DETALIMOGENE VORAPLASMID for Non-muscle invasive bladder cancer (NMIBC)

Inclusion criteria

• {"criterion_text":"- 1.\tBCG-unresponsive NMIBC with Cis of the bladder, with or without coexisting papillary Ta/T1 tumor(s) who are ineligible for or have elected not to undergo cystectomy, and have experienced 1) persistent disease within 12 months of treatment or 2) a recurrence within 6 months of completion of adequate BCG therapy, 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 of 6 treatments) or maintenance (at least 2 of 3 doses), • Patients with BCG-unresponsive NMIBC may have received subsequent approved treatment for NMIBC that discontinued no more than 4 months of Screening, and • Cis must be documented or indicated by pathology at Screening or within 4 months of Screening (provided no therapy for Cis disease was given after the most recent biopsy). • Prior to enrollment, all patients should have TURBT of all visible papillary tumors.\n- 10.\tHepatic inclusion at Screening: • Total bilirubin must be ≤1.5 x the upper limit of normal (ULN). • Aspartate aminotransferase and alanine aminotransferase ≤2.5 x ULN, and alkaline phosphatase ≤2.5 x ULN.\n- 11.\tAdequate renal function with creatinine clearance >30 mL/min.\n- 12.\tProthrombin time and partial thromboplastin time 1.25 x ULN at Screening or within the therapeutic range if on anticoagulation therapy.\n- 13.\tMust have satisfactory bladder function with ability to retain study drug for a minimum of 60 minutes.\n- 14.\tPatient or legally authorized representative (LAR) must be willing and able to comply with all protocol requirements.\n- 15. Patient or LAR must be willing and able to give informed consent and any authorizations required by local law for participation in the study.\n- 16.\tAll specimens must be predominantly urothelial (transitional cell) and have less than 10% variant (e.g., sarcomatoid, squamous component) histology.\n- 2.\tPhase 2, Other than -Cohort 1: Inclusion for Cohorts 2A, 2B, OR 3:2 Only): Patient is to meet inclusion of Cohort 2A (BCG-naïve NMIBC with CIS), Cohort 2B (BCG exposed NMIBC with CIS), or Cohort 3 (BCG-unresponsive, HG Ta/T1 papillary disease without CIS), where: Cohort 2A (BCG-naïve NMIBC with CIS) OR Cohort 2B (BCG-exposed NMIBC with CIS): NMIBC with current CISis 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: 2Aa) BCG-naïve: no treatment with BCG or treatment with intravesical BCG > 5 years prior to enrollment (includes patients who have never been treated with BCG), but may be allowed to have received: a single dose of intravesical chemotherapy following TURBT (peri-operative) or who may have received a course of prior intravesical chemotherapy after TURBT. • Or 2B) BCG-exposed: incomplete BCG treatment (at least 1 dose and less than the 5 + 2 doses required for adequate dosing per cohort 1). or b) no treatment with BCG due to unavailability, but who have previously been treated with at least 1 dose of intravesical chemotherapy following transurethral resection of bladder tumor (TURBT), and •\tApproved treatment for NMIBC must have been discontinued prior to the Screening biopsy. • • CIS is must be documented or indicated by pathology within 4 months of or at Screening (without subsequent CISCis treatment). • Prior to enrollment, all patients should have TURBT of all visible papillary tumors. OR Cohort 3: BCG-unresponsive HG Ta/T1 papillary disease without CIS, where: • Ta/T1 tumor(s) who are ineligible for or have elected not to undergo cystectomy, and have experienced 1) persistent disease within 12 months of treatment or 2) a recurrence within 6 months of completion of adequate BCG therapy. • Adequate BCG regimen consists of at least 2 courses of BCG where the first course (induction) must have included at least 5 of 6 doses and the second course may have included a reinduction (at least 2 of 6 treatments) or maintenance (at least 2 of 3 doses). Notes: - In patients receiving a second induction course of BCG, this second induction course should ideally follow the first induction course within 4 months of first TURBT) if the repeat pathology shows non-invasive (Ta or less) or no disease.\n- 3.\tPatients who have previously been treated with an investigational or approved checkpoint inhibitor (e.g., pembrolizumab) are eligible for inclusion 30 days post-treatment (Phase 1) or 43 months post-treatment (Phase 2).\n- 4.\tMale or non-pregnant, non-lactating female, 18 years or older.\n- 5.Women of child-bearing potential must have a negative pregnancy test at Screening.\n- 6.\tFemale patients of child-bearing potential must be willing to consent to using highly effective birth control methods while on treatment and for 3 months (6 months in France) after their participation in the study ends; male patients are required to utilize a condom for the duration of the study treatment through 3 months post-dose.\n- 7.\tIn Phase 2, for patients with T1 lesions for Cohort 1 or Cohort 2 (CIS + T1) or Cohort 3 (T1), patients with HG T1 may be eligible after repeat-TURBT (ideally within 4 weeks of first TURBT) if the repeat pathology shows non-invasive (Ta or less) or no disease. Original or repeat TURBT must confirm that muscularis propria is present and uninvolved in the specimen. TURBT to occur within 4 months of Screening.\n- 8.\tPerformance Status: Eastern Cooperative Oncology Group 0, 1, and 2.\n- 9.\tHematologic inclusion at Screening: • Absolute neutrophil count >1,500/mm3. • Hemoglobin >9.0 g/dL. • Platelet count >100,000/mm3."}

Exclusion criteria

• {"criterion_text":"- 1. Active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Potential allowed exceptions include the following (others may be allowed under Sponsor approval): • Skin cancer (non-melanoma or melanoma) that is considered to be cured. • Non-invasive cervical cancer that is considered to be cured. • Adequately treated lobular LCIS and ductal CIS. • History of localized breast cancer and receiving antihormonal agents. • History of localized prostate cancer (N0M0) and receiving androgen deprivation therapy. • Localized prostate cancer (N0M0): - With a Gleason score of 6, treated within the last 24 months or untreated and under surveillance, - With a Gleason score of 3+4 that has been treated more than 6 months prior to full study Screening and considered to have a very low risk of recurrence, or - With a history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.\n- 8. History of severe asthma or other respiratory diseases (bronchiectasis, tuberculosis, interstitial pneumonia, occupational lung disease, sarcoidosis, etc.); patients with objective evidence of radiation pneumonitis, drug-associated pneumonitis, or severe impairment of pulmonary function.\n- 9. History of lung lobectomy.\n- 10. History of unresolved vesicoureteral reflux or an indwelling urinary stent.\n- 20. Known human immunodeficiency virus, Hepatitis B, or Hepatitis C infection.\n- 21. Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months).\n- 22. Hypersensitivity to any of the excipients of the study drug.\n- 23. Consideration by the Investigator that the patient is an unsuitable candidate for the study; due to a personal issue (e.g., inability to comply with protocol or relationship to study staff or Sponsor), mental health considerations, or other reason, that may impede successful study participation.\n- 11. History of unresolved hydronephrosis due to ureteral obstruction.\n- 12. Participation in any other research protocol involving administration of an investigational agent (not approved) within 30 days prior to Screening, or any prior treatment of NMIBC with any investigational gene or immunotherapy agent.\n- 13. History of external beam radiation to the pelvis or prostate brachytherapy within the last 2 months of Screening.\n- 18. Active interstitial cystitis on cystoscopy or biopsy.\n- 14. History of interstitial lung disease and/or pneumonitis in patients who have previously received a PD-1 or PD-L1 inhibitor therapy.\n- 15. Evidence of metastatic disease.\n- 16. History of difficult catheterization that in the opinion of the Investigator will prevent administration of EG-70.\n- 17. Current indwelling urinary catheter; however, intermittent catheterization is acceptable.\n- 19. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.\n- 2. Has had urothelial carcinoma outside of the urinary bladder (i.e., urethra, ureter, or renal pelvis). Ta/any T1, CIS of the upper urinary tract is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study. • Participant has tumor(s) involving the prostatic urethra (ductal or stromal). • N+ and/or M+ per CT/MR urography.\n- 3.\tHistory of prior T2/T3 urothelial carcinoma of the bladder.\n- 4. Concurrent treatment with any chemotherapeutic agent.\n- 5. History of partial cystectomy for urothelial carcinoma.\n- 6. Treatment with last therapeutic agent (including intravesical chemotherapy post-TURBT) within 30 days of Screening for Phase 1, and for Phase 2, within at least 30 days of Screening and prior to the Screening biopsy, with the exception of cytotoxic agents (e.g., Mitomycin C, gemcitabine) when administered as a single instillation immediately following a TURBT procedure which is permitted 14 days or more prior to beginning study treatment.\n- 7. Patients who have received systemic immunosuppressive medication including high-dose corticosteroids (e.g., systemic corticosteroids 20 mg prednisone or equivalent) within 4 weeks prior to Day 1 Notes: • Patients must not be receiving doses of 20 mg/day of prednisone or equivalent at the time of study entry or during the study and corticosteroids may not be used for premedication. • Intravesical therapy within 8 weeks prior to beginning study treatment, with the exception of cytotoxic agents (e.g., Mitomycin C, gemcitabine, doxorubicin, and epirubicin) when administered as a single instillation immediately following a TURBT procedure, which is permitted 14 days or more prior to beginning study treatment. • Patients with contrast dye allergies may be given a single dose of a systemic steroid in order to complete a contrast-enhanced computerized tomography (CT) urogram (CT urogram) for trial purposes. A 14-day minimum separation of the steroid dose and detalimogene dose must occur."}

Primary endpoints

• {"endpoint_text":"- Percentage of patients with cystoscopic CR at 48 weeks, based on cystoscopic exam, urine cytology, and biopsies with central laboratory confirmation of pathology.","definition_or_measurement_approach":"CR determined at 48 weeks by cystoscopic exam, urine cytology, and biopsies with central laboratory confirmation of pathology."}
• {"endpoint_text":"- Nature, incidence, relatedness, and severity of treatment-emergent AEs (as assessed by CTCAE v5.0).","definition_or_measurement_approach":"Adverse events assessed and graded using CTCAE v5.0 to capture nature, incidence, relatedness, and severity."}

Secondary endpoints

• {"endpoint_text":"- 1. Progression-free survival","definition_or_measurement_approach":"Time-to-event analysis measuring time from baseline to disease progression or death (as per protocol-defined criteria)."}
• {"endpoint_text":"- 2. Recurrence-free survival among responders.","definition_or_measurement_approach":"Time from response to documented recurrence among responders (as per protocol assessments)."}
• {"endpoint_text":"- 3. CR rate at 12, 24, 36, and 96 weeks, as well as CR rate by 24 and 48 weeks, and overall treatment CR including Maintenance Period.","definition_or_measurement_approach":"Cystoscopic and pathology-based CR rates assessed at specified timepoints (12, 24, 36, 48, 96 weeks) and during maintenance per protocol assessments."}
• {"endpoint_text":"- 4. Duration of response","definition_or_measurement_approach":"Measured from first documented CR to time of recurrence or progression."}
• {"endpoint_text":"- 5. Cystectomy-free survival.","definition_or_measurement_approach":"Time from baseline to cystectomy or death."}
• {"endpoint_text":"- 6. CR rate at week 48 as assessed by the Investigator","definition_or_measurement_approach":"Investigator-assessed CR at week 48 using cystoscopy, cytology, and biopsy as appropriate."}
• {"endpoint_text":"- 7. Health-related quality of life (EORTC Quality of Life Questionnaire Core 30 [QLQ-C30] and NMIBC-24)","definition_or_measurement_approach":"Patient-reported outcomes collected using EORTC QLQ-C30 and NMIBC-24 instruments per schedule."}
• {"endpoint_text":"- Other endpoints: Anti-drug antibodies, EG-70 plasmid DNA in urine and blood, levels of IL-12 gene expression and RIG-I activators and/or biomarkers in specimens","definition_or_measurement_approach":"Laboratory assessments for ADA, plasmid DNA in urine/blood, gene expression and biomarker analyses in tissue/urothelial/urine/blood samples per exploratory endpoint definitions."}

Other endpoints

• {"endpoint_text":"- Anti-drug antibodies, EG-70 plasmid DNA in urine and blood, levels of IL-12 gene expression and RIG-I activators and/or biomarkers in specimens","definition_or_measurement_approach":"Exploratory laboratory endpoints measuring ADA titers, plasmid DNA in urine and blood, IL-12 gene expression and RIG-I activators/biomarkers in urotelial, urine, blood and surgical pathology specimens."}

France

Earliest CTIS Part Ii Submission Date

17-10-2024

Latest Decision Or Authorization Date

14-05-2025

Processing Time Days

209

Number Of Sites

7

Number Of Participants

16

Italy

Earliest CTIS Part Ii Submission Date

17-09-2024

Latest Decision Or Authorization Date

13-05-2025

Processing Time Days

238

Number Of Sites

9

Number Of Participants

20

Spain

Earliest CTIS Part Ii Submission Date

09-10-2024

Latest Decision Or Authorization Date

22-07-2025

Processing Time Days

286

Number Of Sites

12

Number Of Participants

27

Germany

Earliest CTIS Part Ii Submission Date

16-10-2024

Latest Decision Or Authorization Date

10-12-2025

Processing Time Days

420

Number Of Sites

7

Number Of Participants

16

Primary sponsor

Full Name

Engene Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Canada

Contract research organisations

Name

Pivotal S.L.

Responsibilities

Multiple sponsor duties including study management/regulatory support (codes 1,12,13,2,5,7,8 as listed).

Name

Almac Clinical Services (Ireland) Limited / Almac Clinical Services Limited

Responsibilities

Depot, distribution, EU QP release and other operational services.

Name

Medpace Inc. / Medpace Reference Laboratories LLC / MEDPACE LABORATORIES

Responsibilities

Clinical operations, pharmacovigilance, sample storage and laboratory services.

Third parties

• {"country":"Belgium","full_name":"MEDPACE LABORATORIES","duties_or_roles":"samples storage; sponsor duties codes: 15, 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Almac Clinical Services (Ireland) Limited","duties_or_roles":"roles codes include 14; 15 (Depot, distribution, EU QP release)","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Pivotal S.L.","duties_or_roles":"sponsor duties codes: 1, 12, 13, 2, 5, 7, 8 (as provided)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"roles codes include 14; 15 (Depot, distribution, EU QP release)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Dcl Pathology LLC","duties_or_roles":"sponsor duties code: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Medpace Reference Laboratories LLC","duties_or_roles":"samples storage; sponsor duties code: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Medpace Inc.","duties_or_roles":"duties include clinical operations codes: 10; Pharmacovigilance; codes 3, 6, 8","organisation_type":"Pharmaceutical company"}