Clinical Trials /

Durvalumab and Standard Chemotherapy Before Surgery in Treating Patients With Variant Histology Bladder Cancer

NCT03912818

Description:

This phase II trial studies the side effects of durvalumab and chemotherapy before surgery in treating patients with variant histology bladder cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as methotrexate, vinblastine, doxorubicin, cisplatin, gemcitabine, and carboplatin, 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. Giving durvalumab in addition to standard chemotherapy may lead to better outcomes in patients with variant histology bladder cancer.

Related Conditions:
  • Bladder Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab and Standard Chemotherapy Before Surgery in Treating Patients With Variant Histology Bladder Cancer
  • Official Title: Phase 2 Open Label Study of Durvalumab With Neoadjuvant Chemotherapy in Variant Histology Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: BLDR0028
  • SECONDARY ID: NCI-2019-01364
  • SECONDARY ID: BLDR0028
  • SECONDARY ID: IRB-48062
  • NCT ID: NCT03912818

Conditions

  • Bladder Adenocarcinoma
  • Bladder Mixed Adenocarcinoma
  • Bladder Squamous Cell Carcinoma
  • Bladder Urothelial Carcinoma
  • Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant
  • Infiltrating Bladder Urothelial Carcinoma With Giant Cells
  • Infiltrating Bladder Urothelial Carcinoma With Glandular Differentiation
  • Infiltrating Bladder Urothelial Carcinoma With Trophoblastic Differentiation
  • Infiltrating Bladder Urothelial Carcinoma, Clear Cell Variant
  • Infiltrating Bladder Urothelial Carcinoma, Micropapillary Variant
  • Infiltrating Bladder Urothelial Carcinoma, Nested Variant
  • Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant

Interventions

DrugSynonymsArms
CarboplatinCarboplat, Carboplatino, Carbosol, Paraplatin, ParaplatineCohort III (Durvalumab, carbo-gem)
CisplatinAbiplatin, Briplatin, Cis-platinum, Cismaplat, Citoplatino, Plastistil, PlatinolTreatment (durvalumab, DD MVAC)
DoxorubicinAdriablastin, Hydroxyl Daunorubicin, RubexTreatment (durvalumab, DD MVAC)
DurvalumabImfinzi, MEDI-4736Treatment (durvalumab, DD MVAC)
GemcitabineDifluorodeoxycytidine, GemzarCohort II (durvalumab, cis-gem)
MethotrexateAbitrexate, Amethopterin, Brimexate, Methotrexate Methylaminopterin, MetotrexatoTreatment (durvalumab, DD MVAC)
VinblastineVincaleucoblastine, Vinblastine Sulfate, vincaleukoblastine, sulfateTreatment (durvalumab, DD MVAC)

Purpose

This phase II trial studies the side effects of durvalumab and chemotherapy before surgery in treating patients with variant histology bladder cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as methotrexate, vinblastine, doxorubicin, cisplatin, gemcitabine, and carboplatin, 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. Giving durvalumab in addition to standard chemotherapy may lead to better outcomes in patients with variant histology bladder cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety and tolerability of durvalumab in combination with chemotherapy in
      subjects with variant histology bladder cancer.

      SECONDARY OBJECTIVES:

      I. To determine the percent of subjects post-neoadjuvant chemo-immunotherapy who achieve
      tumor stage of pT2 N0 M0 or better (pT1 N0 or pT0) at cystectomy.

      II. To assess the response rate (RR) in post-neoadjuvant chemo immunotherapy as assessed by
      the investigator using imaging at screening and post treatment.

      III. To assess the molecular characterization of tumor tissue pre-neoadjuvant therapy and at
      post treatment cystectomy (for subject who have persistent disease).

      IV. To determine circulating free deoxyribonucleic acid (DNA) (cfDNA) (cell free DNA) at
      baseline, during treatment and following post treatment cystectomy using Natera sequencing
      platform.

      OUTLINE: Patients are assigned to 1 of 3 cohorts.

      COHORT I: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1,
      methotrexate over 3 minutes on day 1, vinblastine IV over 3 minutes on day 2, doxorubicin IV
      over 5 minutes on day 2, and cisplatin IV over 60 minutes on day 2. Cycles repeat every 14
      days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients
      undergo cystectomy within 6 weeks.

      COHORT II: Patients receive durvalumab IV over 60 minutes on day 1, cisplatin IV over 60
      minutes on day 1, and gemcitabine IV over 60 minutes on days 1 and 8. Cycles repeat every 21
      days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients
      undergo cystectomy within 6 weeks.

      COHORT III: Patients receive durvalumab IV over 60 minutes on day 1, carboplatin IV over 60
      minutes on day 1, and gemcitabine IV over 60 minutes on days 1 and 8. Cycles repeat every 21
      days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients
      undergo cystectomy within 6 weeks.

      After surgery, patients are followed up at 30 and 90 days.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort II (durvalumab, cis-gem)ExperimentalPatients receive durvalumab IV over 60 minutes on day 1, cisplatin IV over 60 minutes on day 1, and gemcitabine IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.
  • Cisplatin
  • Durvalumab
  • Gemcitabine
Cohort III (Durvalumab, carbo-gem)ExperimentalPatients receive durvalumab IV over 60 minutes on day 1, carboplatin IV over 60 minutes on day 1, and gemcitabine IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.
  • Carboplatin
  • Durvalumab
  • Gemcitabine
Treatment (durvalumab, DD MVAC)ExperimentalPatients receive durvalumab IV over 60 minutes on day 1, methotrexate over 3 minutes on day 1, vinblastine IV over 3 minutes on day 2, doxorubicin IV over 5 minutes on day 2, and cisplatin IV over 60 minutes on day 2. Cycles repeat every 14 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.
  • Cisplatin
  • Doxorubicin
  • Durvalumab
  • Methotrexate
  • Vinblastine

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent.

          -  Eastern Collaborative Oncology Group (ECOG) performance status score of 0 or 1.

          -  Body weight > 30 kg.

          -  Absolute neutrophil count (ANC) >= 1500 mm^3 (within 28 days before the first study
             treatment).

          -  Hemoglobin >= 9.0 g/dL (within 28 days before the first study treatment).

          -  Platelet count >= 100,000 per mm^3 (within 28 days before the first study treatment).

          -  Serum bilirubin =< 1.5 X upper limit of normal (ULN) (within 28 days before the first
             study treatment). Subjects with Gilbert's syndrome will be considered after
             consultation with the principal investigator (PI).

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X ULN
             (within 28 days before the first study treatment).

          -  For subjects who will be treated with dose dense methotrexate, vinblastine,
             doxorubicin, and cisplatin (DD MVAC) or cisplatin and gemcitabine (CG), creatinine
             clearance >= 50 mL/min as measured based on Cockcroft-Gault glomerular filtration rate
             estimation (within 28 days before the first study treatment).

          -  For subjects who will be treated with carboplatin and gemcitabine (Carbo Gem),
             creatinine clearance >= 30 mL/min as measured based on Cockcroft-Gault glomerular
             filtration rate estimation (within 28 days before the first study treatment).

          -  Anticipated life expectancy of >= 12 weeks as assessed by the investigator.

          -  Histologically proven carcinoma of the bladder of variant urothelial carcinoma
             histologies which include squamous, adenocarcinoma, nested, plasmacytoid,
             micropapillary, glandular differentiation, lipid cell, clear cell, undifferentiated,
             giant cell, trophoblastic, sarcomatoid, carcinosarcoma; subjects with mixed cell types
             are eligible.

          -  Clinical T stage 2 (cT2) T4a, N0 N1, M0 disease. Clinical T stage is based on the
             transurethral resection of bladder tumor (TURBT) sample and imaging studies. Subjects
             must undergo cystoscopy and TURBT as part of screening within 30 days prior to
             registration.

          -  Abdominal/pelvic imaging by computed tomography (CT) or magnetic resonance imaging
             (MRI) scan; chest imaging by CT scan or x-ray (CT/positron emission tomography (PET)
             within 30 days prior to registration.

          -  Resting 12 lead electrocardiogram (ECG) documenting Fridericia's correction formula
             (QTcF) =< 470 ms.

          -  Consent to provide a formalin fixed paraffin embedded (FFPE) tissue block and 1
             hematoxylin and eosin (H and E) slide (preferred) or one of the following:

               -  10 unstained slides and 1 H and E slide OR

               -  Tissue block punches and 1 H and E slide, OR

               -  4 to 6 cores and 1 H and E slide.

          -  Willing and able to comply with the protocol for the duration of the study including
             undergoing treatment, scheduled visits and examinations including follow up.

          -  For female subjects:

               -  Women < 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  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, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

        Exclusion Criteria:

          -  Prior treatment with systemic cytotoxic chemotherapy for muscle invasive bladder
             cancer (MIBC).

          -  Class III or IV heart failure, according to New York Heart Association
             Classifications. For patient on the dd MVAC or Cis-Gem arm, left ventricular ejection
             fraction of less than 50%

          -  Administration of an investigational therapeutic agent within 28 days of protocol
             registration.

          -  Current participation in a trial using an investigational agent. Subjects may
             participate in non-interventional, observational studies.

          -  Prior treatment with an anti-programmed cell death 1(PD1) or anti--programmed cell
             death ligand 1(PDL1) inhibitor including durvalumab.

          -  Receiving chronic systemic steroid therapy in dosing exceeding 10 mg daily of
             prednisone or equivalent per day within 7 days prior to the first dose of study
             treatment.

          -  History of another malignancy within 5 years before the first dose of study drug, or
             any evidence of residual disease from a previously diagnosed malignancy. Subjects with
             the following are allowed on study:

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

               -  Adequately treated carcinoma in situ without evidence of disease e.g., cervical
                  cancer in situ.

          -  Immunosuppressive medication within 28 days before the first dose of durvalumab, with
             the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids
             at physiological doses, which are not to exceed 10 mg/day of prednisone, or an
             equivalent corticosteroid. The following are exceptions to this criterion:

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

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

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication) or anti emetic during chemotherapy.

          -  History of allogenic organ transplantation.

          -  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:

               -  Subjects with vitiligo or alopecia

               -  Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Subjects with celiac disease controlled by diet alone.

          -  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 adverse events (AEs) or compromise the ability of the subject to
             give written informed consent.

          -  History of active primary immunodeficiency.

          -  Active infection including:

               -  Tuberculosis (clinical evaluation that includes clinical history, physical
                  examination and radiographic findings, and tuberculosis (TB) testing in line with
                  local practice)

               -  Hepatitis B (known positive hepatitis B virus (HBV) surface antigen (HBsAg)
                  result)

               -  Hepatitis C

               -  Human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies).

               -  Subjects with a past or resolved HBV infection (defined as the presence of
                  hepatitis B core antibody (anti HBc) and absence of HBsAg) are eligible. Subjects
                  positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
                  reaction is negative for HCV ribonucleic acid (RNA).

          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of study
             medication. Note: subjects, if enrolled, should not receive live vaccine while
             receiving study medication and up to 30 days after the last dose of study medication.

          -  Pregnant or lactating.

          -  Male or female subject of reproductive potential who are not willing to employ
             effective birth control from screening to 90 days after the last dose of durvalumab
             monotherapy.

          -  Known allergy or hypersensitivity to any of the study medications or any of the study
             medication excipients.

          -  Judgment by the investigator that the subject is unsuitable to participate in the
             study and the subject is unlikely to comply with study procedures, restrictions and
             requirements.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of grade 3-5 adverse events
Time Frame:At 120 days
Safety Issue:
Description:Will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The safety and tolerability of durvalumab in combination with chemotherapy in subjects with variant histology bladder cancer who initiate study treatment will be assessed as the number, by treatment cohort, of grade 3, 4, or 5 adverse events, considered probably or definitely related by the investigator. The outcome will be reported as a number.

Secondary Outcome Measures

Measure:Proportion of subjects who initiate study treatment and achieve tumor stage of pT2 N0 M0 or better (e.g., pT0, pT1 N0) at cystectomy
Time Frame:At 20 weeks
Safety Issue:
Description:Achievement of tumor staging will be determined by pathologist at cystectomy and reported by treatment cohort. Assessed per National Comprehensive Cancer Network bladder cancer guidelines. T0 N0 M0 = No evidence of primary tumor T1 N0 M0 = Tumor staging by pathological assessment detected in lamina propria (T0), with no tumor positive nodes (N0). T2 N0 M0 = Tumor staging by pathological assessment detected in muscularis propria (pT2), with no tumor positive nodes (N0) or tumor metastases (M0) observed.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Stanford University

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