Dose expansion, safety and efficacy study of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Protara Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2023-09-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Protara Therapeutics, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Others

Cohort A: To assess the preliminary anti-tumor activity of TARA-002 administered intravesically
Cohort B: To assess the anti-tumor activity of TARA-002 administered intravesically using cystoscopy, bladder biopsy and urine cytology

Secondary objectives 8

1. Cohort A: • To characterize the safety profile of TARA-002 administered intravesically
2. Cohort A: • To evaluate cytokine level changes after TARA-002 is administered intravesically
3. Cohort A: • To assess QoL
4. Cohort B: • To assess the duration of CR for subjects receiving TARA-002 administered intravesically
5. Cohort B: • To further assess the antitumor activity of TARA-002 administered intravesically
6. Cohort B: • To characterize the safety profile of TARA-002 administered intravesically
7. Cohort B: • To evaluate cytokine level changes after TARA-002 is administered intravesically
8. Cohort B: • To assess QoL

Conditions and MedDRA coding

Non-muscle invasive bladder cancer

Regulatory references

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Male or female subjects 18 years of age or older at the time of signing the informed consent
2. 2. 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
3. 3. 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.
4. 4. 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
5. 5. 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)
6. 6. 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.
7. 7. Subjects who the Investigator believes can and will comply with the requirements of the protocol
8. 8. Subjects with an ECOG performance status of 0, 1 or 2
9. 9. 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
10. 10. 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
11. 11. Females of childbearing age with a negative pregnancy test per local read
12. 12. Subjects whose treating physician must confirm availability and access to TARA-002
13. 13. 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.

Exclusion criteria 17

1. 1. 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).
2. 2. 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.
3. 3. 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
4. 4. 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).
5. 5. 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.
6. 6. Life expectancy of less than 5 years
7. 7. ECOG performance status 3 or 4
8. 8. Has received prior radiotherapy to the pelvis
9. 9. Has significant urinary incontinence or otherwise unable to hold intravesical immunotherapy in the bladder for 2 hours, per the Investigator’s assessment
10. 10. 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
11. 11. 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
12. 12. 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.
13. 13. 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)
14. 14. Current indwelling ureteral stent. If stent is anticipated to be removed prior to drug administration, this is allowed
15. 15. A woman who is nursing, pregnant, or intending to become pregnant during the study period
16. 16. 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
17. 17. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Cohort A: • Incidence of high-grade CR at any time
2. Cohort A: • Incidence of high-grade CR at any time by subgroup (BCG naïve and BCG exposed > 24 months)
3. Cohort B • Incidence of high-grade CR at any time

Secondary endpoints 24

1. Cohort A: • Incidence and severity of AEs
2. Cohort A:• Incidence and severity of TEAEs
3. Cohort A:• Incidence and severity of SAEs
4. Cohort A:• Incidence and severity of TESAEs
5. Cohort A:• Cytokine urine levels pre-treatment, during treatment and post-treatment
6. Cohort A:• QoL as assessed by the EORTC: QLQ-C30 and QLQ-NMIBC24
7. Cohort B: • Duration of high-grade CR
8. Cohort B: • High-grade CR rate at Months 3, 6, 9, 12, 15, 18, 21, and 24
9. Cohort B: • Duration of CR (all recurrent bladder cancer, including low grade Ta)
10. Cohort B: • CR rate (all recurrent bladder cancer, including low grade Ta) at Months 3, 6, 9, 12, 15, 18, 21, and 24
11. Cohort B: • Progression Free Survival (PFS)
12. Cohort B: • Disease-specific Progression Free Survival (DSPFS)
13. Cohort B: • Overall Survival (OS)
14. Cohort B: • Disease-specific Survival (DSS)
15. Cohort B: • Time to Cystectomy
16. Cohort B: • Time to Recurrence Delayed Cystectomy
17. Cohort B: • Time to Progression
18. Cohort B: • Time to Disease Worsening
19. Cohort B: • Incidence and severity of AEs
20. Cohort B: • Incidence and severity of TEAEs
21. Cohort B: • Incidence and severity of SAEs
22. Cohort B: • Incidence and severity of TESAEs
23. Cohort B: • Cytokine urine levels pre-treatment, during treatment and post-treatment
24. Cohort B: • QoL as assessed by the EORTC: QLQ-C30 and QLQ-NMIBC24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Protara Therapeutics Inc.

Sponsor organisation

Protara Therapeutics Inc.

Address

345 Park Avenue South South Floor 3rd

City

New York

Postcode

10010-1707

Country

United States

Scientific contact point

Organisation

Protara Therapeutics Inc.

Contact name

R&D

Public contact point

Organisation

Protara Therapeutics Inc.

Contact name

R&D

Third parties 8

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications