phase 2, for patients with T1 lesions may be eligible after repeat TURBT if pathology shows non-invasive (Ta or less) or no disease.
• Performance Status: Eastern Cooperative Oncology Group 0, 1, and 2.
• Hematologic inclusion: a. Absolute neutrophil count >1,500/mm3. b. Hemoglobin >9.0 g/dL. c. Platelet count >100,000/mm3.
• Hepatic inclusion: a. Total bilirubin must be ≤1.5 x the upper limit of normal (ULN). b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤2.5 x ULN.
• Adequate renal function with creatinine clearance >30 mL/min
• Prothrombin time and partial thromboplastin time ≤1.25 x ULN or within the therapeutic range if on anticoagulation therapy.
• Must have satisfactory bladder function with ability to retain study drug for 60 minutes.

Критерии исключения

• Active malignancies (i.e., progressing or requiring treatment change in the last 24 months). Exceptions allowed under Sponsor review.
• Concurrent treatment with any chemotherapeutic agent.
• History of partial cystectomy.
• Treatment with last therapeutic agent (including intravesical chemotherapy post-TURBT) within 30 days of Screening (prior to the screening biopsy).
• Patients who have received systemic immunosuppressive medication including high-dose corticosteroids.
• History of severe asthma or other respiratory diseases.
• History of unresolved vesicoureteral reflux or an indwelling urinary stent.
• History of unresolved hydronephrosis due to ureteral obstruction.
• Participation in any other research protocol involving administration of an investigational agent within 30 Days prior to screening or any prior treatment of NMIBC with any investigational gene or immunotherapy agent.
• History of external beam radiation to the pelvis or prostate brachytherapy within the last 12 months.
• History of interstitial lung disease and/or pneumonitis in patients who have previously received a PD-1 or PD-L1 inhibitor therapy.
• Evidence of metastatic disease.
• History of difficult catheterization that in the opinion of the Investigator will prevent administration of EG-70.
• Active interstitial cystitis on cystoscopy or biopsy.
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
• Known human immunodeficiency virus, Hepatitis B, or Hepatitis C infection.
• Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months).
• Hypersensitivity to any of the excipients of the study drug.

Exclusionary for Bladder Rinse cohorts: known allergy to polidocanol

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 50 центров

• The University of Alabama at Birmingham Clinical Research Unit (CRU) — Birmingham
• Mayo Clinic — Scottsdale
• Urological Associates of South Arizona — Tucson
• Arkansas Urology — Little Rock
• University of California - Irvine Medical Center — Irvine
• UC San Diego Moores Cancer Center — La Jolla
• USC/Norris Comprehensive Cancer Center — Los Angeles
• Tower Urology — Los Angeles
• … и ещё 42 центра

Испания · 12 центров

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Франция · 7 центров

• CHU d'Angers — Angers
• CHU Bordeaux Pellegrin — Bordeaux
• lnstitut Bergonie 229 Cour de l'Argonne — Bordeaux
• CHU de Lille — Lille
• Hospices Civils de Lyon — Lyon
• Hopital Bichat Claude-Bernard — Paris
• CHU de Rauen- Hopital Charles Nicolle — Rouen

Италия · 7 центров

• Clinic Unit of Urology, IRCCS Ospedale San Raffaele — Milan
• Istituto Europeo di Oncologia — Milan
• Istituto Nazionale Tumori IRCCS Fondazione G. Pascale — Naples
• Fondazione Policlinico Universitario "A.Gemelli" IRCCS, Largo — Rome
• Azienda Ospedaliero-Universitaria Sant'Andrea — Rome
• UOC Urologia, IFO- lstituto Tumori "Regina Elena" — Rome
• Ospedelae Molinette San Giovanni Battista Di Torino — Torino

Канада · 6 центров

• Prostate Cancer Centre — Calgary
• Vancouver Prostate Centre — Vancouver
• Nova Scotia Health Authority — Halifax
• University Health Network, Princess Margaret Cancer Centre — Toronto
• McGill University Health Center - Glen site — Montreal
• CHUM Centre Hospitalier de l Universite de Montreal — Montreal

Германия · 6 центров

• Klinik fur Urologie, Uro-Onkologie, spezielle urologische und Roboter-assistierte Chirurgi — Cologne
• Urologicum Duisburg — Duisburg
• Universitaetsklinikum Erlangen — Erlangen
• Urologie Neandertal Mettmann — Mettmann
• Studienpraxis Urologie — Nürtingen
• Universitaetsklinikum Tubingen — Tübingen

South Korea · 5 центров

• Seoul National University Bundang Hospital — Seongnam
• … и ещё 4 центра

Тайвань · 5 центров

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Австралия · 3 центра

• Sydney Adventist Hospital — Wahroonga
• Gold Coast University Hospital — Southport
• Icon Cancer Center Windsor Gardens — Windsor Gardens

Великобритания · 1 центр

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Идентификаторы

NCT: NCT04752722 · EG-70-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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