Clinical Trials /

Safety and Tolerability of TAR-200 and Nivolumab in Subjects With Muscle-Invasive Bladder Cancer

NCT03518320

Description:

The purpose of this study is to determine if TAR-200, an investigational drug delivery system, in combination with nivolumab is safe and tolerable in patients with muscle-invasive bladder cancer (MIBC) who are scheduled for radical cystectomy (RC) during an 84-day dosing cycle induction period comprised of four consecutive 21-day dosing cycles.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety and Tolerability of TAR-200 and Nivolumab in Subjects With Muscle-Invasive Bladder Cancer
  • Official Title: A Multicenter Study of TAR-200 in Combination With Nivolumab (OPDIVO) in Subjects With Muscle-Invasive Urothelial Carcinoma of the Bladder Who Are Scheduled for Radical Cystectomy and Are Ineligible for or Refusing Platinum-Based Neoadjuvant Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: TAR-200-104
  • NCT ID: NCT03518320

Conditions

  • Bladder Cancer TNM Staging Primary Tumor (T) T2
  • Bladder Cancer TNM Staging Primary Tumor (T) T2A
  • Bladder Cancer TNM Staging Primary Tumor (T) T2B
  • Bladder Cancer TNM Staging Primary Tumor (T) T3
  • Bladder Cancer TNM Staging Primary Tumor (T) T3A
  • Bladder Cancer TNM Staging Primary Tumor (T) T3B
  • Bladder Cancer TNM Staging Regional Lymph Node (N) N0
  • Bladder Cancer TNM Staging Regional Lymph Node (N) N1
  • Bladder Cancer TNM Staging Distant Metastasis (M) M0

Interventions

DrugSynonymsArms
Gemcitabine-Releasing Intravesical System (GemRIS)/TAR-200TAR-200 and Nivolumab Combination
Nivolumab Injection [Opdivo]TAR-200 and Nivolumab Combination

Purpose

The purpose of this study is to determine if TAR-200, an investigational drug delivery system, in combination with nivolumab is safe and tolerable in patients with muscle-invasive bladder cancer (MIBC) who are scheduled for radical cystectomy (RC) during an 84-day dosing cycle induction period comprised of four consecutive 21-day dosing cycles.

Trial Arms

NameTypeDescriptionInterventions
TAR-200 and Nivolumab CombinationExperimentalGemcitabine-Releasing Intravesical System (GemRIS)/TAR-200 is placed into the bladder through an Inserter and gradually releases gemcitabine during the 21-day indwelling period before being removed. In combination, subjects are dosed intravenously with a Nivolumab Injection [Opdivo] within 3 days of TAR-200 placement. Subjects will receive four consecutive 21-day dosing cycles of the combination of TAR-200 and Nivolumab prior to radical cystectomy.
  • Gemcitabine-Releasing Intravesical System (GemRIS)/TAR-200
  • Nivolumab Injection [Opdivo]

Eligibility Criteria

        Inclusion Criteria:

          1. Histological proof of muscle-invasive urothelial carcinoma of the bladder (stage
             cT2-cT3b, N0-1, M0). Subjects with mixed histology are required to have documented
             dominant transitional cell pattern with no more than 10% squamous differentiation and
             10% glandular differentiation. Micropapillary/sarcomatoid/adenocarcinoma/plasmacytoid
             variants are not allowed.

          2. Subjects with a total tumor size of ≤2 cm following TURBT are eligible. Subjects with
             a tumor or tumors totaling >2 cm at screening must undergo a second debulking TURBT to
             reduce the tumor(s) to ≤2 cm to be eligible for treatment.

          3. Adequate bone marrow, liver, and renal function, as documented by the following
             laboratory assessments conducted within 28 days prior to dosing:

               -  Hemoglobin ≥9.0 g/dL

               -  Absolute neutrophil count (ANC) ≥1,500/mm3

               -  Platelet count ≥100,000/mm3

               -  Total bilirubin ≤1.5x upper limit of normal (ULN)

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x ULN

               -  Glomerular filtration rate (GFR) ≥30 ml/min/1.73 m2 (assessed using the Chronic
                  Kidney Disease Epidemiology Collaboration [CKD-EPI] equation)

          4. Willing to undergo multiple cystoscopies during the study for TAR-200 removal and
             post-insertion examination.

          5. Deemed eligible for and willing to undergo RC by the attending urologist.

          6. Subjects must refuse cisplatin-based combination chemotherapy (and understand the risk
             and benefits of doing so) or be deemed ineligible for cisplatin-based chemotherapy by
             meeting at least one of the following criteria:

               -  GFR <60 mL/min/1.73 m2 (assessed using the CKD-EPI equation)

               -  Common Terminology Criteria for Adverse Events (CTCAE) v4 Grade ≥2 audiometric
                  hearing loss

               -  CTCAE v4 Grade ≥2 peripheral neuropathy

          7. Prior systemic chemotherapy for indications other than urothelial cell carcinoma of
             the bladder is permitted. All toxicities attributed to prior anti-cancer therapy other
             than alopecia and fatigue must have resolved to Grade 1 (National Cancer Institute
             CTCAE version 4.03) or baseline before administration of study drug. Participants with
             toxicities attributed to prior anti cancer therapy which are not expected to resolve
             and result in long lasting sequelae, such as peripheral neuropathy after
             platinum-based therapy or audiometric hearing loss, are permitted to enroll.

          8. Written informed consent and authorization for release of personal health information
             obtained according to local laws.

          9. Age ≥18 years at the time of consent.

         10. Women of childbearing potential (WOCBP) must be willing to use a highly effective
             method of contraception (hormonal or intrauterine device [IUD] method of birth control
             with a failure rate of <1% when used consistently and correctly; or abstinence) for
             the duration of treatment with TAR-200 in combination with nivolumab plus 5 half-lives
             of study treatment, plus 30 days (duration of ovulatory cycle), for a total of 5
             months post treatment completion. Note: WOCBP who are continuously not heterosexually
             active are exempt from contraceptive requirements, but still must undergo pregnancy
             testing as described in this protocol.

         11. WOCBP must have a negative pregnancy test within 24 hours prior to Study Day 0.

         12. Males must be willing to use an effective method of contraception to avoid seminal
             transfer (double barrier method) or abstinence for the duration of treatment with TAR
             200 in combination with nivolumab plus 5 half-lives of the study treatment, plus 90
             days (duration of sperm turnover), for a total of 7 months post-treatment completion.
             In addition, male participants must be willing to refrain from sperm donation during
             this time.

         13. Azoospermic males should also use double barrier contraceptive methods to avoid
             contamination of the non-treatment sexual partner.

        Exclusion Criteria:

          1. Active malignancies within 3 years except for those with a negligible risk of
             metastasis or death treated with expected curative outcome.

          2. Prior systemic chemotherapy for urothelial cell carcinoma of the bladder.

          3. Prior treatment with an anti-programmed death-1 (PD-1), anti-PD-L1, anti PD L2,
             anti-CD137, or anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody, or any other
             antibody or drug specifically targeting T-cell co stimulation or checkpoint pathways.

          4. Pelvic radiotherapy administered within less than 6 months prior to enrollment.
             Subjects who received radiotherapy ≥6 months prior to enrollment must demonstrate no
             cystoscopic evidence or symptoms of radiation cystitis.

          5. Subjects who require immunosuppressive medications such as methotrexate, tumor
             necrosis factor inhibitors, or systemic corticosteroids (>10 mg/day prednisone
             equivalents) within 2 weeks prior to study drug administration. Inhaled or topical
             steroids and adrenal replacement doses >10 mg daily prednisone equivalents are
             permitted in the absence of active autoimmune disease.

          6. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
             type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
             requiring hormone replacement, psoriasis not requiring systemic treatment, or
             conditions not expected to recur in the absence of an external trigger are permitted
             to enroll.

          7. Presence of any bladder or urethral anatomic feature that in the opinion of the
             investigator may prevent the safe placement, indwelling use, or removal of TAR 200.

          8. Pyeloureteral tube externalized to the skin is exclusionary. Unilateral nephrostomy
             tube or ureteral stent is permitted as long as it does not interfere with placement or
             retention of TAR-200 in the bladder.

          9. Indwelling catheters are not permitted.

         10. Subjects with evidence of bladder perforation during diagnostic cystoscopy may be
             treated if perforation has resolved prior to dosing.

         11. Bladder post-void residual volume of >500 mL.

         12. History of diagnosis of neurogenic bladder requiring intermittent catheterization.

         13. Active, uncontrolled urogenital bacterial, viral or fungal infections, including
             urinary tract infection (UTI). Skin/nail fungal infections are not exclusionary.
             Subjects with active shingles (varicella zoster infection) will be excluded from the
             study.

         14. Subjects with a positive test for hepatitis B virus surface antigen (HBV sAg) or
             hepatitis C virus RNA or hepatitis C antibody (HCV antibody) indicating acute or
             chronic infection.

         15. Known history of positive test for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome. Note: Testing for HIV must be performed at sites
             where mandated locally.

         16. Uncontrolled adrenal insufficiency.

         17. New York Heart Association Functional Classification of Heart Failure: Class III or IV
             (Appendix 1).

         18. Eastern Cooperative Oncology Group (ECOG) performance status ≥2.

         19. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, unstable angina pectoris, or psychiatric illness/social situations that
             would limit compliance with study requirements.

         20. Subjects who have had a history of acute diverticulitis, intra-abdominal abscess,
             gastrointestinal obstruction and abdominal carcinomatosis which are known risk factors
             for bowel perforation.

         21. Subjects with interstitial lung disease that is symptomatic or may interfere with the
             detection or management of suspected drug-related pulmonary toxicity.

         22. Subjects must have recovered from the effects of major surgery requiring general
             anesthetic or significant traumatic injury at least 14 days before Study Day 0.

         23. History of allergy or hypersensitivity to gemcitabine (or other drug excipients in
             TAR-200) or drugs chemically-related to gemcitabine.

         24. History of allergy or hypersensitivity to the device constituent or Inserter
             materials.

         25. History of allergy or hypersensitivity to nivolumab drug components.

         26. Female subject who is pregnant (as verified by urine test at time of screening) or
             lactating or of childbearing potential and not using acceptable methods of
             contraception.

         27. Difficulty providing blood samples.

         28. Dementia, altered mental status, or any psychiatric condition that would prohibit the
             understanding or rendering of informed consent.

         29. Use of an investigational product (IP) within 30 days or 5 half-lives, whichever is
             longer, preceding Study Day 0.

         30. Prisoners or subjects who are involuntarily incarcerated. (Note: under certain
             specific circumstances a person who has been imprisoned may be included or permitted
             to continue as a subject. Strict conditions apply and sponsor approval is required.)

         31. Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical (e.g., infectious disease) illness

        Other protocol defined inclusion/exclusion criteria could apply.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with incidence of treatment emergent adverse events (TEAEs) over 4 consecutive 21-day dosing cycles of TAR-200 in combination with Nivolumab as assessed by CTCAE V4.0.
Time Frame:Study Day 0 to Study Day 180
Safety Issue:
Description:Will be assessed through the duration of the study by reported AEs

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Taris Biomedical LLC

Trial Keywords

  • Bladder Cancer
  • Urothelial Carcinoma
  • Cystectomy
  • Radical Cystectomy

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