Clinical Trials /

Durvalumab And Radiation Therapy Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder

NCT02891161

Description:

This is an open label, multi-institutional, single arm study of a phase Ib study, followed by a phase II study of durvalumab with radiation therapy (RT) in patients with urothelial cancer (UC). No randomization or blinding is involved.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab And Radiation Therapy Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder
  • Official Title: Phase Ib/II Study of Concurrent Durvalumab And Radiation Therapy (DUART) Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder: Big Ten Cancer Research Consortium BTCRC-GU15-023

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-GU15-023
  • NCT ID: NCT02891161

Conditions

  • Urothelial Cancer

Interventions

DrugSynonymsArms
durvalumabArm A: Safety Run In Phase Ib

Purpose

This is an open label, multi-institutional, single arm study of a phase Ib study, followed by a phase II study of durvalumab with radiation therapy (RT) in patients with urothelial cancer (UC). No randomization or blinding is involved.

Detailed Description

      OUTLINE: This is a multi-center study.

      The phase Ib study will evaluate the safety of combining durvalumab with RT followed by
      adjuvant durvalumab. The phase II study will estimate the Progression Free Survival (PFS)
      and Disease Control Rate (DCR) with durvalumab plus RT followed by single agent durvalumab
      for patients with UC of bladder.

      PHASE Ib INVESTIGATIONAL TREATMENT:

      Cohort 1 will consist of up to 6 patients who will receive durvalumab 1500mg 2 doses Q4
      weekly with RT to gross disease, 64.8 Gy, 36 fractions on weekdays over about 7 weeks.
      Durvalumab will start on Day 1 of RT.

      Three patients will be enrolled initially. If 2 or more patients (out of 3) experience
      dose-limiting toxicity (DLT), the combined treatment will be considered unsafe. Otherwise,
      an additional 3 patients will be treated at the same dose. If 0 or 1 patient experience DLT,
      the dose of durvalumab will be deemed safe for phase 2 part of the study. If, however, 2 or
      more patients (out of 6) experience DLT, the combined treatment will be considered unsafe.

      Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks
      (±7 days) for a total period of up to 12 months. Adjuvant durvalumab treatment will be
      started 3-4 weeks post completion of durvalumab and RT.

      PHASE II INVESTIGATIONAL TREATMENT:

      Subjects will receive durvalumab 1500mg 2 doses Q4 weekly with RT to gross disease, 64.8 Gy,
      36 fractions on weekdays over about 7 weeks. Durvalumab will start on Day 1 of RT.

      Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks
      (±7 days) for a total period of up to 12 months. Adjuvant durvalumab treatment will be
      started 3-4 weeks post completion of durvalumab and RT.

      Life expectancy of >6 months per treating physician.

      Adequate organ and marrow function as defined below:

        1. Hemoglobin ≥ 9.0 g/dL

        2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)

        3. Platelet count ≥ 100 x 109/L (>100,000 per mm3)

        4. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply
           to subjects 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)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver
           metastases are present, in which case it must be ≤ 5x ULN.

        6. Serum creatinine CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)
           or by 24-hour urine collection for determination of creatinine clearance:
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Safety Run In Phase IbExperimentalSubjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1 of RT. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT.
  • durvalumab
Arm B: Investigational Treatment Phase IIExperimentalSubjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1 of RT. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT.
  • durvalumab

Eligibility Criteria

        Inclusion Criteria:

        Phase Ib subjects must meet the following inclusion criteria:

          -  Locally advanced urothelial cancer of bladder with any of the following:

               1. T3-4, N0-2 M0, OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR
                  medically unfit for surgery, OR cisplatin ineligible. T3 N0 M0 patients can be
                  included if they are cisplatin ineligible.

               2. Patients who have T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-neoadjuvant
                  chemotherapy who become unresectable OR medically unfit for surgery.

                  Phase II subjects must meet the following inclusion criteria:

          -  Locally advanced urothelial cancer of bladder with any of the following:

               1. T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR
                  medically unfit for surgery OR cisplatin ineligible. T3 N0 M0 patients can be
                  included if they are cisplatin ineligible.

               2. T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients post-neoadjuvant chemotherapy
                  who become unresectable OR medically unfit for surgery.

          -  T2, N0, M0 who are ineligible to get cisplatin based chemotherapy.

        All subjects:

          -  Written informed consent and HIPAA authorization for personal health information,
             obtained from the subject prior to performing any protocol-related procedures,
             including screening evaluations. NOTE: HIPAA authorization may be included in the
             informed consent or obtained separately.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          -  Subjects must have undergone maximal TURBT or be able to undergo maximal TURBT (the
             extent of TURBT may vary for each patient and will be determined by the treating
             urologist) prior to the start of treatment and tumor tissue must be available at
             baseline from TURBT (preferred) or LN for testing of PD-L1 status. If the potential
             subject does not have tumor amenable to biopsy or there is insufficient tissue for
             PD-L1 testing, enrollment must be disclosed with the sponsor-investigator on a case
             by case basis.

          -  Histologically proven urothelial carcinoma of bladder with predominant transitional
             cell component. Adenocarcinoma, squamous cell differentiation, or other atypical
             histology (such as plasmacytoid or sarcomotoid) of the bladder will be allowed on the
             study, provided they form <50% of the histology

          -  Females of childbearing potential must have a negative urine and serum pregnancy test
             within 3 days of study registration.

        NOTE: Female subjects are considered of child bearing potential unless they are surgically
        sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral
        oophorectomy) or they are ≥60 years old and naturally postmenopausal for at least 12
        consecutive months.

          -  Subject 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:

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site).

          -  Participation in another clinical study with an investigational product within 2
             weeks prior to registration.

          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.

          -  Previous systemic immunotherapy. Previous use of intravesical BCG is acceptable.

          -  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 study drug and of low potential risk for
                  recurrence. However adequately treated prostate cancer >3 years ago with no
                  significant change in PSA for past 6 months can be included. Patients with a
                  history of prostate cancer must not have any definitive radiation therapy to
                  prostate area.

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

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

          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, other investigational agent) within14 days prior to the first dose of
             study drug (14 days prior to the first dose of study drug for subjects who have
             received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks
             for nitrosourea or mitomycin C).

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms on electrocardiogram (ECG)
             using Frediricia's Correction.

          -  Current or prior use of 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.

          -  Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. (Subjects
             with irreversible toxicity that is not reasonably expected to be exacerbated by the
             investigational product may be included (e.g., hearing loss, peripheral neuropathy).

          -  Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1.

          -  Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
             the past 2 years) are not excluded. Patients with h/o completely resolved childhood
             asthma or atopy will not be excluded. Patients with well-controlled hypothyroidism on
             thyroxine replacement will be eligible as well.

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis).

          -  History of and/or confirmed pneumonitis.

          -  History of primary immunodeficiency.

          -  History of allogeneic organ transplant.

          -  History of hypersensitivity to durvalumab or any excipient.

          -  History of hypersensitivity to the combination or radiation therapy.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
             bleeding diatheses including any subject known to have evidence of acute or chronic
             hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
             illness/social situations that would limit compliance with study requirements or
             compromise the ability of the subject to give written informed consent.

          -  Known history of previous clinical diagnosis of tuberculosis.

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of starting treatment with durvalumab.

        Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
        are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated
        vaccines, and are not allowed.

          -  Female subjects who are pregnant, breast-feeding or male or female patients of
             reproductive potential who are not employing an effective method of birth control.
             For this study male or female patients of reproductive potential need to employ two
             highly effective and acceptable forms of contraception throughout their participation
             in the study and for 90 days after last dose of study drug

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

          -  Brain metastases or history of leptomeningeal carcinomatosis.

          -  Subjects with uncontrolled seizures.

          -  Previous definitive radiation to pelvic area.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety Assessment - Evaluation of DLT (dose limiting toxicity) rate
Time Frame:6 months
Safety Issue:
Description:Assess the safety of combining durvalumab with RT in that DLT rate is lower than than 33% using CTCAE version 4.

Secondary Outcome Measures

Measure:Complete Remission
Time Frame:2 years
Safety Issue:
Description:Estimate the rate of complete remission (CR) post durvaRT by modified RECIST 1.1
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:Estimate the overall survival (OS), defined as time from start of treatment, D1, to the date of death due to any cause.
Measure:Correlate the expression of PD-L1 on immunohistochemistry at pre-treatment and post- durvaRT treatment with DCR
Time Frame:2 years
Safety Issue:
Description:2. To correlate the expression of PD-L1 on immunohistochemistry at pre-treatment (TURBT specimen if possible) and post- durvaRT treatment (cystoscopy-biopsy 2-3 weeks post durvaRT) with DCR.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Monika Joshi

Trial Keywords

  • durvalumab
  • MEDI4736
  • anti-PD-L1

Last Updated

March 20, 2017