Phase 1/2 Evaluation of Detalimogene Voraplasmid in BCG-Unresponsive and High-Risk Non-Muscle Invasive Bladder Cancer Patients

Trial ID: 2024-512900-20-00
Protocol: EG-70-101
Sponsor: Engene Inc.

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Diseases & Conditions

Bladder cancer

Objectives

The primary objective of this study is to evaluate the **efficacy** of EG-70, determined by Complete Response (CR), at 48 weeks in each cohort separately. Additionally, the study aims to assess the safety of the recommended Phase 2 dose (RP2D) of EG-70 when administered via intravesical instillation in patients with Bacillus Calmette-Guérin (BCG)-unresponsive **non-muscle invasive bladder cancer (NMIBC)** and in patients with high-risk NMIBC who are BCG-naïve or have received incomplete BCG treatment. This evaluation is clinically relevant as it seeks to provide an alternative therapeutic option for patients with limited response to BCG, potentially improving treatment outcomes and patient safety.

Secondary objectives include:

Evaluating the disease-free survival rate in each cohort separately.
Assessing the CR at the efficacy analysis following each cycle and the duration of CR in each cohort separately.
Evaluating the Quality of Life Assessment in each cohort separately.

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on patient survival, response durability, and overall quality of life, which are critical factors in the management of NMIBC.

Participants

The clinical trial involves a total of **211 participants** diagnosed with **non-muscle invasive bladder cancer (NMIBC)**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on specific inclusion criteria, including those with BCG-unresponsive NMIBC or high-risk NMIBC who are BCG-naïve or have received incomplete BCG treatment. The trial population is characterized by individuals who are ineligible for or have elected not to undergo cystectomy. Participants must have satisfactory bladder function and meet specific hepatic, renal, and hematologic parameters. Lifestyle considerations such as diet and physical activity are not specified. The trial includes a vulnerable population, and all participants are required to provide informed consent. The study aims to evaluate the efficacy and safety of EG-70 administered by intravesical instillation.

Plans and Procedures

The clinical trial is designed as a **Phase 1/2** study to evaluate the efficacy and safety of **detalimogene voraplasmid** administered via intravesical instillation in patients with **non-muscle invasive bladder cancer (NMIBC)**. The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The primary objective is to assess the complete response (CR) rate at 48 weeks, with secondary endpoints including progression-free survival, recurrence-free survival, and health-related quality of life. The trial is expected to conclude by October 31, 2028, with recruitment starting on February 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as bladder function, renal and hepatic function, and prior treatment history. Following successful screening, participants will be enrolled and randomized into treatment cohorts. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. These visits will include cystoscopic exams, urine cytology, and biopsies to confirm pathology. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the long-term efficacy and safety of the treatment.

The expected length of participant involvement is approximately 48 weeks, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. Participants must comply with all protocol requirements, including the ability to retain the study drug for a minimum of 60 minutes during administration. The study aims to provide comprehensive data on the therapeutic potential of detalimogene voraplasmid in treating NMIBC, contributing valuable insights into its clinical application.

Treatment

The clinical trial involves the administration of **detalimogene voraplasmid**, an experimental medication developed by ENGENE INC. This investigational product is a **solution for infusion** and is administered via **intravesical instillation**. The active substance, detalimogene voraplasmid, is a nucleic acid-based therapy, specifically a DNA plasmid encoding Interleukin 12. The pharmaceutical form is a polymer-encapsulated, non-integrative DNA plasmid expressing RIG-I agonists and human IL-12, designed for non-viral delivery. The product is identified by the sponsor product code EG-70 and is classified under the ATC code L03AC, which pertains to interleukins. The trial aims to evaluate the efficacy and safety of this treatment in patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) and high-risk NMIBC patients who are BCG-naïve or have received incomplete BCG treatment.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies as deemed necessary by the clinical investigators. However, no specific non-experimental treatments, such as placebo or comparator treatments, are explicitly mentioned in the trial data. The dosing schedule and participant compliance monitoring details are not provided in the available data. The trial's primary objective is to assess the complete response at 48 weeks and evaluate the safety of the recommended phase 2 dose (RP2D) of EG-70 in the specified patient cohorts.

Efficacy

Efficacy in this clinical trial will be assessed primarily by evaluating the **Complete Response (CR)** rate at 48 weeks. This will be determined through a combination of cystoscopic examination, urine cytology, and biopsies, with central laboratory confirmation of pathology. The primary endpoints include the percentage of patients achieving cystoscopic CR at 48 weeks and the nature, incidence, relatedness, and severity of treatment-emergent adverse events, as assessed by CTCAE v5.0.

Secondary endpoints will further evaluate efficacy through various measures, including progression-free survival, recurrence-free survival among responders, and CR rates at multiple timepoints (12, 24, 36, and 96 weeks), as well as overall treatment CR including the Maintenance Period. Additional assessments will include the duration of response, cystectomy-free survival, and health-related quality of life, measured using the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and NMIBC-24. Other endpoints will involve the analysis of anti-drug antibodies, EG-70 plasmid DNA in urine and blood, and levels of IL-12 gene expression and RIG-I activators and/or biomarkers in specimens.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1.BCG-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 at the time of enrollment, 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 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). In addition, the qualifying course of BCG must have consisted of full dose BCG (i.e., 50 mg per dose): at least 5 of the 6 doses of the first course (induction) must be full dose BCG and at least 2 doses of the second course (maintenance or reinduction) must be full dose BCG. Adequacy of the BCG regimen to be reviewed determined by the Investigator in conjunction with the Sponsor. Notes: -In patients receiving a second induction course of BCG, this second induction course should ideally follow the first induction course within 6 months of completion of the first course of BCG. Additionally, there should ideally be no disease free interval between the first induction BCG course and the second BCG, and patients should not have received non-BCG therapies (e.g., intravesical gemcitabine). -In patients receiving a maintenance course of BCG, the maintenance course should ideally follow the induction course within 6 months and can have a disease-free interval. However, patients should NOT have received any intervening intravesical therapies (e.g., intravesical gemcitabine). -Completion of qualifying BCG treatment (e.g., “5+2” minimum exposure) within 12 months of the initial qualifying dose of BCG (e.g., induction and initial maintenance or reinduction cycle must be completed within approximately 12 months, with Sponsor review). • Patients with BCG-unresponsive NMIBC may have received subsequent approved treatment for NMIBC (i.e., other than BCG) for NMIBC that was discontinued prior to the Screening biopsy. • 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.
2.Phase 2, Other than Cohort 1: Inclusion for Cohorts 2A, 2B, OR 3: 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:Patients are ineligible for or have elected not to undergo cystectomy at the time of enrollment. Cohort 2A (BCG-naïve NMIBC with CIS) OR Cohort 2B (BCG-exposed NMIBC with 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: 2A) BCG-naïve: no previous treatment with BCG or treatment with intravesical BCG > 5 years prior to enrollment but may be allowed to have received a single dose of intravesical chemotherapy at the time of TURBT (perioperative) or who may have received a course of prior intravesical chemotherapy after TURBT. Where: -patients are in countries/ regions impacted by BCG shortages or unavailability, or - patients may have exhausted Standard of Care (SoC) options, may be intolerant to, or have been offered and refused, SoC, or the patient’s treating physician considers that the lack of SoC treatment is not detrimental for the patient (and where patient consents to investigational medicinal product study). • Or 2B) BCG-exposed: includes incomplete BCG treatment (at least 1 dose and less than 5+2 doses required for adequate dosing per Cohort 1, and/or timing of relapse > 12 months and ≤ 5 years. For example, this includes delayed relapse after adequate or inadequate BCG treatment where > 12 months and ≤ 5 years have elapsed. This cohort also includes patients who received ≥ 1 partial dose of BCG (i.e., < 50 mg) as part of their qualifying course of BCG. •Approved treatment for NMIBC must have been discontinued prior to the Screening biopsy. •CIS must be documented or indicated by pathology within 4 months of or at Screening (without subsequent CIS 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 at the time of enrollment and have experienced disease within 12 months of BCG treatment. • 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). •Patients with BCG-unresponsive NMIBC may have received subsequent approved treatment for NMIBC that discontinued prior to the Screening biopsy. • Absence of CIS must be documented or indicated by pathology at Screening or within 4 months of Screening (provided no therapy for HG disease was given after the most recent biopsy). • Prior to enrollment, all patients should have TURBT of all visible papillary tumors.
Patients 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).
Male or non-pregnant, non-lactating female, 18 years or older.
5.Women of child-bearing potential must have a negative pregnancy test at Screening.
Female 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.
In 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. Repeat TURBT must confirm that muscularis propria is present and uninvolved in the specimen. TURBT to occur within 4 months of Screening
Performance Status: Eastern Cooperative Oncology Group 0, 1, and 2.
Hematologic inclusion at Screening: • Absolute neutrophil count >1,500/mm3. • Hemoglobin >9.0 g/dL. • Platelet count >100,000/mm3.
Hepatic 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.
Adequate renal function with creatinine clearance >30 mL/min.
Prothrombin time and partial thromboplastin time 1.25 x ULN at Screening or within the therapeutic range if on anticoagulation therapy.
Must have satisfactory bladder function with ability to retain study drug for a minimum of 60 minutes.
Patient or legally authorized representative (LAR) must be willing and able to comply with all protocol requirements.
Patient or LAR must be willing and able to give informed consent and any authorizations required by local law for participation in the study.
All specimens must be predominantly urothelial (transitional cell) and have less than 10% variant (e.g., sarcomatoid, squamous component) histology.

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Exclusion Criteria

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 indolent or definitively treated disease not expected to require treatment during the study. Others may be allowed under Sponsor approval. Examples of potential allowed exceptions include: • 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 CIS and ductal CIS. • History of localized breast cancer and receiving antihormonal agents. • 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.
Active interstitial cystitis on cystoscopy or biopsy.
Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
Has had urothelial carcinoma outside of the urinary bladder (i.e., urethra, ureter, or renal pelvis), that is stage T2 or higher, Ta/any T1, CIS of the upper urinary tract is allowable if treated with complete nephroureterectomy more than 24 months prior to study enrollment. • Excluded: Participant has tumor(s) involving the prostatic urethra (ductal or stromal) on the screening biopsy. • Excluded: N+ and/or M+ per CT/MR urography.
History of prior T2/T3 urothelial carcinoma of the bladder.
Concurrent treatment with any chemotherapeutic agent.
History of partial cystectomy for urothelial carcinoma.
Treatment with last therapeutic agent (including BCG or 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.
Patients who have received systemic immunosuppressive medication including high-dose corticosteroids (e.g., systemic corticosteroids 20 oral mg prednisone or equivalent) within 4 weeks prior to Day 1. Exception: intermittent or sporadic use of inhaled, topical or intra-articular steroids is allowed when given 14 days or more prior to enrollment. Notes: • Patients must not be receiving doses of 20 mg/day of oral prednisone or equivalent at the time of study entry or during the study. • 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.
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 (e.g., requiring supplemental oxygen, chronic oral or inhaled steroids, or hospitalization within the past 6 months [prior to Day 1] for treatment of dyspnea or associated symptoms).
History of lung lobectomy resulting in severe impairment of pulmonary function (e.g., requiring supplemental oxygen, chronic oral or inhaled steroids, or hospitalization within the past 6 months [prior to Day 1] for treatment of dyspnea or associated symptoms).
History of unresolved vesicoureteral reflux or current indwelling indwelling urinary stent. (Note: any indwelling urinary stent[s] must be removed prior to detalimogene instillation).
Known active human immunodeficiency virus, Hepatitis B (HBV), or Hepatitis C (HCV) infection. Exception for active HIV: patients who are currently stable on antiretroviral therapy (ART) for at least 4 weeks and agree to adhere to ART during study therapy, have HIV viral load of < 400 copies per milliliter (/mL) at screening (or undetectable per local criteria), and have CD4 T cell counts ≥ 200/microliter will be eligible for enrollment. Exception for active Hepatitis: For patients with evidence of HBV infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. For patients with HCV, infection must have been treated and cured or patients are currently on treatment and have an undetectable HCV viral load NOTE: HBV and HBC antibody or antigen positivity alone, in the absence of an active infection, does not exclude a patient.
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.
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. In the event of any unstable or clinically significant concurrent medical condition that would, in the opinion of the Medical Monitor, jeopardize the safety of a subject and/or their ability to comply with the protocol, enrollment will not be authorized by the Sponsor Medical Monitor.
History of unresolved hydronephrosis due to ureteral obstruction.
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 investigational immunotherapy agent.
History of external beam radiation to the pelvis or prostate brachytherapy within the last 2 months of Screening.
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.
Current indwelling urinary catheter (including Foley catheters or suprapubic tubes); however, intermittent catheterization is acceptable.