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A Study of Chemotherapy and Radiation Therapy Compared to Chemotherapy and Radiation Therapy Plus MEDI4736 (Durvalumab) Immunotherapy for Bladder Cancer Which Has Spread to the Lymph Nodes, the INSPIRE Study

NCT04216290

Description:

This phase II trial studies how well chemotherapy and radiation therapy alone works compared to chemotherapy and radiation therapy plus MEDI4736 (durvalumab) immunotherapy in treating bladder cancer which has spread to the lymph nodes. Standard chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with durvalumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving chemotherapy and radiation therapy with the addition of durvalumab may work better in helping tumors respond to treatment compared to chemotherapy and radiation therapy alone.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Chemotherapy and Radiation Therapy Compared to Chemotherapy and Radiation Therapy Plus MEDI4736 (Durvalumab) Immunotherapy for Bladder Cancer Which Has Spread to the Lymph Nodes, the INSPIRE Study
  • Official Title: Phase 2 Study of Bladder-SparIng Chemoradiation With MEDI4736 (Durvalumab) in Clinical Stage 3, Node PosItive Bladder Cancer (INSPIRE)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-08628
  • SECONDARY ID: NCI-2019-08628
  • SECONDARY ID: EA8185
  • SECONDARY ID: EA8185
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04216290

Conditions

  • Bladder Urothelial Carcinoma
  • Stage III Bladder Cancer AJCC v8
  • Stage IIIA Bladder Cancer AJCC v8
  • Stage IIIB Bladder Cancer AJCC v8

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboStep I, Arm B (chemotherapy)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinStep I, Arm B (chemotherapy)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexStep I, Arm B (chemotherapy)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Step II, Arm C (durvalumab, radiation therapy, chemotherapy)
Fluorouracil5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-Fu, 5FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Step II, Arm C (durvalumab, radiation therapy, chemotherapy)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Step I, Arm B (chemotherapy)
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Step I, Arm B (chemotherapy)
MitomycinAmetycine, Jelmyto, MITO, Mito-C, Mito-Medac, Mitocin, Mitocin-C, Mitolem, Mitomycin C, Mitomycin-C, Mitomycin-X, Mitomycine C, Mitosol, Mitozytrex, Mutamycin, Mutamycine, NCI-C04706Step II, Arm C (durvalumab, radiation therapy, chemotherapy)
Vinblastine Sulfate29060 LE, 29060-LE, Exal, Velban, Velbe, Velsar, VINCALEUKOBLASTINEStep I, Arm B (chemotherapy)

Purpose

This phase II trial studies how well chemotherapy and radiation therapy alone works compared to chemotherapy and radiation therapy plus MEDI4736 (durvalumab) immunotherapy in treating bladder cancer which has spread to the lymph nodes. Drugs used in standard chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with durvalumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving chemotherapy and radiation therapy with the addition of durvalumab may work better in helping tumors respond to treatment compared to chemotherapy and radiation therapy alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare the clinical complete response rate (cCR) after chemoradiotherapy (chemoRT)
      with or without MEDI4736 (durvalumab) in node-positive bladder cancer patients.

      SECONDARY OBJECTIVES:

      I. To compare the toxicity profile in both arms using the Common Terminology Criteria for
      Adverse Events (CTCAE).

      II. To estimate the progression-free survival (PFS) in both arms. III. To estimate overall
      survival (OS) post randomization in both arms. IV. To estimate the bladder intact event free
      survival (BIEFS) in both arms. V. To estimate the metastasis free survival (MFS) in both
      arms. VI. To estimate bladder cancer specific survival in both arms. VII. To estimate the
      complete clinical response duration in both arms. VIII. To estimate salvage cystectomy rates
      in both arms.

      EXPLORATORY OBJECTIVE:

      I. Planned subgroup analyses for clinical outcome (clinical complete response [CR] rate post
      chemoRT+/- MEDI4736 [durvalumab], MFS, OS, PFS) based on stratification factors.

      TRANSLATIONAL OBJECTIVE:

      I. To collect specimens- urine, blood, stool and tissue, at pre- and post-treatment, at 6
      months and 12 months' time from completing chemoRT+/- MEDI4736 (durvalumab) to determine
      predictive or prognostic markers.

      OUTLINE:

      STEP 1 - REGISTRATION: Patients are assigned to 1 of 2 arms.

      ARM A: Patients registered after completion of >= 3 cycles of induction chemotherapy proceed
      to Step 2 - Randomization.

      ARM B: Chemotherapy naive patients receive 1 of 4 chemotherapy regimens: gemcitabine
      hydrochloride intravenously (IV) over 30-60 minutes on days 1 and 8 every 21 days for 3
      cycles; carboplatin IV over 30-60 minutes and gemcitabine hydrochloride IV over 30-60 minutes
      on days 1 and 8 every 21 days for 3 cycles; gemcitabine hydrochloride IV over 30-60 minutes
      on days 1 and 8 and cisplatin IV 30-60 minutes on day 1 every 21 days for 3 cycles; or
      methotrexate IV over 3 minutes, vinblastine sulfate IV over 3 minutes, doxorubicin
      hydrochloride IV over 5 minutes, and cisplatin IV over 30-60 minutes on day 1 every 14 days
      for 3 cycles. Cycles repeat in the absence of disease progression or unacceptable toxicity.

      STEP 2 - RANDOMIZATION: Patients are randomized to 1 of 2 arms.

      ARM C: Patients undergo radiation therapy for 6-8 weeks. Beginning 4 days before or after
      starting radiation therapy, patients receive durvalumab IV over 60 minutes on day 1. Cycles
      repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable
      toxicity. Beginning 4 days before or after starting radiation therapy, patients also receive
      gemcitabine hydrochloride IV over 30-60 minutes twice weekly for 6 weeks; cisplatin IV over
      30-60 minutes for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and
      fluorouracil IV on days 1-5 and 16-20 of radiation in the absence of disease progression or
      unacceptable toxicity.

      ARM D: Patients undergo radiation therapy for 6-8 weeks. Beginning 4 days before or after
      starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60
      minutes twice weekly for 6 weeks; cisplatin IV over 30-60 minutes for 6 weeks; or mitomycin
      IV over 30 minutes on day 1 of radiation and fluorouracil IV on days 1-5 and 16-20 of
      radiation in the absence of disease progression or unacceptable toxicity.

      STEP 3 - REGISTRATION (POST CONCURRENT CHEMORT +/- DURVALUMAB): Patients are assigned to 1 of
      2 arms.

      ARM E: Patients previously randomized to Arm C (chemoradiation and durvalumab) who achieve
      clinical CR or clinical benefit receive durvalumab IV over 60 minutes on day 1. Cycles repeat
      every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity.

      ARM F: Patients previously randomized to Arm D who achieve clinical CR or clinical benefit,
      or patients previously randomized to Arm C with no clinical CR or clinical benefit undergo
      observation.

      After completion of study treatment, patients are followed up every 12 weeks for 1 year,
      every 6 months for 1 year, and then annually for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Step I, Arm A (no intervention)No InterventionARM A: Patients registered after completion of >= 3 cycles of induction chemotherapy proceed to Step 2 - Randomization.
    Step I, Arm B (chemotherapy)ExperimentalChemotherapy naive patients receive 1 of 4 chemotherapy regimens: gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 every 21 days for 3 cycles; carboplatin IV over 30-60 minutes and gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 every 21 days for 3 cycles; gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and cisplatin IV 30-60 minutes on day 1 every 21 days for 3 cycles; or methotrexate IV over 3 minutes, vinblastine sulfate IV over 3 minutes, doxorubicin hydrochloride IV over 5 minutes, and cisplatin IV over 30-60 minutes on day 1 every 14 days for 3 cycles. Cycles repeat in the absence of disease progression or unacceptable toxicity.
    • Carboplatin
    • Cisplatin
    • Doxorubicin Hydrochloride
    • Gemcitabine Hydrochloride
    • Methotrexate
    • Vinblastine Sulfate
    Step II, Arm C (durvalumab, radiation therapy, chemotherapy)ExperimentalPatients undergo radiation therapy for 6-8 weeks. Beginning 4 days before or after starting radiation therapy, patients receive durvalumab IV over 60 minutes on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes twice weekly for 6 weeks; cisplatin IV over 30-60 minutes for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity.
    • Durvalumab
    • Fluorouracil
    • Gemcitabine Hydrochloride
    • Mitomycin
    Step II, Arm D (radiation therapy, chemotherapy)Active ComparatorPatients undergo radiation therapy for 6-8 weeks. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes twice weekly for 6 weeks; cisplatin IV over 30-60 minutes for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity.
    • Cisplatin
    • Fluorouracil
    • Gemcitabine Hydrochloride
    • Mitomycin
    Step III, Arm E (durvalumab)ExperimentalPatients previously randomized to Arm C (chemoradiation and durvalumab) who achieve clinical CR or clinical benefit receive durvalumab IV over 60 minutes on day 1. Cycles repeat every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity.
    • Durvalumab
    Step III, Arm F (observation)Active ComparatorPatients previously randomized to Arm D who achieve clinical CR or clinical benefit, or patients previously randomized to Arm C with no clinical CR or clinical benefit undergo observation.

      Eligibility Criteria

              Inclusion Criteria:
      
                -  Step 1 (Registration) Inclusion
      
                -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
                   0-2 at the time of registration
      
                -  Patient must have histologically proven pure or mixed urothelial cancer of the bladder
      
                     -  NOTE: Small cell carcinoma is excluded, however other variant histologies are
                        permitted provided a component of urothelial carcinoma is present
      
                -  Prior to receiving any induction chemotherapy, patient must have documented
                   node-positive and non-metastatic disease (any T, N1-2 M0). For non-muscle invasive
                   disease on transurethral resection of bladder tumor (TURBT), node positive disease
                   MUST be biopsy proven for patient to be eligible
      
                     -  Node positivity will be defined by the official interpretation of imaging
                        studies. Positive lymph nodes must be imaging read with suspicious lymph node
                        (LN) >= 1.0 cm in short axis to be eligible, with or without biopsy as documented
                        by a radiologist at the treating center. LN Biopsy is not mandatory but
                        encouraged if feasible and safe per physician discretion. Patients with a
                        negative biopsy of nodes determined to be suspicious on imaging are not eligible
      
                     -  Patients with clinical N3 disease are ineligible
      
                -  Induction Chemotherapy Requirements
      
                     -  For patients registered to this protocol post-completion of induction systemic
                        chemotherapy:
      
                          -  Patient must have received at least 3 cycles of induction chemotherapy
                             (cisplatin-based chemotherapy OR non-cisplatin based chemotherapy) with no
                             evidence of progressive disease (PD) on post-chemotherapy imaging. The last
                             dose of chemotherapy must be within 12 weeks of registration
      
                          -  Patient who have received more than 3 cycles of induction systemic
                             chemotherapy are also eligible
      
                          -  Patient must have had a CR, PR or SD to induction chemotherapy on standard
                             imaging
      
                               -  NOTE: Patients who have only received 2 cycles of induction
                                  chemotherapy and demonstrated clinical response (complete response [CR]
                                  OR partial response [PR], OR stable disease [SD]) may be considered for
                                  enrollment only after consultation and approval by the study chair
                                  under exceptional circumstances where 3rd cycle cannot be delivered.
                                  Documentation of correspondences with the study chair must be kept on
                                  file. We encourage all patients to get 3 cycles of induction
                                  chemotherapy
      
                     -  For patients registered to this protocol prior to starting induction systemic
                        chemotherapy:
      
                          -  Patient must agree to a planned treatment with 3 cycles of induction
                             chemotherapy (physician's choice)
      
                          -  Patient will again be restaged after completion of induction chemotherapy
                             and prior to randomization to chemoRT +/- MEDI4736 (durvalumab)
      
                          -  Patient must have a CR, PR or SD to induction chemotherapy on standard
                             imaging prior to randomization to chemoradiotherapy
      
                -  History of previously adequately treated non-muscle invasive bladder cancer (NMIBC)
                   are not excluded; presence of concomitant active upper tract tumors or urethra tumors
                   are not allowed. Previously treated urothelial cancer or histological variant at any
                   site outside of the urinary bladder are allowed, provided they have been
                   Ta/T1/carcinoma in situ (CIS) and post treatment follow up imaging and endoscopic
                   evaluation shows no evidence of disease
      
                -  Previous exposure to immune checkpoint inhibitor for non-muscle invasive disease is
                   allowed. If given for NMIBC, the last dose must have been completed > 12 months prior
                   to registration
      
                -  For female patients registered on the study
      
                     -  Women must not be pregnant or breast-feeding due to the potential harm to an
                        unborn fetus and possible risk for adverse events in nursing infants with the
                        treatment regimens being used
      
                     -  All female of childbearing potential must have a blood test or urine study within
                        14 days prior to registration to rule out pregnancy
      
                     -  A female of childbearing potential is defined as any woman, regardless of sexual
                        orientation or whether they have undergone tubal ligation, who meets the
                        following criteria: 1) has achieved menarche at some point, 2) has not undergone
                        a hysterectomy or bilateral oophorectomy; or 3) has not been naturally
                        postmenopausal (amenorrhea following cancer therapy does not rule out
                        childbearing potential) for at least 24 consecutive months (i.e., has had menses
                        at any time in the preceding 24 consecutive months)
      
                -  For patients registered prior to induction chemotherapy only:
      
                     -  Women of childbearing potential and sexually active males must not expect to
                        conceive or father children by using accepted and effected method(s) of
                        contraception or by abstaining from sexual intercourse from the time of
                        registration for the duration of their participation in the study and continue
                        for at least 3 months after the last dose of protocol treatment
      
                -  Leukocytes >= 3,000/mcL (obtained < 14 days prior to registration)
      
                -  Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to registration)
      
                -  Hemoglobin >= 9 g/dL (obtained < 14 days prior to registration)
      
                -  Platelets >= 100,000/mcL (obtained < 14 days prior to registration)
      
                -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days
                   prior to registration)
      
                -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
                   [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
                   =< 2.5 x institutional ULN (obtained < 14 days prior to registration)
      
                -  Must have adequate renal function as evidenced by calculated (Cockcroft's formula)
                   creatinine clearance or 24 hours actual creatinine clearance >= 30mL/min. The
                   creatinine used to calculate the clearance result must have been obtained within 14
                   days prior to registration. Actual body weight, not ideal body weight, must be used in
                   the calculation
      
                -  Patients with human immunodeficiency virus (HIV) on effective anti-retroviral therapy
                   with undetectable viral load within 6 months of registration are eligible for this
                   trial
      
                -  Patients with a prior or concurrent malignancy whose natural history or treatment does
                   not have the potential to interfere with the safety or efficacy assessment of the
                   investigational regimen are eligible for this trial. Site is encouraged to discuss
                   with the chair if needed prior to enrollment
      
                -  Patients with known history or current symptoms of cardiac disease, or history of
                   treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
                   function using the New York Heart Association Functional Classification. To be
                   eligible for this trial, patients should be class 2B or better
      
                -  Patient must have a life expectancy of at least 12 weeks, as determined by the
                   treating physician
      
                -  Patient must be 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
      
                -  Step 2 (Randomization) Inclusion Criteria
      
                -  Patient must have an ECOG performance status of 0-1 at the time of randomization
      
                -  Patient must undergo selection of concurrent chemotherapy regimen
      
                -  Patient must agree to undergo CT simulation and treatment planning on the day of
                   randomization. If this is the first case registered at the site, then a pre-treatment
                   radiation therapy (RT) review will be required and will take up to 3 business days.
                   The patient cannot start radiation treatment prior to successful completion of this
                   pre-treatment review. Therefore, careful planning is necessary to meet the deadline of
                   starting radiation with approximately 3 weeks of randomization and within 12 weeks of
                   the end of induction chemotherapy. We anticipate that the radiation oncologist should
                   get at least 3 weeks of time between CT simulation and start of chemoRT
      
                -  Chemoradiotherapy should be planned to start up to 12 weeks after the end of induction
                   chemotherapy, but after imaging and cystoscopic restaging, randomization, and any
                   pretreatment radiation quality assurance (QA) that is required
      
                -  Women must not be pregnant or breast-feeding due to the potential harm to an unborn
                   fetus and possible risk for adverse events in nursing infants with the treatment
                   regimens being used
      
                     -  All females of childbearing potential must have a blood test or urine study
                        within 14 days prior to registration to rule out pregnancy
      
                     -  A female of childbearing potential is defined as any woman, regardless of sexual
                        orientation or whether they have undergone tubal ligation, who meets the
                        following criteria: 1) has achieved menarche at some point, 2) has not undergone
                        a hysterectomy or bilateral oophorectomy; or 3) has not been naturally
                        postmenopausal (amenorrhea following cancer therapy does not rule out
                        childbearing potential) for at least 24 consecutive months (i.e., has had menses
                        at any time in the preceding 24 consecutive months)
      
                -  Women of childbearing potential and sexually active males must not expect to conceive
                   or father children by using accepted and effective method(s) of contraception or by
                   abstaining from sexual intercourse at least one week prior to the start of treatment
                   and continue for at least 3 months after the last dose of the protocol treatment
      
                -  Leukocytes >= 3,000/mcL (obtained < 14 days prior to randomization)
      
                -  Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to randomization)
      
                -  Hemoglobin >= 9 g/dL (obtained < 14 days prior to randomization)
      
                -  Platelets >= 100,000/mcL (obtained < 14 days prior to randomization)
      
                -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days
                   prior to randomization)
      
                -  AST (SGOT)/ALT (SGPT) =< 2.5 x institutional ULN (obtained < 14 days prior to
                   randomization)
      
                -  Must have adequate renal function as evidenced by calculated (Cockcroft's formula)
                   creatinine clearance or 24 hours actual creatinine clearance >= 30 mL/min. The
                   creatinine used to calculate the clearance result must have been obtained within 14
                   days prior to randomization. Actual body weight, not ideal body weight, must be used
                   in the calculation
      
                -  Step 3 (Post chemoRT+/- MEDI4736 [durvalumab], prior to starting adjuvant MEDI4736
                   [durvalumab] versus [vs.] observation) Inclusion Criteria
      
                -  Patient must have evaluation to determine clinical outcome post chemoRT+/- MEDI4736
                   (durvalumab) with imaging and cystoscopy with biopsy confirmation to ensure no
                   progression and absence of >= T2 disease in the bladder
      
                -  Patient must have achieved either complete clinical response OR have demonstrated
                   clinical benefit prior to continuing onto adjuvant MEDI4736 (durvalumab)
      
                -  Patients who are to go on the adjuvant MEDI4736 (durvalumab) arm must have recovered
                   to at least grade 2 or less immune related adverse events (AE) prior to starting
                   treatment except for immune related alopecia, clinically asymptomatic
                   endocrinopathies. For patients who may have gotten immune related AEs during chemoRT+
                   MEDI4736 (durvalumab), registration could be delayed up to additional 4 weeks to
                   ensure recovery to at least grade 2 or lower prior to starting adjuvant therapy.
                   However patients with MEDI4736 (durvalumab) related AEs that require permanent
                   discontinuation of MEDI4736 (durvalumab) will not continue on the adjuvant treatment
                   regardless of the response
      
                -  ANC >= 1,000 mcL (within 4 weeks of start of day 1 [D1] of adjuvant treatment)
      
                -  Hemoglobin >= 8 g/dL (within 4 weeks of start of D1 of adjuvant treatment)
      
                -  Platelets >= 70,000 mcL (within 4 weeks of start of D1 of adjuvant treatment)
      
                -  Patient on the chemoRT arm must have achieved either complete clinical response OR
                   have demonstrated clinical benefit prior to be placed on the observation alone arm
      
              Exclusion Criteria:
      
                -  Step 1 (Registration) Exclusion
      
                -  Patient must not have received any previous radiation therapy to the pelvic area
      
                -  Autoimmune conditions: patient must not have history of prior documented autoimmune
                   disease within the past 2 years
      
                     -  NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring
                        systemic treatment within the past 2 years) are not excluded. Patients with
                        history of completely resolved childhood asthma or atopy are not excluded.
                        Patients with asthma not requiring more than 10 mg/d or equivalent of prednisone
                        are not excluded. Patients with well-controlled hypothyroidism on thyroxine
                        replacement will be eligible as well. Patients with known history of
                        hypoadrenalism on maintenance steroids will be eligible. Patients with type I
                        diabetes mellitus will be eligible, provided their disease is well controlled.
                        History of autoimmune related alopecia is also not an exclusion criteria
      
                     -  Patient with active or prior documented inflammatory bowel disease (e.g., Crohn's
                        disease, ulcerative colitis) will be excluded
      
                     -  Patient with a history of and/or confirmed pneumonitis will not be eligible
      
                     -  Patient with a history of primary immunodeficiency will not be eligible
      
                     -  Patient with history of allogeneic organ transplant are not eligible
      
                -  Patient must not have clinically significant liver disease that precludes patient from
                   treatment regimens prescribed on the study (including, but not limited to, active
                   viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease)
      
                -  Patient must not have any unresolved toxicity (National Cancer Institute [NCI] CTCAE
                   grade >= 2) from previous anti-cancer therapy with the exception of alopecia,
                   vitiligo, and the laboratory values
      
                     -  Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis
                        after consultation with the study chair
      
                     -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                        treatment with MEDI4736 (durvalumab) may be included only after consultation with
                        the study chair. Documentation of correspondences with the study chair must be
                        kept on file
      
                -  Step 2 (Randomization) Exclusion Criteria
      
                -  Patient must have no signs of progression (CR/PR or SD) based on restaging imaging and
                   cystoscopy after completion of induction chemotherapy, which consists of:
      
                     -  Computed tomography (CT) chest, abdomen, or pelvis. Magnetic resonance imaging
                        (MRI) pelvis can be used instead of CT per treating physician discretion. The
                        imaging must be done within 4 weeks prior to randomization
      
                     -  Cystoscopic evaluation and attempt to perform maximal transurethral resection of
                        bladder tumor (TURBT) performed by the participating urologist ideally within 8
                        weeks but up to 10 weeks is allowed prior to randomization. If maximal TURBT is
                        not possible for medical reasons, the enrollment must be discussed and approved
                        with the study chair. Documentation of correspondences with the study chair must
                        be kept of file
      
                -  Autoimmune conditions: Patient must not have a history of active or prior documented
                   autoimmune disease within the past 2 years
      
                     -  NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring
                        systemic treatment within the past 2 years) are not excluded. Patients with
                        history of completely resolved child
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Clinical complete response (CR)
      Time Frame:Up to 6 years
      Safety Issue:
      Description:

      Secondary Outcome Measures

      Measure:Metastasis-free survival
      Time Frame:From randomization to first evidence of metastatic disease or death from any cause, assessed up to 6 years
      Safety Issue:
      Description:Will be estimated by the Kaplan-Meier method.
      Measure:Bladder-intact event-free survival (BI-EFS)
      Time Frame:From randomization to the first BI-EFS event, assessed up to 6 years
      Safety Issue:
      Description:Will be estimated by the Kaplan-Meier method.
      Measure:Bladder cancer specific survival
      Time Frame:From randomization to death from bladder cancer, assessed up to 6 years
      Safety Issue:
      Description:Will be estimated by the Kaplan-Meier method.
      Measure:Overall survival
      Time Frame:From randomization to death from any cause, assessed up to 6 years
      Safety Issue:
      Description:Will be estimated by the Kaplan-Meier method.
      Measure:Progression-free survival
      Time Frame:From randomization to first of local progression, nodal or distant metastasis, or death from any cause, assessed up to 6 years
      Safety Issue:
      Description:Will be estimated by the Kaplan-Meier method.
      Measure:Complete response duration
      Time Frame:From the date of the biopsy documenting the complete response to the time of muscle invasive recurrence, local progression, evidence of metastatic disease or death due to any cause, assessed up to 6 years
      Safety Issue:
      Description:Stratified Cox proportional hazards models will be used to estimate hazard ratios in all eligible patients.
      Measure:Salvage cystectomy rate
      Time Frame:Up to 6 years
      Safety Issue:
      Description:Rate will be reported as a proportion of patients who do not experience clinical benefit after chemoradiotherapy (chemoRT) +/- MEDI4736 (durvalumab) along with a 90% confidence interval. Stratified Cox proportional hazards models will be used to estimate hazard ratios in all eligible patients.
      Measure:Incidence of adverse events
      Time Frame:Up to 1 year
      Safety Issue:
      Description:Assessed using the Common Terminology Criteria for Adverse Events (CTCAE). Toxicity will be evaluated in all treated patients, regardless of eligibility.

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:National Cancer Institute (NCI)

      Last Updated

      September 18, 2020