Evaluation of Safety and Anti-Tumor Activity of Intravesical TARA-002 in High-Grade Non-Muscle Invasive Bladder Cancer

Trial ID: 2023-505062-28-00
Protocol: TARA-002-101-Ph1b/2
Sponsor: Protara Therapeutics Inc.

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Diseases & Conditions

Bladder cancer stage 0 with cancer in situ Bladder cancer stage I with cancer in situ

Objectives

The primary objective of this study is to evaluate the **anti-tumor activity** of TARA-002 when administered intravesically in adults with high-grade **non-muscle invasive bladder cancer**. This is assessed through cystoscopy, bladder biopsy, and urine cytology, which are critical for determining the therapeutic potential of TARA-002 in reducing tumor burden and improving patient outcomes.

Secondary objectives include:

Cohort A: Characterizing the safety profile of TARA-002, evaluating cytokine level changes, and assessing quality of life (QoL).
Cohort B: Assessing the duration of complete response (CR), further evaluating the antitumor activity, characterizing the safety profile, evaluating cytokine level changes, and assessing QoL.

Participants

The clinical trial involves a total of **67 participants** diagnosed with **non-muscle invasive bladder cancer**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including the requirement for central histologic confirmation of high-grade non-muscle invasive carcinoma in situ (CIS) with active disease. The trial population is characterized by a diverse age range and includes individuals who are considered part of a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating they are in relatively good health. Lifestyle considerations such as the use of medically acceptable contraception methods are mandated for sexually active participants to prevent pregnancy during the study. The trial does not specify any particular dietary or physical activity requirements for participants. The selection process ensures that participants have voluntarily given informed consent and are capable of complying with the study protocol.

Plans and Procedures

The clinical trial is designed as a **Phase 1b/2**, open-label study to evaluate the safety and anti-tumor activity of **TARA-002**, a **lyophilized powder for preparation for injection**, administered via **intravesical use** in adults with high-grade **non-muscle invasive bladder cancer**. The trial is structured to include two cohorts: Cohort A aims to assess the preliminary anti-tumor activity of TARA-002, while Cohort B focuses on evaluating the anti-tumor activity using cystoscopy, bladder biopsy, and urine cytology. The study is expected to commence recruitment on November 1, 2023, and conclude by December 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histologic confirmation of disease, and prior treatment history. Following the screening, eligible participants will receive the investigational product, with follow-up visits scheduled to monitor safety and efficacy outcomes. These visits will include assessments of adverse events, cytokine urine levels, and quality of life using the EORTC QLQ-C30 and QLQ-NMIBC24 questionnaires. The end-of-study visit will mark the completion of the trial for each participant, where final evaluations will be conducted.

The expected duration of participant involvement varies, with follow-up assessments occurring at specified intervals, including months 3, 6, 9, 12, 15, 18, 21, and 24 for Cohort B. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with study protocols. The trial's primary endpoints focus on the incidence of high-grade complete response (CR), while secondary endpoints include the incidence and severity of adverse events, progression-free survival, and overall survival metrics.

Treatment

The clinical trial involves the administration of **TARA-002**, a **biological** investigational product, which is formulated as a **lyophilized powder for preparation for injection**. The active substance in TARA-002 is **Streptococcus pyogenes, Group A, Type 3, Strain SU, inactivated**. This substance is classified as a structurally diverse substance of other origin. The pharmaceutical form of TARA-002 is specifically designed for **intravesical use**, which involves the direct instillation of the medication into the bladder. The study aims to evaluate the safety and anti-tumor activity of TARA-002 in adults with high-grade non-muscle invasive bladder cancer. The dosing schedule and frequency of administration are determined based on the study protocol, and participant compliance is monitored throughout the trial.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on assessing the effects of TARA-002. The trial is conducted in an open-label manner, allowing for the direct observation of the drug's effects without the use of blinding. The study is structured to include different cohorts, with specific objectives to assess the preliminary anti-tumor activity of TARA-002 through various diagnostic methods such as cystoscopy, bladder biopsy, and urine cytology. The trial does not include a pediatric formulation, and the product is not classified as an orphan drug. Compliance with the dosing regimen is crucial, and adherence is monitored to ensure the integrity of the study results.

Efficacy

The clinical trial aims to evaluate the efficacy of TARA-002, a **biological** product, in adults with high-grade non-muscle invasive bladder cancer. Efficacy will be assessed through several primary and secondary endpoints. The primary endpoints include the incidence of high-grade complete response (CR) at any time for both Cohort A and Cohort B. Secondary endpoints for Cohort A include the incidence and severity of adverse events (AEs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and treatment-emergent serious adverse events (TESAEs). Additionally, cytokine urine levels will be measured pre-treatment, during treatment, and post-treatment, and quality of life (QoL) will be assessed using the EORTC QLQ-C30 and QLQ-NMIBC24 instruments.

For Cohort B, secondary endpoints include the duration of high-grade CR, high-grade CR rate at specified months, duration of CR for all recurrent bladder cancer, and CR rate for all recurrent bladder cancer at specified months. Other secondary endpoints for Cohort B include progression-free survival (PFS), disease-specific progression-free survival (DSPFS), overall survival (OS), disease-specific survival (DSS), time to cystectomy, time to recurrence delayed cystectomy, time to progression, and time to disease worsening. The incidence and severity of AEs, TEAEs, SAEs, and TESAEs will also be evaluated, along with cytokine urine levels and QoL assessments using the same EORTC instruments as in Cohort A.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female subjects 18 years of age or older at the time of signing the informed consent
Subjects who have voluntarily given written informed consent after the nature of the study has been explained according to applicable requirements prior to study entry
Central histologic confirmation of high-grade non-muscle invasive CIS (± Ta/T1) with active disease a. CIS with active disease is defined as CIS (± Ta/T1) present on last tumor evaluation prior to signing ICF. The specimen containing CIS should be submitted for central review to determine eligibility. If re-staging TURBT was performed prior to signing informed consent, CIS with active disease may be determined from ANY specimen during this tumor evaluation period (i.e., staging or re-staging). b. Subjects with CIS + T1 without muscle in specimen should undergo re-staging TURBT to confirm eligibility (e.g., absence of muscle invasion). If re-staging was not completed prior to signing ICF, re-staging cystoscopy/cytology/TURBT can be performed in the same setting during screening. Local interpretation of restaging is acceptable to confirm eligibility. Study visits may be delayed by up to 28 days after TURBT/biopsy procedure only if required per the site’s standard of care. c. All papillary disease should be completely resected prior to dosing. d. If there is discrepancy for inclusion/exclusion between local pathology and central pathology, please contact the sponsor for guidance.
Cohort A only: Subjects with CIS (± Ta/T1) who are unable to obtain intravesical BCG or have not received intravesical BCG for 24 months prior to CIS diagnosis a. Inability to access BCG may include, but is not limited to, medical reasons or shortage-related reasons b. Inability to access BCG due to affordability-related reasons is not permitted
Cohort B only: BCG unresponsive CIS a. Persistent or recurrent CIS (± Ta/T1) within 12 months of completion of adequate BCG (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course)
Subjects enrolled in other investigational treatment studies (unrelated to high-grade NMIBC) should have received their last treatment at least 6 weeks prior to the time of signing the informed consent (i.e., 6-week washout period). Subjects who were enrolled in other investigational treatment studies and received investigational therapies for highgrade NMIBC are excluded.
Subjects who the Investigator believes can and will comply with the requirements of the protocol
Subjects with an ECOG performance status of 0, 1 or 2
If sexually active with male partners, the female of childbearing potential agrees to use a medically acceptable method of contraception and abstains from donating eggs for the duration of the study and for at least 4 weeks after the last dose of investigational product. Females are considered of childbearing potential if they are post-menarche, have not been surgically sterile for at least 6 weeks (i.e., total hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation) and are pre-menopausal (menopause is defined as complete cessation of menstruation for at least 12 months). Acceptable methods of contraception include: a. The simultaneous use of stable hormonal contraception in conjunction with a double-barrier method (e.g., condom with spermicide or diaphragm with spermicide), or; b. The use of an intrauterine device in place for at least 12 weeks, in conjunction with a double barrier method, or; c. Abstinence if this is the subject’s usual lifestyle and preferred contraception
If sexually active with female partners, the sexually mature, nonsterile male agrees to use a medically acceptable method of contraception and abstains from donating sperm for the duration of the study and for at least 4 weeks after the last dose of investigational product. Males are considered surgically sterile if they have undergone bilateral orchiectomy or vasectomy at least 12 weeks prior to signing informed consent. Acceptable methods of contraception include: a. The simultaneous use of stable hormonal contraception by the female partner in conjunction with a double-barrier method (e.g., condom with spermicide or diaphragm with spermicide), or; b. The female partner’s use of an intrauterine device in place for at least 12 weeks, in conjunction with a double barrier method, or; c. The female partner is surgically sterile for at least 6 weeks or is at least 12 months postmenopausal, or; d. Abstinence if this is the subject’s usual lifestyle and preferred contraception
Females of childbearing age with a negative pregnancy test per local read
Subjects whose treating physician must confirm availability and access to TARA-002
Subjects who have not completed vaccination against COVID-19 should be negative for COVID-19 infection (according to local site requirements, e.g., rapid test, polymerase chain reaction [PCR] within the 42-day screening window PRIOR to receiving their first dose of TARA-002 at Treatment Day 1). Results can be read and interpreted locally.

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Exclusion Criteria

Penicillin allergy (subjects with a questionable history of allergy to penicillin will undergo penicillin blood allergy testing via central laboratory. If penicillin blood allergy test is negative, subject is eligible for the study).
Central histologic review, predominant (defined as > 50%) adenocarcinoma, squamous cell carcinoma, or histological variants including plasmacytoid, sarcomatoid, or squamous components (Note: If predominant histology is urothelial, the subject is eligible for the study). Subjects with any micropapillary component will be excluded.
Concomitant prostatic or upper tract urothelial involvement per Investigator’s assessment a. Prior history of prostatic and upper tract disease is acceptable as long as there is no disease in these areas at the time of dosing
Nodal and metastatic disease are excluded if they existed at any time (whether present or in the past). The determination of nodal and metastatic disease is determined by the Investigator after reviewing local imaging results. Note: A diagnosis of nodal and metastatic disease is not solely based on radiographic imaging, a clinical judgement and/or a histological investigation (if applicable) are factors the Investigator may use to assist in diagnosis of nodal or metastatic disease).
Any history of ≥ T2 bladder cancer that existed at any point in time in the subject’s history is excluded. This determination is based on Investigator’s assessment.
Life expectancy of less than 5 years
ECOG performance status 3 or 4
Has received prior radiotherapy to the pelvis
Has significant urinary incontinence or otherwise unable to hold intravesical immunotherapy in the bladder for 2 hours, per the Investigator’s assessment
Concurrent or planned biologic therapy, hormonal therapy (other than oral contraception), chemotherapy, surgery (other than TURBT and/or biopsy), or other cancer therapy during study period. Note: concurrent or planned hormonal therapy refers to hormone treatment for cancer or immunosuppression, and does not refer to routine medications for chronic disease e.g. diabetes, hypothyroidism, osteoporosis
Concurrent malignancy diagnosed within 6 months prior to the time of signing the informed consent. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer, or low or very low risk prostate cancer. Note: history of prior malignancy is allowed so long as it is not concurrent or is stable for more than 6 months per the Investigator’s assessment
Receipt of any other anti-cancer therapy (including investigational agents) within 6 weeks prior to signing informed consent. Subjects who enrolled in any investigational treatment studies and received investigational therapies for high-grade NMIBC are excluded.
Inadequate organ and bone marrow function based on central laboratory defined as: a. Hemoglobin ≤ 8.0g/dL b. Absolute neutrophil count ≤ 1.5 x 109 / L c. Platelet count ≤ 80 x 109 / L d. Aspartate aminotransferase (AST)/aspartate transaminase (SGOT) and/or alanine aminotransferase (ALT)/alanine transaminase (SGPT) ≥ 2.5 x upper limit of normal (ULN) e. Total bilirubin >1.0 x ULN f. Creatinine Clearance < 30 mL/min (as calculated by central laboratory)
Current indwelling ureteral stent. If stent is anticipated to be removed prior to drug administration, this is allowed
A woman who is nursing, pregnant, or intending to become pregnant during the study period
Known human immunodeficiency (HIV) infection or other immunodeficiency disorders, either primary or acquired. Exceptions include subjects requiring use of inhaled or intranasal corticosteroids or local steroid injections
In the opinion of the treating Investigator, the subject has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate