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.
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.
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
