PRIMARY OBJECTIVES:
I. To identify a safe dose of guadecitabine in combination with atezolizumab and to assess
the safety and tolerability of the combination in patients with myelodysplastic syndrome
(MDS) who are refractory to or have lost their confirmed response to one or more
hypomethylating agents (HMAs) and in patients with newly diagnosed MDS.
II. To evaluate the efficacy of guadecitabine in combination with atezolizumab for the
treatment of patients with MDS who are refractory to or have lost their confirmed response to
one or more HMAs.
III. To evaluate the efficacy of guadecitabine in combination with atezolizumab for the
treatment of patients with newly diagnosis MDS.
SECONDARY OBJECTIVES:
I. To measure the impact of the combination of guadecitabine and atezolizumab on overall
survival among patients with relapsed/refractory MDS.
II. To measure the impact of the combination of guadecitabine and atezolizumab on overall
survival among patients with treatment-naive MDS.
III. To evaluate the impact of the combination of guadecitabine and atezolizumab on the
duration of response in patients with relapsed/refractory MDS and treatment-naive MDS.
IV. To evaluate the impact of the combination of guadecitabine and atezolizumab on
transfusion-dependence among patients with relapsed/refractory and treatment-naive MDS.
TERTIARY OBJECTIVES:
I. To determine the baseline expression/methylation of programmed cell death protein 1 (PD-1)
in T cells among patients with relapsed, refractory and treatment-naive MDS.
II. To quantify the impact of combination therapy with guadecitabine and atezolizumab on PD-1
expression/methylation in T cells.
III. To correlate response with expression/methylation of PD-1 by T cells and with expression
of programmed cell death-ligand 1 (PD-L1) in the bone marrow of patients with MDS treated
with guadecitabine and atezolizumab.
IV. To investigate the expression of tumor antigens on MDS blasts during combination therapy
with guadecitabine and atezolizumab V. To investigate the specific T-cell subsets in MDS
blood and bone marrow during combination therapy with guadecitabine and atezolizumab.
VI. To investigate the specific antigens (epitopes) which are recognized by T-cells in MDS
blood and bone marrow during combination therapy with guadecitabine and atezolizumab.
OUTLINE: This is a phase I, dose-escalation study of guadecitabine followed by a phase II
study.
Patients receive guadecitabine subcutaneously (SC) on days 1-5 and atezolizumab intravenously
(IV) over 30-60 minutes on days 8 and 22. Courses repeat every 28 days for up to 24 months in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 or 90 days and every 6
months thereafter.
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
