Clinical Trials /

A Feasibility Study of Durvalumab +/- Oleclumab as Neoadjuvant Therapy for Muscle-invasive Bladder Cancer (BLASST-2)

NCT03773666

Description:

This research study is studying a new anti-cancer drug durvalumab (MEDI4736) with or without another new anti-cancer drug Oleclumab (MEDI9447) before surgery for bladder cancer. The drugs involved in this study are: - Durvalumab (MEDI4736) - Oleclumab (MEDI9447)

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Feasibility Study of Durvalumab +/- Oleclumab as Neoadjuvant Therapy for Muscle-invasive Bladder Cancer (BLASST-2)
  • Official Title: A Feasibility Study of Durvalumab (MEDI4736) Alone or in Combination With Oleclumab (MEDI9447) as Neoadjuvant Therapy for Muscle-invasive Bladder Cancer (BLASST-2)

Clinical Trial IDs

  • ORG STUDY ID: 18-507
  • NCT ID: NCT03773666

Conditions

  • Muscle Invasive Bladder Cancer

Interventions

DrugSynonymsArms
DurvalumabMEDI4736Durvalumab
OleclumabMEDI9447Durvalumab + Oleclumab

Purpose

This research study is studying a new anti-cancer drug durvalumab (MEDI4736) with or without another new anti-cancer drug Oleclumab (MEDI9447) before surgery for bladder cancer. The drugs involved in this study are: - Durvalumab (MEDI4736) - Oleclumab (MEDI9447)

Detailed Description

      This research study is a Feasibility Study, which is the first time investigators are
      examining these drugs, Durvalumab (MEDI4736) and Oleclumab (MEDI9447) in patients with
      muscle-invasive bladder cancer (MIBC) cancer prior to surgery. Cisplatin-containing
      chemotherapy given before surgery is the standard of care in patients with MIBC because it
      increases the rate of cure after surgery. Participants may still be eligible for this study
      if their doctor determines that participants are able to receive cisplatin-containing
      chemotherapy, but the participants elect not to undergo chemotherapy before surgery,
      understanding the potential benefits of chemotherapy. The FDA (the U.S. Food and Drug
      Administration) has not approved Durvalumab (MEDI4736) for localized bladder cancer prior to
      surgery, but it has been approved for other uses, including for locally advanced or
      metastatic bladder cancer after progression on platinum-containing chemotherapy. The FDA (the
      U.S. Food and Drug Administration) has not approved Oleclumab (MEDI9447) as a treatment for
      any disease. Durvalumab is a monoclonal antibody (an antibody is a protein produced by the
      body's immune system) that works by blocking the Programmed Cell Death Ligand 1 (PD-L1), a
      protein on cancer cells that stops the body's immune system from killing cancer cells, to
      increase the body's immune response to prevent or slow down cancer growth. Oleclumab is a
      monoclonal antibody that works by reducing the amount of adenosine, a small molecule called a
      metabolite that binds to adenosine receptors on immune cells to regulate the immune system
      and suppress the immune response. Reducing the amount of immunosuppressive adenosine can
      increase the body's immune response to kill cancer cells. It is hoped that by combining
      Oleclumab with Durvalumab, an even greater immune response against the tumor will be
      generated. This research study is designed to see if the new anti-cancer drug Durvalumab
      (MEDI4736) with or without another new anti-cancer drug Oleclumab (MEDI9447) can be safely
      administered before surgery for bladder cancer
    

Trial Arms

NameTypeDescriptionInterventions
DurvalumabExperimental-Durvalumab will be administered intravenously every 2 weeks, with 14 consecutive days defined as a treatment cycle
  • Durvalumab
Durvalumab + OleclumabExperimentalDurvalumab will be administered intravenously every 2 weeks, with 14 consecutive days defined as a treatment cycle Oleclumab will be administered intravenously every 2 weeks, with 14 consecutive days defined as a treatment cycle
  • Durvalumab
  • Oleclumab

Eligibility Criteria

        Inclusion Criteria:

          -  For inclusion in the study patients must fulfil all of the following criteria: Written
             informed consent and any locally-required authorization (e.g. HIPAA) obtained from the
             patient prior to performing any protocol-related procedures, including screening
             evaluations

          -  Age > 18 years at time of study entry

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (See Appendix
             A).

          -  Histologically confirmed bladder transitional cell carcinoma (TCC)

             ---Patients with mixed histology are required to have a component of TCC, and no
             component of small cell histology

          -  T2-T4a N0 M0 disease, considered appropriate and planned for radical cystectomy

          -  Ineligible for cisplatin-based chemotherapy, defined by any of the following:

               -  Creatinine clearance (CL) <60 mL/min. GFR should be calculated from serum/plasma
                  creatinine using the Cockcroft-gault formula.

               -  CTCAE v5.0 Grade > 1 hearing loss

               -  CTCAE v5.0 Grade > 1 neuropathy

               -  NYHA Class > II cardiac dysfunction

          -  Patients not meeting the above criteria are eligible if she/he declines perioperative
             cisplatin-based chemotherapy after specific informed consent describing the known
             benefits of cisplatin-based chemotherapy.

          -  Adequate organ function laboratory values as defined below:

               -  Hemoglobin ≥ 9.0 g/dL

               -  Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3)

               -  Platelet count ≥100 x 109/L (>75,000 per mm3)

               -  Albumin > 2.5 g/dL

               -  International Normalized Ratio (INR) or activated partial thromboplastin time
                  (aPTT) < 1.5 x ULN, unless the patient is receiving anticoagulation therapy
                  provided INR or PTT is within the therapeutic range of the intended anticoagulant
                  therapy.

               -  Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN)

                  ---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.

               -  AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal

               -  Measured creatinine CL >30 mL/min or Calculated 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:

                    -  Males:

                    -  Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine
                       (mg/dL)

                    -  Females:

                    -  Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum
                       creatinine (mg/dL)

          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  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 postmenopausal 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 radiationinduced 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).

          -  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.

          -  Availability of baseline archival tumor tissue obtained for correlative studies dated
             within 8 weeks of study registration.

               -  Either FFPE tumor tissue block or a minimum of fifteen 5μm unstained FFPE slides
                  and fifteen 10μm unstained FFPE slides with an associated pathology report is
                  required.

               -  Patients without adequate baseline tumor tissue or have archival tumor tissue >8
                  weeks from registration must undergo cystoscopic tumor biopsy, meeting the above
                  tissue criteria.

        Exclusion Criteria:

          -  Patients with primary TCC of the ureter, urethra, or renal pelvis without TCC of the
             bladder

          -  Inoperable tumor(s) with fixation to the pelvic wall on clinical exam

          -  Any previous systemic chemotherapy or radiotherapy for TCC of bladder

          -  Participation in another clinical study with an investigational product during the
             last 6 months

          -  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

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

          -  History of another primary malignancy except for:

               -  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

               -  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)

          -  Receipt of the last dose of intravesical chemotherapy or biologic therapy

             ≤ 42 days (6 weeks) prior to the first dose of study drug for patients who have
             received prior intravesical chemotherapy or biologic therapy (e.g. BCG)

          -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF)

             ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) for durvalumab +
             oleclumab cohorts only. Patient safety and the cardiac EKG should be consulted as
             needed.

          -  Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer
             therapy with the exception of alopecia, vitiligo, and the laboratory values defined in
             the inclusion criteria

               -  Patients with Grade ≥2 neuropathy will be evaluated on a case-bycase basis after
                  consultation with the Study Physician.

               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab and/or oleclumab may be included only after
                  consultation with the Study Physician.

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

          -  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.

          -  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:

               -  Patients with vitiligo or alopecia

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

               -  Any chronic skin condition that does not require systemic therapy

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

               -  Patients 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 AEs or compromise the ability of the patient to give written
             informed consent

          -  History of leptomeningeal carcinomatosis

          -  Brain metastases or spinal cord compression. Patients with suspected brain metastases
             at screening should have an MRI (preferred) or CT each preferably with IV contrast of
             the brain prior to study entry.

          -  History of active primary immunodeficiency

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

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of study drug. 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)

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

          -  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 180 days after the last dose of durvalumab

             + oleclumab or 90 days after the last dose of durvalumab monotherapy, whichever is the
             longer time period

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

          -  Prior randomization or treatment in a previous durvalumab and/or oleclumab clinical
             study regardless of treatment arm assignment

          -  Judgment by the investigator that the patient is unsuitable to participate in the
             study and the patient 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:Number of Participants Receiving at least One Dose of Study Therapy Followed by Surgery without Dose-Limiting Toxicity (DLT) up to Twelve Weeks Post-Radical Cystectomy (RC)
Time Frame:2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of Participants Receiving at least One Cycle of Study Therapy and Undergone RC Having <pT2N0 Disease at Time of RC
Time Frame:2 years
Safety Issue:
Description:
Measure:Duration of Time of RC to Time of Documented Disease Relapse or Recurrence after RC
Time Frame:2 years
Safety Issue:
Description:
Measure:Radiographic Progression by RECIST 1.1 Criteria from Time of Baseline Screening Imaging to the End of Treatment Imaging Pre-RC
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Bladder Cancer

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