Clinical Trials /

Durvalumab and Tremelimumab in Treating Patients With Muscle-Invasive, High-Risk Urothelial Cancer That Cannot Be Treated With Cisplatin-Based Therapy Before Surgery

NCT02812420

Description:

This pilot phase I trial studies the side effects of durvalumab and tremelimumab in treating patients with muscle-invasive, high-risk urothelial cancer that cannot be treated with cisplatin-based therapy before surgery. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 (Tremelimumab) in Patients With Muscle-Invasive, High-Risk Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Neoadjuvant Chemotherapy
  • Official Title: A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 (Tremelimumab) in Patients With Muscle-Invasive, High-Risk Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Neoadjuvant Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: 2016-0033
  • SECONDARY ID: NCI-2016-01147
  • NCT ID: NCT02812420

Conditions

  • Malignant Neoplasms of Urinary Tract

Interventions

DrugSynonymsArms
DurvalumabMEDI4736Durvalumab + Tremelimumab
TremelimumabDurvalumab + Tremelimumab

Purpose

The goal of this clinical research study is to learn if the combination of durvalumab and tremelimumab is safe and tolerable when given to patients with bladder cancer before surgery to remove the bladder.

Detailed Description

      Study Drug Administration:

      If participant is found to be eligible to take part in this study, participant will receive
      durvalumab and tremelimumab by vein on Day 1 of Weeks 1 and 5. Each study drug infusion will
      last 1 hour. Participant will receive tremelimumab first and then participant will receive
      durvalumab about 1 hour later.

      Study Visits:

      During Day 1 of Weeks 1 and 5:

        -  Participant will have a physical exam.

        -  Participant's vital signs will be measured within 30 minutes before, every 15 minutes
           while participant is receiving the study drugs, and 3 times over 1 hour after the end
           of participant's dose of durvalumab.

        -  Blood (about 3-4 teaspoons) and urine will be collected for routine tests. The blood
           will also be used to test for hepatitis A, B, and C. This blood or urine collection
           will also include a pregnancy test if participant can become pregnant.

        -  Blood (about 3-4 tablespoons) will be drawn for immune system testing and thyroid
           function testing.

        -  Participant will have a cystoscopy to check the status of the disease. If the doctor
           thinks it is needed, participant may need to have a surgery to remove the tumors. If
           participant needs this surgery because the disease got worse very quickly, participant
           may be taken off study.

      During Week 9 to 11:

        -  Participant will have a physical exam, including measurement of participant's vital
           signs.

        -  Blood (about 3-4 teaspoons) and urine will be collected for routine tests. The blood
           will also be used to test for hepatitis A, B, and C.

        -  Participant will have an EKG.

        -  Blood (about 3-4 tablespoons) will be drawn for immune system testing.

      During Week 9 to 11, participant will have surgery to remove part or all of participant's
      bladder. Participant will sign a separate consent explaining the surgery and its risks. If
      during screening participant was told that participant was not eligible to have surgery at
      Week 9 to 11, participant will have a biopsy after participant's last dose of study drugs.

      After Surgery (during Weeks 15-17):

        -  Participant will have a physical exam, including measurement of participant's vital
           signs.

        -  Blood (about 3-4 teaspoons) and urine will be collected for routine tests. The blood
           will also be used to test for hepatitis A, B, and C.

        -  Blood (about 3-4 tablespoons) will be drawn for immune system testing.

      Length of Study:

      Participant will be off study after the Week 17 visit. Participant will no longer be able to
      take the study drugs if the disease gets worse, if intolerable side effects occur, or if
      participant is unable to follow study directions.

      Participation on the study will be over after the follow-up visits.

      Follow-up Visits:

        -  About 90 days after last dose of study drug, participant will be asked about any side
           effects and how participant is doing.

        -  Every 3 months for a total of 1 year from the start on the study, participant will be
           called and asked how participant is doing. This phone call should last about 15
           minutes.

      This is an investigational study. Tremelimumab and durvalumab are not FDA or commercially
      available for the treatment of bladder cancer. The use of these drugs are considered
      investigational.

      Up to 15 participants will be enrolled in this study. All will take part at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Durvalumab + TremelimumabExperimentalParticipants receive Durvalumab and Tremelimumab by vein on Day 1 of Weeks 1 and 5. Surgery (cystectomy with pelvic lymph node dissection) performed 4-6 weeks after the last infusion of Durvalumab and Tremelimumab. Every 3 months for a total of 1 year from the start on the study, participants called and asked how they are doing.
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          1. Age >/= 18 years at the time of screening. In general, urothelial cancer occurs in
             the 6th to 8th decade of life, so it is unlikely that pediatric patients will be
             included.

          2. Patients must have tissue resected by transurethral resection of bladder tissue
             (TURBT) at the MD Anderson Cancer Center.

          3. Patients must have histologic proof of urothelial cancer. This includes bladder
             cancer, in addition to other tumors of the urothelial lining including renal pelvis,
             ureteral, and urethral cancer. Upper tract urothelial carcinoma will also be
             included. This group may include any patient requiring cystectomy, including muscle
             invasive disease (cT2-3aN0M0), whose tumor could not be completely removed at
             transurethral resection.

          4. continued 3) Patients with the following high-risk features who are not candidates
             for traditional neoadjuvant chemotherapy will be included for this trial:
             micropapillary, sarcomatoid and plasmacytoid features; 3-D mass on exam under
             anesthesia (EUA); lymphovascular continued from 3)invasion; hydronephrosis (unless in
             the opinion of the treating physician, this is not due to tumor); high grade (grade
             3) tumors of the ureter, renal pelvis, or tumors in these areas with radiographic
             abnormality large enough to recognize as an abnormal mass by CT or MRI imaging;
             direct invasion of the prostatic stroma or the vaginal wall (i.e. cT4a disease).
             Patients who are candidates for but refusing conventional chemotherapy may be
             considered eligible. For patients in whom eligibility is unclear, final arbitration
             will be determined by the Principal Investigator.

          5. Subjects must have no prior exposure to immunotherapy, such as, but not limited to
             other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccines

          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          7. Able and willing to give valid written consent for available archival tumor samples
             or fresh tumor biopsies/resections.

          8. Adequate organ and marrow function (subjects must not have received transfusions or
             growth factor support within 28 days prior to first dose), as defined below: a.
             Hemoglobin >/= 9 g/dL b. Absolute neutrophil count >/= 1,000/mm^3 c. Platelet count
             >/= 100,000/mm^3 d. Total bilirubin </= 1.5 × ULN except subjects with documented
             Gilbert's syndrome (> 3 × ULN), who must have a baseline total bilirubin </= 3.0
             mg/dL e. Renal function: creatinine > 1.5 x ULN, or a creatinine clearance of < 60
             ml/min as calculated by Cockcroft-Gault or by 24-hour urine collection.

          9. Females of childbearing potential who are sexually active with a nonsterilized male
             partner must use a highly effective method of contraception from the time of
             screening, and must agree to continue using such precautions for 180 days after the
             final dose of investigational product. Cessation of contraception after this point
             should be discussed with a responsible physician. Periodic abstinence, the rhythm
             method, and the withdrawal method are not acceptable methods of contraception. They
             must also refrain from egg cell donation for 180 days after the final dose of
             investigational product.

         10. Nonsterilized males who are sexually active with a female partner of childbearing
             potential must agree to use a highly effective method of contraception from Day 1
             through 90 days after receipt of the final dose of investigational product. In
             addition, they must refrain from sperm donation for 90 days after the final dose of
             investigational product

        Exclusion Criteria:

          1. Concurrent enrollment in another clinical trial, unless in a follow-up period or it
             is an observational study.

          2. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
             treatment. Concurrent use of hormones for non-cancer-related conditions (e.g. insulin
             for diabetes and hormone replacement therapy) is acceptable.

          3. Any investigational anticancer therapy received within 28 days prior to the first
             dose of durvalumab and tremelimumab.

          4. Major surgical procedure (as defined by the PI or co-PIs within 28 days prior to the
             first dose of durvalumab and tremelimumab or still recovering from prior surgery.

          5. Unresolved toxicities from prior anticancer therapy, defined as having not resolved
             to NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values
             listed per the inclusion criteria. Subjects with irreversible toxicity that is not
             reasonably expected to be exacerbated by durvalumab and tremelimumab may be included
             (e.g. hearing loss) after consultation with the Principal Investigator.

          6. Known or suspected autoimmune disease. Patients with a history of inflammatory bowel
             disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders
             such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic
             Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are
             excluded from this study. Patients with a history of Hashimoto's thyroiditis only
             requiring hormone replacement, Type I diabetes, or psoriasis not requiring systemic
             treatment, or conditions not expected to recur in the absence of an external trigger
             are allowed to participate. Any condition requiring systemic treatment with
             corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive
             medications within 14 days prior to first dose of study drug. Inhaled steroids and
             adrenal replacement steroids doses >10mg daily prednisone equivalents are permitted
             in the absence of active autoimmune disease.

          7. History of primary immunodeficiency.

          8. Patients who have organ allografts.

          9. True positive test results for hepatitis A, B, or C during screening.

         10. Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS).

         11. Receipt of live, attenuated vaccine within 28 days prior to the first dose of
             durvalumab and tremelimumab (NOTE: Subjects, if enrolled, should not receive live
             vaccine during the study and for 180 days after the last dose of both drugs).

         12. Females who are pregnant, lactating, or intend to become pregnant during their
             participation in the study.

         13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, current pneumonitis, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric
             illness/social situations that would limit compliance with study requirements or
             compromise the ability of the subject to give written informed consent.

         14. Other invasive malignancies within 2 years except for noninvasive malignancies such
             as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal
             carcinoma in situ of the breast, etc. that has/have been surgically cured.

         15. Any evidence of metastatic urothelial carcinoma.

         16. Known allergy or hypersensitivity to study drug formulations.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicity of Durvalumab Plus Tremelimumab
Time Frame:4 months
Safety Issue:
Description:Participant determined to have an extreme toxicity (ETOX) as follows: Participant experiences any grade 3 or higher adverse event (AE) that is possibly, probably, or definitely related to therapy received on this protocol and occurs up to 30 days after the last dose of therapy. a. Exception: Any such AE that is potentially treatable with steroids will only count as an ETOX if it does not improve to grade 1 or better within 2 weeks Participant has a delay in surgery of 2 months or more due to AE, even if that AE does not meet the definition of ETOX. Method of Thall (1995) used to monitor ETOX continually after the 5th patient receives treatment.

Secondary Outcome Measures

Measure:Immune Changes in Peripheral Blood and Tumor Tissues
Time Frame:17 weeks
Safety Issue:
Description:Immune changes measured by pathologic downstaging to pT0.
Measure:Molecular Changes in Peripheral Blood and Tumor Tissues
Time Frame:17 weeks
Safety Issue:
Description:Molecular changes measured by pathologic downstaging to pT0.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Malignant neoplasms of urinary tract
  • Urothelial Carcinoma
  • Muscle-invasive, high-risk bladder cancer
  • Ineligible for neoadjuvant cisplatin-containing chemotherapies
  • Bladder cancer
  • Cystectomy
  • Bladder cancer surgery
  • Durvalumab
  • MEDI4736
  • Tremelimumab
  • Phone calls

Last Updated

April 19, 2017