| Eligibility |
Inclusion Criteria:
- Phase I: Adult subjects with advanced MDS requiring therapy who were previously
treated with either azacitidine or decitabine for at least 4 cycles and deemed to have
failed therapy due to progression of disease using International Working Group (IWG)
criteria ("refractory") or losing their previously documented response to the therapy
("relapsed")
- Phase II: Adult subjects with advanced MDS requiring therapy who were previously
treated with either azacitidine or decitabine for at least 4 cycles and deemed to have
failed therapy due to progression of disease using IWG criteria ("refractory") or
losing their previously documented response to the therapy ("relapsed")
- MDS should be classified as:
- Intermediate 1-risk or higher risk according to the international prognostic
scoring system (IPSS) or revised IPSS
- Chronic myelomonocytic leukemia (CMML)
- During the 8 weeks prior to inclusion in study, subjects must have a baseline bone
marrow examination including all of the following:
- Cytomorphology to confirm bone marrow blasts;
- Cytogenetics; AND
- Eastern Cooperative Oncology Group (ECOG) status 0-2
- Subject is able to understand and willing to comply with protocol requirements and
instructions
- Subject has signed and dated informed consent
- Total bilirubin (except for Gilbert's syndrome) =< 2.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (ALT) and alanine aminotransferase (AST) =< 3 x ULN
- Creatinine =< 2.5 x ULN
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure rate
of < 1% per year during the treatment period and for at least 90 days after the last
dose of atezolizumab
- A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (>= 12 continuous months of amenorrhea
with no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus)
- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, proper use of hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
and copper intrauterine devices
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined
below:
- With female partners of childbearing potential, men must remain abstinent or use
a condom plus an additional contraceptive method that together result in a
failure rate of < 1% per year during the treatment period and for at least 120
days after the last dose of guadecitabine; men must refrain from donating sperm
during this same period
- With pregnant female partners, men must remain abstinent or use a condom during
the treatment period and for at least 30 days after the last dose of
guadecitabine to avoid exposing the embryo
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception
- Women of childbearing potential (WOCBP) must have a negative serum test (minimum
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within
72 hours prior to the start of investigational product
Exclusion Criteria:
- Any active history of a known autoimmune disease; subjects with vitiligo, type 1
diabetes mellitus, residual hypothyroidism requiring hormone replacement, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll
- Subjects with a history of interstitial lung disease; patients requiring continuous
supplemental oxygen are excluded to avoid possible complications from pneumonitis
- History of idiopathic pulmonary fibrosis, organizing pneumonitis (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis
- Patients who are actively receiving any other anticancer therapy
- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to HMAs
- Patients with a diagnosis of acute myeloid leukemia (AML) not transformed from MDS or
transformed from MDS with > 30% blasts in bone marrow or white blood cells (WBC) > 25
x 10^3/L
- Patients with short life expectancy (less than 3 months) due to comorbidity other than
MDS
- Female subjects who are nursing or pregnant (positive serum or urine beta-human
chorionic gonadotropin [B-hCG] pregnancy test)
- Patients with current alcohol or drug abuse
- Patients who have received treatment with an investigational drug within 30 days
preceding the first dose of study medication
- Patients with uncontrolled inter-current illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements
- Patients with prior infections must be afebrile for >= 72 hours and completed any
antibiotics prior to receiving study drug
- In patients who received IV antibiotics for active infection, a washout period of
14 days is required prior to initiating study therapy (exception: patients with
febrile neutropenia in whom no infectious etiology has been
determined/documented)
- Patients receiving chronic antimicrobial prophylaxis therapy (e.g. antifungal
prophylaxis) may be included in the study provided there is no active infection
- Patients infected with hepatitis B, C or human immunodeficiency virus (HIV), unless
they are on stable and effective antiviral treatment
- Serious infection requiring oral or IV antibiotics/antifungals/antivirals and/or
hospitalization within 28 days prior to screening
- Patients on prophylactic oral antibiotics, antifungals and antivirals due to
prolonged neutropenia in the absence of documented infection are eligible
- Patients who are treated with IV antibiotics for neutropenic fever, are eligible
if no infectious etiology was determined and the last dose of antibiotics was >=
7 days from cycle 1, day 1
- Patients with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive
medications within 14 days of randomization. Inhaled or topical steroids and
adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are
permitted in the absence of uncontrolled autoimmune disease
- Medication-related exclusion criteria
- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
pathway-targeting agents
- Prior treatment with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
therapeutic agents (e.g. ipilimumab)
- Treatment with systemic immunostimulatory agents (including but not limited to
interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks or five half-lives of the
drug (whichever is shorter) prior to cycle 1, day 1
- Treatment with any investigational agent within 4 weeks prior to cycle 1, day 1 (or
within five half-lives of the investigational product, whichever is longer)
- Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1
- Patients who have received acute, low-dose, systemic immunosuppressant medications may
be enrolled
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for
patients with orthostatic hypotension or adrenocortical insufficiency is allowed
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation
|
