- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02935361
Guadecitabine and Atezolizumab in Treating Patients With Advanced Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia That Is Refractory or Relapsed
A Phase I/II Multicenter Study Combining Guadecitabine, a DNA Methyltransferase Inhibitor, With Atezolizumab, an Immune Checkpoint Inhibitor, in Patients With Intermediate or High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
California
-
Los Angeles, California, United States, 90033
- USC / Norris Comprehensive Cancer Center
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-
Maryland
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Baltimore, Maryland, United States, 21201
- University of Maryland Medical Center
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19111
- Fox Chase Cancer Center
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Philadelphia, Pennsylvania, United States, 19140
- Temple University Hospital
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (guadecitabine, atezolizumab)
Patients receive guadecitabine SC on days 1-5 and atezolizumab 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.
|
Given IV
Other Names:
Given SC
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of dose-limiting toxicities evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)
Time Frame: Up to 56 days
|
Descriptive summaries and analyses of CTCAE 4.0 toxicities that occur will be produced, both by patient and by cycle.
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Up to 56 days
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Overall response (complete response [CR] + partial response + marrow CR + hematological improvement) (Phase II)
Time Frame: Up to 168 days
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Up to 168 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of grade 3 or higher adverse events and grade 2 toxicities that do not resolve after 3 weeks assessed by CTCAE 4.0
Time Frame: Up to 8 weeks
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Descriptive summaries of toxicities that occur will be produced, both by patient and by course.
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Up to 8 weeks
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Overall response rate (Phase II)
Time Frame: Up to 4 years
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Up to 4 years
|
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Overall survival
Time Frame: From start of treatment to death from any cause, assessed up to 4 years
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Will be analyzed using survival analysis methods.
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From start of treatment to death from any cause, assessed up to 4 years
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Percentage of patients who were transfusion-dependent on study entry who become transfusion-independent
Time Frame: Up to 4 years
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Up to 4 years
|
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Progression free survival
Time Frame: From start of treatment to the first disease progression or recurrence, assessed up to 4 years
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Will be analyzed using survival analysis methods.
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From start of treatment to the first disease progression or recurrence, assessed up to 4 years
|
Time to best response
Time Frame: Up to 4 years
|
Will be analyzed using survival analysis methods.
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Up to 4 years
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Degree of PD-L1 expression assessed in bone marrow, T cells, and malignant cells by immunohistochemistry or flow cytometry
Time Frame: Up to 4 years
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Up to 4 years
|
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PD-1 expression by T cells and malignant cells
Time Frame: Up to 4 years
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Relationship of PD-1/PD-L1 expression to efficacy endpoints will be explored.
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Up to 4 years
|
Percentage of T cells expressing PD-1/methylation levels
Time Frame: Up to 4 years
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Up to 4 years
|
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T-cell antigen recognition in MDS blood and bone marrow
Time Frame: Up to 4 years
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Relationship of T-cell antigen recognition to efficacy endpoints will be explored.
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Up to 4 years
|
T-cell subset combinations in MDS blood and bone marrow
Time Frame: Up to 4 years
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Relationship of T-cell subset combination to efficacy endpoints will be explored.
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Up to 4 years
|
Tumor antigen expression on MDS blasts
Time Frame: Up to 4 years
|
Relationship of tumor expression to efficacy endpoints will be explored.
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Up to 4 years
|
Collaborators and Investigators
Investigators
- Principal Investigator: Casey O'Connell, University of Southern California
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Disease Attributes
- Disease
- Bone Marrow Diseases
- Hematologic Diseases
- Precancerous Conditions
- Myelodysplastic-Myeloproliferative Diseases
- Leukemia, Myeloid
- Chronic Disease
- Syndrome
- Myelodysplastic Syndromes
- Leukemia
- Preleukemia
- Leukemia, Myelomonocytic, Acute
- Leukemia, Myelomonocytic, Chronic
- Leukemia, Myelomonocytic, Juvenile
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunologic Factors
- Antineoplastic Agents, Immunological
- Immune Checkpoint Inhibitors
- Azacitidine
- Antibodies, Monoclonal
- Atezolizumab
- Guadecitabine
Other Study ID Numbers
- 9L-16-3 (Other Identifier: USC / Norris Comprehensive Cancer Center)
- P30CA014089 (U.S. NIH Grant/Contract)
- NCI-2016-01233 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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