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TRIO Bladder: A Study of Durvalumab Plus Tremelimumab Followed by Concurrent Durvalumab Plus Bladder Radiation in Muscle-Invasive Bladder Cancer

NCT04073160

Description:

The purpose of this study is to describe the safety and tolerability of Durvalumab plus Tremelimumab followed by concurrent Durvalumab plus bladder radiation in patients with localized muscle invasive urothelial carcinoma of the bladder, who are either Decipher-Non-Basal OR Decipher-Basal and cisplatin-ineligible. Eligible subjects will receive 2 cycles of Durvalumab plus Tremelimumab followed by imaging and cystoscopy. Subjects whose cancer responds or is stable will receive a combination of 2 cycles of Durvalumab plus 6.5 weeks of radiation to the bladder followed by imaging and a TURBT. Subjects whose cancer continues to respond and meets certain criteria will continue to receive Durvalumab for up to 12 months from initial dose or until the cancer recoccurs or progresses, whichever occurs earlier. During this time, subjects may also receive intravesicular therapy if clinically indicated. Subjects will be followed for 5 years from initial dose.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TRIO Bladder: A Phase Ib Study of Durvalumab (MEDI 4736) Plus Tremelimumab Followed by Concurrent Durvalumab Plus Bladder Radiation, Based on Molecular Subtypes in Muscle-Invasive Bladder Cancer
  • Official Title: TRIO Bladder: A Phase Ib Study of Durvalumab (MEDI 4736) Plus Tremelimumab Followed by Concurrent Durvalumab Plus Bladder Radiation, Based on Molecular Subtypes in Muscle-Invasive Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: Pro00102352
  • NCT ID: NCT04073160

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
TremelimumabDecipher Bladder test subtype non-basal
DurvalumabImfinziDecipher Bladder test subtype non-basal
Intravesicular TherapyDecipher Bladder test subtype non-basal

Purpose

The purpose of this study is to describe the safety and tolerability of Durvalumab plus Tremelimumab followed by concurrent Durvalumab plus bladder radiation in patients with localized muscle invasive urothelial carcinoma of the bladder, who are either Decipher-Non-Basal OR Decipher-Basal and cisplatin-ineligible. Eligible subjects will receive 2 cycles of Durvalumab plus Tremelimumab followed by imaging and cystoscopy. Subjects whose cancer responds or is stable will receive a combination of 2 cycles of Durvalumab plus 6.5 weeks of radiation to the bladder followed by imaging and a TURBT. Subjects whose cancer continues to respond and meets certain criteria will continue to receive Durvalumab for up to 12 months from initial dose or until the cancer recoccurs or progresses, whichever occurs earlier. During this time, subjects may also receive intravesicular therapy if clinically indicated. Subjects will be followed for 5 years from initial dose.

Trial Arms

NameTypeDescriptionInterventions
Decipher Bladder test subtype non-basalExperimentalSubjects with localized muscle invasive urothelial carcinoma of the bladder, whose tumor is Decipher Bladder test subtype non-basal
  • Tremelimumab
  • Durvalumab
  • Intravesicular Therapy
Decipher Bladder test subtype basal and cisplatin-ineligibleExperimentalSubjects with localized muscle invasive urothelial carcinoma of the bladder, whose tumor is Decipher Bladder test subtype basal and the subject is cisplatin-ineligible
  • Tremelimumab
  • Durvalumab
  • Intravesicular Therapy

Eligibility Criteria

        Inclusion Criteria:

          1. Ability to understand and the willingness to sign a written informed consent document.

          2. Age ≥ 18 years

          3. Histologically or cytologically confirmed urothelial carcinoma of the bladder.
             Non-urothelial histologies and upper tract disease are excluded.

          4. Has clinical stage T2-T4b, N0-3, M0 urothelial carcinoma

          5. DECIPHER-Non-basal (Group A) OR DECIPHER-Basal but cisplatin-ineligible (Group B)

             a. Cisplatin-ineligible based on ≥1 of the following:

             i. CrCl <60 ml/min

             ii. Grade 2 hearing loss or peripheral neuropathy

             iii. ECOG performance status of 2

          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

          7. Life expectancy of at least 12 weeks

          8. Body weight >30kg

          9. Adequate normal organ and marrow function as defined below:

               1. Hemoglobin ≥ 8.0 g/dL and asymptomatic

               2. Absolute neutrophil count (ANC ≥1.5 x 109/L)

               3. Platelet count ≥100 x 109/L

               4. Serum bilirubin ≤ 1.5 x Institutional Upper Limit of Normal (ULN) (Note: This
                  will not apply to patients with confirmed Gilbert's syndrome (persistent or
                  recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
                  hemolysis or hepatic pathology), who will be allowed only in consultation with
                  their physician.)

               5. AST/SGOT and ALT/SGPT ≤ 2.5 x ULN

               6. Measured creatinine clearance (CL) >30 mL/min

         10. Evidence of post-menopausal status or negative serum pregnancy test for female
             pre-menopausal patients. Women will be considered post-menopausal if they meet the
             requirements below.

               1. Women < 45 years of age would be considered post-menopausal if they underwent
                  surgical sterilization (bilateral oophorectomy or hysterectomy.

               2. Women 45 to <50 years of age would be considered post-menopausal if they have
                  been amenorrheic for 18 months or more following cessation of exogenous hormonal
                  treatments, if they have a documented follicle-stimulating hormone levels in the
                  post-menopausal range (> 40 mlU/mL) or underwent surgical sterilization
                  (bilateral oophorectomy or hysterectomy).

               3. Women ≥50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, if they have a
                  documented follicle-stimulating hormone levels in the post-menopausal range (> 40
                  mlU/mL) or underwent surgical sterilization (bilateral oophorecomy, bilateral
                  salpingectomy or hysterectomy).

         11. Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

        Exclusion Criteria:

        Subjects must not have any of the following:

          1. Prior systemic chemotherapy for bladder cancer

          2. Any prior treatment with CTLA-4, including tremelimumab PD-1 or PD-L1 including
             durvalumab checkpoint inhibitors

          3. Administration of an investigational therapeutic within 28 days prior to Cycle 1, Day
             1

          4. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
             therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal
             antibodies) ≤28 days prior to the first dose of study drug.

          5. Prior pelvic radiation that precludes bladder radiation

          6. Concurrent enrolment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study

          7. Prior cystectomy

          8. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria

               1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Duke Principal Investigator.

               2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab or tremelimumab may be included only after consultation
                  with the Duke Principal Investigator.

          9. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy
             for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
             conditions (e.g., hormone replacement therapy) is acceptable.

         10. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks of the first dose of study drug

         11. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
             acceptable.

         12. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

         13. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:

               1. Patients with vitiligo or alopecia

               2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               3. Any chronic skin condition that does not require systemic therapy

               4. Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               5. Patients with celiac disease controlled by diet alone

         14. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring AEs or compromise the ability of the patient to give written
             informed consent

         15. History of another primary malignancy except for:

               1. Malignancy treated with curative intent and with no known active disease ≥5 years
                  before the first dose of IP and of low potential risk for recurrence

               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               3. Adequately treated carcinoma in situ without evidence of disease

         16. History of allogenic stem cell transplant

         17. History of active primary immunodeficiency

         18. Active infection including, clinical evidence of active tuberculosis (cough >2 weeks'
             duration, fevers, night sweats, weight loss, and/or abnormal lung imaging), hepatitis
             B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human
             immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved
             HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and
             absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are
             eligible only if polymerase chain reaction is negative for HCV RNA.

         19. Receipt of live attenuated vaccine within 30 days prior to Cycle 1 Day 1. Note:
             Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab or
             tremelimumab and up to 30 days after the last dose of durvalumab or tremelimumab.

         20. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of durvalumab monotherapy or 180 days after
             the last dose of durvalumab + tremelimumab combination therapy.

         21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.

         22. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
             study regardless of treatment arm assignment.

         23. Any condition which, in the opinion of the investigator, would preclude participation
             in this trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 90 days after the last dose of study drug(s)
Safety Issue:
Description:To describe the safety and tolerability of durvalumab plus tremelimumab followed by concurrent durvalumab plus bladder radiation in patients as assessed by CTCAE version 5.0.

Secondary Outcome Measures

Measure:2-year disease-free survival (DFS) for Decipher test sub-type basal vs. Decipher test sub-type non-basal
Time Frame:2 years
Safety Issue:
Description:2-year disease-free survival (DFS) for Decipher test sub-type basal vs. Decipher test sub-type non-basal
Measure:Pathologic complete response rate on post-duravalumab/radiation TURBT
Time Frame:Cycle 4 Day 21
Safety Issue:
Description:Proportion of subjects with a pathologic complete response rate on post-duravalumab/radiation TURBT
Measure:Rate of salvage cystectomy
Time Frame:5 years
Safety Issue:
Description:Proportion of subjects undergoing a salvage cystectomy after discontinuing study drug(s)
Measure:5-year disease-free survival (DFS)
Time Frame:5 years
Safety Issue:
Description:Proportion of subjects remaining disease-free at 5 years
Measure:5-year overall survival (OS)
Time Frame:5 years
Safety Issue:
Description:Proportion of subjects alive at 5 years

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Daniel George, MD

Trial Keywords

  • Muscle-invasive bladder cancer
  • Decipher bladder test
  • Durvalumab
  • Tremelimumab
  • Bladder radiation
  • Urothelial carcinoma of the bladder

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