A Study Evaluating the Safety and Pharmacology of Atezolizumab Administered in Combination With Immunomodulatory Agents in Participants With Acute Myeloid Leukemia (AML)

Phase 1

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Atezolizumab; Drug: Guadecitabine

• Registration Number: NCT02892318
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This is a non-randomized, open-label, Phase Ib study of atezolizumab in combination with immunomodulatory agents for the treatment of participants with AML (relapsed/refractory and treatment-naive, elderly participants unfit for induction chemotherapy). The study has been designed with the intent, over time, to study multiple combinations of atezolizumab with different immunomodulatory agents in participants with AML. The study will begin with the evaluation of the combination of atezolizumab and guadecitabine (Arm A). In the future, additional arms may be added.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-09-02
• Study First Submitted QC: 2016-09-02
• Study First Posted: 2016-09-08
• Study Start: 2016-10-31
• Primary Completion: 2019-12-12
• Study Completion: 2019-12-12
• Status Verified: 2020-03
• Last Update Submitted: 2020-03-11
• Last Update Posted: 2020-03-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• Life expectancy of at least 12 weeks
• Diagnosis of AML per World Health Organization criteria
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2
• Specifically, for participants in Cohorts A1 and A2: Age greater than or equal to (>=) 18 years, disease progression or failure to achieve complete or partial response after intensive cytotoxic therapy, participants cannot have received more than two prior intensive regimens (e.g., induction + consolidation and one salvage therapy + consolidation)
• Specifically, for participants in Cohorts A3 and A4: Treatment naïve participants unfit for induction chemotherapy for AML as defined by the following: Age >= 70 or age 65 to 69 years with at least one of the following: ECOG performance status of 2, Intermediate I/II or adverse risk cytogenetic and molecular alterations per ELN 2010 guidelines or secondary AML, or other comorbidity judged incompatible with intensive chemotherapy
• Adequate end-organ function
• Willing and able to undergo a pre-treatment bone marrow aspirate and biopsy and subsequent bone marrow aspirates and biopsies during treatment
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per year during the treatment period and for at least 30 days after the last dose of guadecitabine or 5 months after the last dose of atezolizumab, whichever is longer
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria

• In Cohorts A3 and A4 only, participants with AML eligible for standard intensive induction therapy with an anthracycline and cytarabine
• Prior allogeneic stem cell transplant or solid organ transplant
• Active central nervous system involvement by leukemia
• Pregnant or lactating, or intending to become pregnant during the study
• History of idiopathic pulmonary fibrosis, organizing pneumonitis, drug-induced pneumonitis, idiopathic pneumonitis, or autoimmune disease
• Treatment with investigational therapy within 14 days prior to initiation of study drug
• Any approved AML-related therapy within 14 days prior to enrollment
• Immunosuppressive therapy within 6 weeks of Cycle 1, Day 1
• Daily requirement for corticosteroids (> 10 mg prednisone daily or equivalent) (except for inhalation corticosteroids) within 2 weeks prior to Cycle 1, Day 1
• Prior treatment with immune checkpoint blockade therapies (anti-cytotoxic T-lymphocyte-associated protein 4 [anti-CTLA-4], anti-programmed death-1 [anti-PD-1] or anti-PD-L1) or immune agonists (anti-cluster of differentiation [CD]137, anti-CD40, anti-OX40)
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to Cycle 1, Day 1
• Treatment with denosumab (or other receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitor) 4 weeks before the first dose and for 10 weeks after the last dose of atezolizumab
• Administration of a live, attenuated vaccine within 4 weeks of Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study
• Planned major surgery during the study
• Positive for hepatitis C virus (HCV) antibody at screening
• Active hepatitis B virus (HBV) infection
• Positive for human immunodeficiency virus (HIV)
• Illicit drug or alcohol abuse within 12 months prior to screening
• Poor peripheral venous access
• Active infection
• Serious infection requiring hospitalization or intravenous (IV) antibiotics within 14 days prior to enrollment
• Any serious medical condition or abnormality in clinical laboratory tests
• History or presence of an abnormal electrocardiogram (ECG)
• History of other malignancy within 2 years prior to screening
• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab or guadecitabine formulations
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort A1: Safety Cohort (Relapsed/refractory AML)	Atezolizumab	An initial safety evaluation of the combination will be performed in 9 participants with relapsed/refractory AML. All participants will receive atezolizumab (840 milligrams \[mg\] IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 milligrams per square meter \[mg/m\^2\] subcutaneously \[SC\] on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit (except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.
Cohort A1: Safety Cohort (Relapsed/refractory AML)	Guadecitabine	An initial safety evaluation of the combination will be performed in 9 participants with relapsed/refractory AML. All participants will receive atezolizumab (840 milligrams \[mg\] IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 milligrams per square meter \[mg/m\^2\] subcutaneously \[SC\] on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit (except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.
Cohort A2: Expansion Cohort (Relapsed/refractory AML)	Guadecitabine	If the combination of atezolizumab and guadecitabine is found to be safe and tolerable in Cohort A1, an expansion cohort of 11 participants with relapsed/refractory AML (Cohort A2) will be evaluated. All participants will receive atezolizumab (840 mg IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 mg/m\^2 SC on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.
Cohort A2: Expansion Cohort (Relapsed/refractory AML)	Atezolizumab	If the combination of atezolizumab and guadecitabine is found to be safe and tolerable in Cohort A1, an expansion cohort of 11 participants with relapsed/refractory AML (Cohort A2) will be evaluated. All participants will receive atezolizumab (840 mg IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 mg/m\^2 SC on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.
Cohort A4: Expansion Cohort (Previously Untreated AML)	Atezolizumab	If Cohort A3 is deemed safe and tolerable, an expansion cohort (Cohort A4) of 14 participants with untreated AML, who are older and unfit for induction chemotherapy will be evaluated. All participants will receive atezolizumab (840 mg IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 mg/m\^2 SC on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.
Cohort A3: Safety Cohort (Previously Untreated AML)	Atezolizumab	If the combination of atezolizumab and guadecitabine is found to be safe and tolerable in Cohort A1, Cohort A3 will assess the safety and tolerability of the combination in 6 participants with untreated AML, who are older and unfit for induction chemotherapy. All participants will receive atezolizumab (840 mg IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 mg/m\^2 SC on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.
Cohort A3: Safety Cohort (Previously Untreated AML)	Guadecitabine	If the combination of atezolizumab and guadecitabine is found to be safe and tolerable in Cohort A1, Cohort A3 will assess the safety and tolerability of the combination in 6 participants with untreated AML, who are older and unfit for induction chemotherapy. All participants will receive atezolizumab (840 mg IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 mg/m\^2 SC on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.
Cohort A4: Expansion Cohort (Previously Untreated AML)	Guadecitabine	If Cohort A3 is deemed safe and tolerable, an expansion cohort (Cohort A4) of 14 participants with untreated AML, who are older and unfit for induction chemotherapy will be evaluated. All participants will receive atezolizumab (840 mg IV on Days 8 and 22 of every 28-day cycle) administered in combination with guadecitabine (60 mg/m\^2 SC on Days 1-5 of every 28-day cycle). Treatment with both study drugs will continue until loss of clinical benefit except in participants who achieve a CR, CRp, or CRi), evidence of unacceptable toxicity, voluntary withdrawal from the study, study termination, or death, whichever occurs first. Participants who achieve a CR, CRp, or CRi will receive an additional six cycles of the combination as consolidation treatment. Participants will discontinue therapy at the end of consolidation response assessment even if the CR, CRp, or CRi is maintained at that time.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants with Adverse Events	Baseline up to approximately 32 months
Percentage of Participants with Complete Remission (CR) as Defined by International Working Group (IWG) 2003 and European Leukemia Net (ELN) 2010 Response Criteria	After 6 cycles of combination therapy (at Week 24; each cycle is 28 days)
Percentage of Participants with Complete Remission with Incomplete Platelet Recovery (CRp) as Defined by IWG 2003 and ELN 2010 Response Criteria	After 6 cycles of combination therapy (at Week 24; each cycle is 28 days)
Percentage of Participants with Complete Remission with Incomplete Recovery (CRi) as Defined by IWG 2003 and ELN 2010 Response Criteria	After 6 cycles of combination therapy (at Week 24; each cycle is 28 days)
Duration of Response as Defined by IWG 2003 and ELN 2010 Response Criteria	Baseline until the date of relapse/progression or death from any cause, assessed up to approximately 32 months

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants with Best Overall Response as Defined by IWG 2003 and ELN 2010 Response Criteria	Baseline until the date of relapse/progression or death from any cause, assessed up to approximately 32 months
Event-free Survival (EFS) as Defined by IWG 2003 and ELN 2010 Response Criteria	Baseline until the date of induction treatment failure or relapse or death from any cause, assessed up to approximately 32 months
Leukemia-free Survival (LFS) as Defined by IWG 2003 and ELN 2010 Response Criteria	Baseline until the date of relapse or death from any cause, assessed up to approximately 32 months
Overall Survival (OS)	Baseline until death from any cause, assessed up to approximately 32 months
Percentage of Participants with Minimal Residual Disease (MRD) Negativity in Participants who Achieve CR, CRp, or CRi	Baseline up to approximately 32 months
Percentage of Participants with Anti-Drug Antibody (ADA) to Atezolizumab	Pre-infusion (0 hours [hrs]) on Day (D) 1 of Cycle (C) 1; D8 of C2, C3, C4, C6, and every 6 cycles thereafter until treatment discontinuation (up to 32 months); at 120 days and 1 year after atezolizumab last dose (up to 32 months; each cycle is 28 days)
Serum Concentration of Atezolizumab	Day 1 up to 32 months (detailed sample collection time points are provided in Outcome Measure Description)	Pre-infusion (0 hrs) on D1 of C1, C4; 30 minutes after end of infusion (infusion duration=30-60 minutes) on D8 of C1, C2, C4; Pre infusion (0 hrs) on D22 of C1, D8 of C2, C3, C4, C6, every 6 cycles thereafter until treatment discontinuation (up to 32 months); at 120 days and 1 year after atezolizumab last dose (up to 32 months; each cycle is 28 days)
Plasma Concentration of Guadecitabine	1, 2, 5, and 8 hours post-injection on D1 of C1 and C4, 1 hour post-injection on D1 of C2, C3, C6, and every 6 cycles thereafter (up to 32 months; each cycle is 28 days)
Plasma Concentration of Decitabine (a Metabolite Product of Guadecitabine)	1, 2, 5, and 8 hours post-injection on D1 of C1 and C4, 1 hour post-injection on D1 of C2, C3, C6, and every 6 cycles thereafter (up to 32 months; each cycle is 28 days)

Trial Locations

Locations (8)

Yale University; 🇺🇸 New Haven, Connecticut, United States

Levine Cancer Institute; 🇺🇸 Charlotte, North Carolina, United States

City of Hope; 🇺🇸 Duarte, California, United States

Temple University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

The NewYork-Presbyterian Hospital Columbia University Medical Center; 🇺🇸 New York, New York, United States

Huntsman Cancer Institute; 🇺🇸 Salt Lake City, Utah, United States

The University of Wisconsin School of Medicine and Public Health; 🇺🇸 Madison, Wisconsin, United States