Acute Myeloid Leukemia
Conditions
Brief summary
This Phase Ib study is designed to evaluate the safety and pharmacokinetics of atezolizumab when given in combination with Hu5F9-G4 to patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).
Interventions
DRUGAtezolizumab
Atezolizumab will be administered to participants by IV infusion at a fixed dose starting on Day 22 of Cycle 1. In subsequent cycles (Cycles 2 and beyond), IV atezolizumab will be given every 2 weeks (Q2W) on Days 8 and 22 of each 28-day cycle.
DRUGHu5F9-G4
Two priming doses of 1 mg/kg of Hu5F9-G4 will be administered to participants by continuous IV infusion on Days 1 and 4 of Cycle 1, followed by loading doses of 15 mg/kg IV on Day 8 and 30 mg/kg IV on Day 11. Starting on Day 15 of Cycle 1, Hu5F9-G4 maintenance will be given by IV infusion at a dose of 30 mg/kg once a week (QW) of each 28-day cycle. Dosing for de-escalation, if needed: Hu5F9-G4 will be given as two priming doses of 1 mg/kg IV on Days 1 and 4, followed by loading doses of 10 mg/kg IV on Day 8 and 15 mg/kg on Day 11. Starting on Day 15, maintenance treatment with Hu5F9-G4 will be given by IV infusion at a dose of 15 mg/kg once a week (QW).
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Life expectancy of at least 12 weeks * Eastern Cooperative Oncology Group Performance Status 0-2 * Documented and confirmed R/R AML per WHO classification, except acute promyelocytic leukemia, and lack of response to all therapies of known benefit * Adequate end-organ function * Negative HIV test at screening * Negative hepatitis B surface antigen (HBsAg) test at screening * Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA \<500 IU/mL at screening * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening * Willingness and ability to provide pretreatment bone marrow aspirate and biopsy and agreement to provide subsequent bone marrow aspirates and biopsies during study treatment * For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating eggs * For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm * For women who are not postmenopausal or surgically sterile: requirement for a negative serum pregnancy test result within 14 days prior to initiation of study treatment
Exclusion criteria
* Previous allogeneic hematopoietic stem cell transplant within 6 months prior to enrollment, active graft versus host disease, or requiring transplant-related immunosuppression * Prior solid organ transplant * Evidence of active central nervous system (CNS) involvement by leukemia * Pregnancy or lactation or intention to become pregnant during the study or within 5 months after the final dose of atezolizumab and/or Hu5F9-G4, whichever is longer * History of idiopathic pulmonary fibrosis, organizing pneumonitis, drug-induced pneumonitis, or idiopathic pneumonitis * History of autoimmune disease. Patients with a history of autoimmune-related hypothyroidism who are on a stable dose of thyroid replacement may be eligible for this study. Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen may be eligible for this study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are eligible for the study provided all of the following conditions are met: (1) Rash must cover \<10% of body surface area, (2) Disease is well controlled at baseline and requires only low-potency topical corticosteroids, (3) No occurrence of acute exacerbations of the underlying condition that require psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. * Treatment with investigational therapy within 14 days prior to initiation of study drug * Any approved AML-related therapy within 14 days prior to enrollment. Granulocyte colony-stimulating factor to treat neutropenic fever and/or infection is permitted. Hydroxyurea may be used throughout the trial to control peripheral blood blast counts in response to the first dose of study treatment and during the first 4 weeks of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | Up to approximately 13 months after first participant enrolled | Percentage of participants with at least one adverse event. |
| Complete Remission (CR) | Up to approximately 3 months after first participant enrolled | The CR rate is assessed as the percentage of participants who achieve a CR, complete remission with incomplete platelet recovery (CRp), complete remission with incomplete hematologic recovery (CRi), or complete remission with partial hematologic recovery (CRh) (as defined by the IWG 2003 and ELN 2010 criteria) after up to six cycles of combination therapy. |
| Duration of Response (DOR) | Up to approximately 3 months after first particpant enrolled | DOR is defined as the time from the initial response (CR, CRp, CRi, CRh, or partial remission \[PR\]) to the time of disease progression or death, whichever occurs first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival | Up to approximately 3 months after first participant enrolled | Event-free survival is defined as the time from study entry to the date of induction treatment failure or relapse from CR, CRp, CRh, CRi, or death from any cause. |
| Leukemia-Free Survival | Up to approximately 3 months after first participant enrolled | Leukemia-free survival is defined (only for participants achieving a CR, CRp, CRh, or CRi) as the time from the date of achievement of remission (CR, CRp, or CRi) until the date of relapse from CR, CRp, CRh, CRi, or death from any cause. |
| Overall Survival | Up to approximately 13 months after first participant enrolled | Overall survival is defined as time from study entry to the date of death from any cause. |
| Progression-Free Survival | Up to approximately 3 months after first participant enrolled | Progression-free survival (Investigator) is defined as the time from the first day of study treatment to disease progression or death, whichever occurs first. |
| Serum Concentrations of Atezolizumab | C1 D22 PTFI of Hu5F9-G4 and atezolizumab, and 30 minutes after atezolizumab infusion; C2 D8 PTFI; C2 D22 PTFI; C3 D22 PTFI; C4 D22 PTFI; C8 D22 PTFI; C12 D22 PTFI; C16 D22 PTFI; TDV (up to C16 D21);120 days after final dose of atezolizumab (UTA 37M) | C=cycle (cycle=28 days) ; D=day; PTFI=prior to first infusion; TDV=treatment discontinuation visit; UTA=up to approximately; M=month |
| Duration of Transfusion Independence | Up to approximately 3 months after first participant enrolled | Duration of transfusion independence is defined as the number of consecutive days of transfusion independence, measured from 1 day after the last transfusion to disease progression or subsequent transfusion. |
| Incidence of Anti-Drug Antibodies (ADAs) Against Atezolizumab During the Study Relative to the Prevalence of ADAs at Baseline | Baseline up to approximately 37 months | — |
| Incidence of ADAs Against Hu5F9-G4 During the Study Relative to the Prevalence of ADAs at Baseline | Baseline up to approximately 37 months | — |
| Rate of Transfusion Independence | Up to approximately 3 months after first participant enrolled | Rate of transfusion independence is defined as the percentage of participants who achieve transfusion independence (i.e., achieving any continuous 56-day window without requiring platelet or RBC transfusions) at any time during study treatment. |
| Serum Concentrations of Hu5F9-G4 | C1D1 PTFI&1H AEOI; C1D8 PTFI,&1H AEOI; C1D11 PTFI,&1H AEOI; C1D22 1H AEOI; C2D1 PTFI,&1H AEOI; C2D8 PTFI; C3D1 PTFI,&1H AEOI; C5D1 PTFI; C7D1 PTFI, C9D1 PTFI; C11D1 PTFI; C13D1 PTFI; C15D1 PTFI; C17D1&D1 E 2C T PTFI(UTA 37M);TDV(up to C16D21)(UTA 37M) | C=cycle (cycle=28 days); D=Day; PTFI=prior to first infusion; H=hour; AEOI=after end of infusion; TDV=treatment discontinuation visit; UTA=up to approximately; M=months; E=every; T=thereafter |
| Objective Response Rate | Up to approximately 3 months after first participant enrolled | Objective response rate is defined as the percentage of participants with a partial remission (PR) or better (i.e., CR + CRp + CRi + CRh+ PR). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atezolizumab + Hu5F9-G4 An initial safety evaluation was performed in participants with relapsed AML. If atezolizumab in combination with Hu5F9-G4 was initially safe and tolerable in participants an additional cohort with R/R AML was to be evaluated to further test the safety and anti-tumor activity. Atezolizumab was administered to participants by IV infusion at a fixed dose of 840 mg starting on Day 22 of Cycle 1. In subsequent cycles, IV atezolizumab was given every 2 weeks (Q2W) on Days 8 and 22 of each 28-day cycle. Two priming doses of 1 mg/kg of Hu5F9-G4 were administered to participants by continuous IV infusion on Days 1 and 4 of Cycle 1, followed by loading doses of 15 mg/kg IV on Day 8 and 30 mg/kg IV on Day 11. Starting on Day 15 of Cycle 1, Hu5F9-G4 maintenance was given by IV infusion at a dose of 30 mg/kg once a week (QW) of each 28-day cycle. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 9 |
| Overall Study | Fall leading to death prior to treatment initiation. | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Atezolizumab + Hu5F9-G4 |
|---|---|
| Age, Continuous | 68.9 Years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 11 |
| other Total, other adverse events | 10 / 11 |
| serious Total, serious adverse events | 10 / 11 |
Outcome results
Primary
Complete Remission (CR)
The CR rate is assessed as the percentage of participants who achieve a CR, complete remission with incomplete platelet recovery (CRp), complete remission with incomplete hematologic recovery (CRi), or complete remission with partial hematologic recovery (CRh) (as defined by the IWG 2003 and ELN 2010 criteria) after up to six cycles of combination therapy.
Time frame: Up to approximately 3 months after first participant enrolled
Population: The efficacy analysis population included all participants who received any amount of either study drug, with participants grouped as a whole.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Hu5F9-G4 | Complete Remission (CR) | 0 Percentage of participants |
Primary
Duration of Response (DOR)
DOR is defined as the time from the initial response (CR, CRp, CRi, CRh, or partial remission \[PR\]) to the time of disease progression or death, whichever occurs first
Time frame: Up to approximately 3 months after first particpant enrolled
Population: The efficacy analysis population included all participants who received any amount of either study drug, with participants grouped as a whole. No participants were analyzed because no participants responded.
Primary
Percentage of Participants With Adverse Events
Percentage of participants with at least one adverse event.
Time frame: Up to approximately 13 months after first participant enrolled
Population: Safety population included all participants with any amount of either study drug, with participants grouped as a whole.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Hu5F9-G4 | Percentage of Participants With Adverse Events | 100 Percentage of participants |
Secondary
Duration of Transfusion Independence
Duration of transfusion independence is defined as the number of consecutive days of transfusion independence, measured from 1 day after the last transfusion to disease progression or subsequent transfusion.
Time frame: Up to approximately 3 months after first participant enrolled
Population: None of the participants achieved transfusion independence, hence duration of independence was not calculated.
Secondary
Event-Free Survival
Event-free survival is defined as the time from study entry to the date of induction treatment failure or relapse from CR, CRp, CRh, CRi, or death from any cause.
Time frame: Up to approximately 3 months after first participant enrolled
Population: The efficacy analysis population included all participants who received any amount of either study drug, with participants grouped as a whole.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Hu5F9-G4 | Event-Free Survival | 1.7 Months |
Secondary
Incidence of ADAs Against Hu5F9-G4 During the Study Relative to the Prevalence of ADAs at Baseline
Time frame: Baseline up to approximately 37 months
Population: Samples for ADA analysis were collected, but due to the small number of participants which reduces the scientific merit of any analysis no ADA assays were performed and samples were discarded, hence no ADA data are available.
Secondary
Incidence of Anti-Drug Antibodies (ADAs) Against Atezolizumab During the Study Relative to the Prevalence of ADAs at Baseline
Time frame: Baseline up to approximately 37 months
Population: Samples for ADA analysis were collected, but due to the small number of participants which reduces the scientific merit of any analysis no ADA assays were performed and samples were discarded, hence no ADA data are available.
Secondary
Leukemia-Free Survival
Leukemia-free survival is defined (only for participants achieving a CR, CRp, CRh, or CRi) as the time from the date of achievement of remission (CR, CRp, or CRi) until the date of relapse from CR, CRp, CRh, CRi, or death from any cause.
Time frame: Up to approximately 3 months after first participant enrolled
Population: No participants were analyzed because no participants received an objective response.
Secondary
Objective Response Rate
Objective response rate is defined as the percentage of participants with a partial remission (PR) or better (i.e., CR + CRp + CRi + CRh+ PR).
Time frame: Up to approximately 3 months after first participant enrolled
Population: The efficacy analysis population included all participants who received any amount of either study drug, with participants grouped as a whole.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Hu5F9-G4 | Objective Response Rate | 0 Percentage of participants |
Secondary
Overall Survival
Overall survival is defined as time from study entry to the date of death from any cause.
Time frame: Up to approximately 13 months after first participant enrolled
Population: The efficacy analysis population included all participants who received any amount of either study drug, with participants grouped as a whole.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Hu5F9-G4 | Overall Survival | 4.1 Months |
Secondary
Progression-Free Survival
Progression-free survival (Investigator) is defined as the time from the first day of study treatment to disease progression or death, whichever occurs first.
Time frame: Up to approximately 3 months after first participant enrolled
Population: The efficacy analysis population included all participants who received any amount of either study drug, with participants grouped as a whole.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Hu5F9-G4 | Progression-Free Survival | 2.8 Months |
Secondary
Rate of Transfusion Independence
Rate of transfusion independence is defined as the percentage of participants who achieve transfusion independence (i.e., achieving any continuous 56-day window without requiring platelet or RBC transfusions) at any time during study treatment.
Time frame: Up to approximately 3 months after first participant enrolled
Population: The efficacy analysis population included all participants who received any amount of either study drug, with participants grouped as a whole.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Hu5F9-G4 | Rate of Transfusion Independence | 0 Percentage of participants |
Secondary
Serum Concentrations of Atezolizumab
C=cycle (cycle=28 days) ; D=day; PTFI=prior to first infusion; TDV=treatment discontinuation visit; UTA=up to approximately; M=month
Time frame: C1 D22 PTFI of Hu5F9-G4 and atezolizumab, and 30 minutes after atezolizumab infusion; C2 D8 PTFI; C2 D22 PTFI; C3 D22 PTFI; C4 D22 PTFI; C8 D22 PTFI; C12 D22 PTFI; C16 D22 PTFI; TDV (up to C16 D21);120 days after final dose of atezolizumab (UTA 37M)
Population: Samples for PK analysis were collected, but due to the small number of participants which reduces the scientific merit of any analysis no PK assays were performed and samples were discarded, hence no PK data are available.
Secondary
Serum Concentrations of Hu5F9-G4
C=cycle (cycle=28 days); D=Day; PTFI=prior to first infusion; H=hour; AEOI=after end of infusion; TDV=treatment discontinuation visit; UTA=up to approximately; M=months; E=every; T=thereafter
Time frame: C1D1 PTFI&1H AEOI; C1D8 PTFI,&1H AEOI; C1D11 PTFI,&1H AEOI; C1D22 1H AEOI; C2D1 PTFI,&1H AEOI; C2D8 PTFI; C3D1 PTFI,&1H AEOI; C5D1 PTFI; C7D1 PTFI, C9D1 PTFI; C11D1 PTFI; C13D1 PTFI; C15D1 PTFI; C17D1&D1 E 2C T PTFI(UTA 37M);TDV(up to C16D21)(UTA 37M)
Population: Samples for PK analysis were collected, but due to the small number of participants which reduces the scientific merit of any analysis no PK assays were performed and samples were discarded, hence no PK data are available.