Clinical Trials /

Trimodal Therapy Plus Atezolizumab in Muscle-invasive Bladder Cancer

NCT03620435

Description:

This is a single arm phase II trial to (1) evaluate safety and toxicity profile of intravenous Atezolizumab (anti-PDL-1) administered in combination with TMT in patients with MIBC, (2) To determine the loco-regional control rate (LCR) of TMT combined with PDL-1 blockade.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trimodal Therapy Plus Atezolizumab in Muscle-invasive Bladder Cancer
  • Official Title: A Phase II Trial of Transurethral Surgery Followed by a Combination of Atezolizumab (Tecentriq™) an Anti-PDL-1 (MPDL3280A) With Trimodal Therapy in Patients With Muscle-Invasive Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: ML-39576
  • NCT ID: NCT03620435

Conditions

  • Safety Issues

Interventions

DrugSynonymsArms
AtezolizumabTecentriqatezolizumab

Purpose

This is a single arm phase II trial to (1) evaluate safety and toxicity profile of intravenous Atezolizumab (anti-PDL-1) administered in combination with TMT in patients with MIBC, (2) To determine the loco-regional control rate (LCR) of TMT combined with PDL-1 blockade.

Detailed Description

      This will be a Phase II trial (stage 1 and 2). This study will initially accrue 3 evaluable
      patients to assess the dose limiting toxicity (DLT) of combination of Gemcitabine (4 weeks at
      100 mg/m2, given intravenously once weekly, 2-4 hours before radiation therapy) plus IMRT (50
      Gy/20 fractions. 2.5 Gy per fraction - 5 times per week for 4 weeks) and Atezolizumab (1200
      mg intravenous on day 1 of 3 week cycle. Once the first 3 patients are accrued, the trial
      will be placed on hold for 3 months until acute toxicity has been assessed and the
      combination is felt to be safe according to the National Cancer Institute Common Terminology
      Criteria for Adverse Events (NCI-CTCAE,v. 4.03). DLT will be defined as: (1) Grade 3 or
      higher immune related Adverse Events (irAEs), (e.g. inflammatory ocular toxicities,
      pneumonitis, hepatitis, colitis), (2) Grade 3 or higher treatment-related AEs (TRAE) that
      delay EBRT by > 21 days. For the safety run-in component of the study, 3 patients will
      receive Atezolizumab at a dose of 1200 mg every 3 weeks, as described above. After the third
      patient has been accrued, the trial will be placed on hold for 3 months for an assessment of
      acute toxicity. Acute toxicity is defined as any toxicity occurring within 90 days from the
      end of the combined treatment of IMRT and gemcitabine. If no grade 3 or higher acute toxicity
      is detected, Atezolizumab 1200 mg will be chosen for the rest of the trial. If one patient
      develops grade 3 toxicity, 3 further patients will be entered at 1200 mg. . If no further
      grade 3 toxicity is observed, this dose level will be considered safe. In case that one
      additional patient develop a grade 3 toxicity, then 3 patients will be enrolled at the
      reduced dose of 840mg. If no grade 3 or higher acute toxicity is detected, Atezolizumab 840mg
      will be chosen for the rest of the trial. If one patient develops grade 3 toxicity at the
      reduced dose, then 3 further patients will be entered at 840 mg. If no further grade 3
      toxicity is observed, this reduced dose level will be considered safe. In case that one
      additional patient develop a grade 3 toxicity at the reduced dose level, it will be
      considered too toxic and the combination will be judged too toxic for the population and
      regimen, and the study will be terminated.

      If treatment is well tolerated, this will be considered the final dose for the study. No
      further de-escalation beyond this level will be considered. For the Stage 2 of this study,,
      up to 22 other patients will be accrued (total of 25 evaluable patients). Atezolizumab will
      be given during combination treatment, and every 3 weeks for 16 cycles or until disease
      progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
atezolizumabExperimentalAtezolizumab will be given during trimodal therapy, and every 3 weeks for 16 cycles or until disease progression or unacceptable toxicity.
  • Atezolizumab

Eligibility Criteria

        Inclusion criteria

          -  18 years old or older

          -  Histologic diagnosis of urothelial carcinoma of the bladder. Focal differentiation
             allowed other than small cell histology.

          -  Stage T2-T4a N0M0 (AJCC-TNM version 6) based on trans-urethral resection of bladder
             tumor (TURBT), CT imaging, +/- bimanual examination under anaesthesia (EUA).

          -  CT scan of chest/abdomen/pelvis within 8 weeks from the start of treatments, showing
             no evidence of metastatic disease.

          -  Attempt of complete TURBT within 56 days (8 weeks) prior to the start of
             chemoradiation. If TURBT was performed > 8 weeks ago but a recent cystoscopy show no
             residual disease, then a repeat TURBT is not necessary.

          -  Life Expectancy greater than 6 months

          -  ECOG performance status of 2 or better

          -  Another primary cancer is allowed only if treated with curative intent at least 3
             years prior to enrollment without evidence of recurrence or if the untreated cancer is
             clinical indolent (eg lower risk prostate cancer).

          -  Adequate hematologic reserve: Platelet count ≥ 150,000/ul, WBC ≥ 4000/ul. Anemia will
             be corrected to minimum hemoglobin of 100 g/L with red cell transfusions, if
             necessary.

          -  Adequate liver function with a bilirubin ≤ 1.5 ULN[27] and SGOT/SGPT < 1.5 X the upper
             normal limit

          -  Patients must be considered able to tolerate systemic chemosensitizer combined with
             pelvic IMRT by the joint agreement of the participating radiation oncologist and
             medical oncologist.

          -  Able and willing to give written informed consent.

        Exclusion criteria

          -  Prior systemic therapy for other urothelial tumors. Neoadjuvant chemotherapy can be
             considered a component of the trimodal therapy and is allowed. Superficial bladder
             treatments including BCG and mitomycin C are permitted if completed 6 weeks prior to
             therapy.

          -  Hypersensitive to Gemcitabine or to any ingredient in the formulation or component of
             the container.

          -  Prior RT to the pelvis

          -  Treatment with any other investigational agent or participation in another clinical
             trial with therapeutic intent within 28 days or five half-lives of the drug, whichever
             is longer, prior to enrollment

          -  Malignancies other than urothelial cancer within 5 years prior to Cycle 1, Day 1:

        Patients with localized lower risk prostate cancer (defined as Stage ≤T2b, Gleason score ≤
        7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL[if measured]) treated with radical
        prostatectomy and without prostate-specific antigen (PSA) recurrence are eligible.

        Patients with lower risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 7 and
        PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.

        Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of
        metastasis or death <5% at 5 years) are eligible provided they meet all of the following
        criteria:

        Malignancy treated with expected curative intent (such as adequately treated carcinoma in
        situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the
        breast treated surgically with curative intent) No evidence of recurrence or metastasis by
        follow-up imaging and any disease-specific tumor markers

          -  Pre-existing medical conditions precluding treatment (e.g. previous history of
             immune-related adverse reactions, pneumonitis, colitis, etc.)

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells
             or any component of the atezolizumab formulation

          -  History of autoimmune disease, including, but not limited to, myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of
             autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may
             be eligible for this study. Patients with controlled Type I diabetes mellitus on a
             stable dose of insulin regimen may be eligible for this study.

          -  Active tuberculosis

          -  Pregnancy or lactating mothers. Women of childbearing age must use contraception
             during treatment and for 5 months after the last dose of Atezolizumab. Acceptable
             methods are: oral contraceptives, hormonal implants, hormonal patches, IDU, Diaphragm
             with spermicides, cervical cape with spermicide, and condom with spermicide.

          -  Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),
             anti-PD-L1, anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB
             ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or
             anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways).

          -  Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
             azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF]
             agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for
             systemic immunosuppressive medications during the trial

          -  Active autoimmune disease that has required systemic treatment in past 2 years

          -  Received or will receive a live vaccine within 4 weeks prior to first dose of study
             drug. Influenza vaccination should be given during influenza season only
             (approximately October through May in the Northern Hemisphere and approximately April
             through September in the Southern Hemisphere). Patients must agree not to receive
             live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to
             randomization, during treatment or within 5 months following the last dose of
             atezolizumab (for patients randomized to atezolizumab)

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan History of radiation pneumonitis in the
             radiation field (fibrosis) is permitted.

          -  Serum albumin < 2.5 g/dL

          -  Active infection requiring IV systemic therapy

          -  Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1.
             Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or to prevent chronic obstructive pulmonary disease exacerbation) are
             eligible.

          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease
             (Class II or greater), myocardial infarction within the previous 3 months, unstable
             arrhythmias, or unstable angina. Patients with known coronary artery disease,
             congestive heart failure not meeting the above criteria, or left ventricular ejection
             fraction < 50% must be on a stable medical regimen that is optimized in the opinion of
             the treating physician, in consultation with a cardiologist if appropriate.

          -  Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day
             1 or anticipation of need for a major surgical procedure during the course of the
             study

          -  Prior allogeneic stem cell or solid organ transplant

          -  Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

          -  Patients with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV)

          -  Not willing or unable to sign a consent form
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety profile of intravenous Atezolizumab (anti-PDL-1) administered in combination with TMT in patients with MIBC
Time Frame:2-2.5 years
Safety Issue:
Description:Safety will be captured as (1) number of patients with Grade 3 or higher immune related Adverse Events (irAEs), (e.g. inflammatory ocular toxicities, pneumonitis, hepatitis, colitis), (2) number of patients with Grade 3 or higher treatment-related AEs (TRAE) that delay EBRT by > 21 days. The safety assessments up to the final follow-up visits will consist of monitoring and recording adverse events, including serious adverse events and adverse events of special interest, protocol−specified safety laboratory assessments, protocol−specified vital signs, and other protocol-specified tests that are deemed critical to the safety evaluation of the study.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:4 years
Safety Issue:
Description:OS is defined as the time from start of treatment to date of death due to any cause. Patients who have not died at the time of the analyses cutoff / end of study, will be censored at their last contact date known to be alive). Patient will be followed for 3 years from completion of radiotherapy
Measure:Bladder cancer therapy impact on quality of life
Time Frame:2-2.5 years
Safety Issue:
Description:Changes from baseline quality of life will be measured longitudinally using the validated Functional Assessment of Cancer Therapy-Bladder questionnaire. FACT-BL scores on the first day of chemo radiotherapy treatment (before starting treatment), on the week 3 of radiation therapy, and again at 3, 6, 12, 18, and 24 months post radiation therapy. Quality of life domains measured includes domains of physical well-being, social and family well-being, emotional well-being, and functional well-being, as well as additional concerns specific to patients undergoing therapy for bladder cancer such as urinary, bowel and sexual function.
Measure:Complete response to TMT combined with PDL-1 blockade
Time Frame:2-2.5 years
Safety Issue:
Description:LCR (loco-regional control rate) or early complete response rates from the combined therapy is the proportion of patients with a confirmed locoregional complete response at 3 months post-radiation. Loco regional complete response will be ascertained on basis of a combination of follow-up CT imaging of the irradiated field (bladder, pelvic lymph nodes), cystoscopy with rebiopsy of involved areas, and urine cytology.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:McGill University Health Centre/Research Institute of the McGill University Health Centre

Last Updated

August 9, 2018