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

Primary Purpose

Acute Myeloid Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Atezolizumab

Guadecitabine

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

City of Hope
Yale University
The NewYork-Presbyterian Hospital Columbia University Medical Center
Memorial Sloan Kettering Cancer Center
Levine Cancer Institute
Temple University Hospital
Huntsman Cancer Institute
The University of Wisconsin School of Medicine and Public Health

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Cohort A1: Safety Cohort (Relapsed/refractory AML)

Cohort A2: Expansion Cohort (Relapsed/refractory AML)

Cohort A3: Safety Cohort (Previously Untreated AML)

Cohort A4: Expansion Cohort (Previously Untreated AML)

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Percentage of Participants with Adverse Events

Percentage of Participants with Complete Remission (CR) as Defined by International Working Group (IWG) 2003 and European Leukemia Net (ELN) 2010 Response Criteria

Percentage of Participants with Complete Remission with Incomplete Platelet Recovery (CRp) as Defined by IWG 2003 and ELN 2010 Response Criteria

Percentage of Participants with Complete Remission with Incomplete Recovery (CRi) as Defined by IWG 2003 and ELN 2010 Response Criteria

Duration of Response as Defined by IWG 2003 and ELN 2010 Response Criteria

Secondary Outcome Measures

Percentage of Participants with Best Overall Response as Defined by IWG 2003 and ELN 2010 Response Criteria

Event-free Survival (EFS) as Defined by IWG 2003 and ELN 2010 Response Criteria

Leukemia-free Survival (LFS) as Defined by IWG 2003 and ELN 2010 Response Criteria

Overall Survival (OS)

Percentage of Participants with Minimal Residual Disease (MRD) Negativity in Participants who Achieve CR, CRp, or CRi

Percentage of Participants with Anti-Drug Antibody (ADA) to Atezolizumab

Serum Concentration of Atezolizumab

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

Plasma Concentration of Decitabine (a Metabolite Product of Guadecitabine)

Full Information

NCT ID

NCT02892318

First Posted

September 2, 2016

Last Updated

March 11, 2020

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT02892318

Brief Title

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

Official Title

A Phase Ib Study Evaluating the Safety and Pharmacology of Atezolizumab (Anti-PD-L1 Antibody) Administered in Combination With Immunomodulatory Agents in Patients With Acute Myeloid Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

March 2020

Overall Recruitment Status

Completed

Study Start Date

October 31, 2016 (Actual)

Primary Completion Date

December 12, 2019 (Actual)

Study Completion Date

December 12, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Cohort A1: Safety Cohort (Relapsed/refractory AML)

Arm Type

Experimental

Arm Description

Arm Title

Cohort A2: Expansion Cohort (Relapsed/refractory AML)

Arm Type

Experimental

Arm Description

Arm Title

Cohort A3: Safety Cohort (Previously Untreated AML)

Arm Type

Experimental

Arm Description

Arm Title

Cohort A4: Expansion Cohort (Previously Untreated AML)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Atezolizumab

Other Intervention Name(s)

MPDL3280A;, Tecentriq

Intervention Description

Atezolizumab 840 mg administered by IV infusion on Days 8 and 22 of each 28-day cycle.

Intervention Type

Drug

Intervention Name(s)

Guadecitabine

Intervention Description

Guadecitabine 60 mg/m^2 SC on Days 1-5 of every 28-day cycle.

Primary Outcome Measure Information:

Title

Percentage of Participants with Adverse Events

Time Frame

Baseline up to approximately 32 months

Title

Percentage of Participants with Complete Remission (CR) as Defined by International Working Group (IWG) 2003 and European Leukemia Net (ELN) 2010 Response Criteria

Time Frame

After 6 cycles of combination therapy (at Week 24; each cycle is 28 days)

Title

Percentage of Participants with Complete Remission with Incomplete Platelet Recovery (CRp) as Defined by IWG 2003 and ELN 2010 Response Criteria

Time Frame

After 6 cycles of combination therapy (at Week 24; each cycle is 28 days)

Title

Percentage of Participants with Complete Remission with Incomplete Recovery (CRi) as Defined by IWG 2003 and ELN 2010 Response Criteria

Time Frame

After 6 cycles of combination therapy (at Week 24; each cycle is 28 days)

Title

Duration of Response as Defined by IWG 2003 and ELN 2010 Response Criteria

Time Frame

Baseline until the date of relapse/progression or death from any cause, assessed up to approximately 32 months

Secondary Outcome Measure Information:

Title

Percentage of Participants with Best Overall Response as Defined by IWG 2003 and ELN 2010 Response Criteria

Time Frame

Baseline until the date of relapse/progression or death from any cause, assessed up to approximately 32 months

Title

Event-free Survival (EFS) as Defined by IWG 2003 and ELN 2010 Response Criteria

Time Frame

Baseline until the date of induction treatment failure or relapse or death from any cause, assessed up to approximately 32 months

Title

Leukemia-free Survival (LFS) as Defined by IWG 2003 and ELN 2010 Response Criteria

Time Frame

Baseline until the date of relapse or death from any cause, assessed up to approximately 32 months

Title

Overall Survival (OS)

Time Frame

Baseline until death from any cause, assessed up to approximately 32 months

Title

Percentage of Participants with Minimal Residual Disease (MRD) Negativity in Participants who Achieve CR, CRp, or CRi

Time Frame

Baseline up to approximately 32 months

Title

Percentage of Participants with Anti-Drug Antibody (ADA) to Atezolizumab

Time Frame

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)

Title

Serum Concentration of Atezolizumab

Description

Time Frame

Day 1 up to 32 months (detailed sample collection time points are provided in Outcome Measure Description)

Title

Plasma Concentration of Guadecitabine

Time Frame

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)

Title

Plasma Concentration of Decitabine (a Metabolite Product of Guadecitabine)

Time Frame

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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Hoffmann-La Roche

Official's Role

Study Director

Facility Information:

Facility Name

City of Hope

City

Duarte

State/Province

California

ZIP/Postal Code

91010

Country

United States

Facility Name

Yale University

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06511

Country

United States

Facility Name

The NewYork-Presbyterian Hospital Columbia University Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

Memorial Sloan Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

Levine Cancer Institute

City

Charlotte

State/Province

North Carolina

ZIP/Postal Code

28204

Country

United States

Facility Name

Temple University Hospital

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19140

Country

United States

Facility Name

Huntsman Cancer Institute

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84112

Country

United States

Facility Name

The University of Wisconsin School of Medicine and Public Health

City

Madison

State/Province

Wisconsin

ZIP/Postal Code

53705

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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