An Investigational Immuno-therapy Study of Ulocuplumab in Combination With Low Dose Cytarabine in Patients With Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and effectiveness of ulocuplumab in combination with low dose cytarabine in the treatment of Newly Diagnosed Acute Myeloid Leukemia (AML).

Official Title
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A Phase 1/2, Open-label Randomized Study of Ulocuplumab (BMS-936564) in Combination With Low Dose Cytarabine in Subjects With Newly Diagnosed Acute Myeloid Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: BMS-936564
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Newly Diagnosed Acute Myeloid Leukemia (AML) Considered inappropriate for intensive remission induction therapy by an investigator Not eligible for stem cell transplantation Exclusion Criteria: Acute promyelocytic leukemia Current Myelodysplastic syndrome only subjects Unstable angina or uncontrolled congestive heart failure Any other malignancy, excluding basal or squamous cell carcinoma of the skin, in situ melanoma, cervical carcinoma in situ, localized prostate cancer, or superficial bladder cancer stage 0, from which the subject has not been disease-free for at least 3 years Respiratory disease requiring continuous supplemental oxygen Other protocol defined inclusion/exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ulocuplumab + low dose Cytarabine<br>Ulocuplumab + low dose Cytarabine (LDAC) Phase 1 (escalation cohort) - closed for enrollment | Drug: BMS-936564<br> <br> * Other names: MDX-1338;Drug: Cytarabine<br> <br> |
| Experimental: Ulocuplumab Dose A + low dose Cytarabine<br>Ulocuplumab Dose A + low dose Cytarabine Phase 2 (expansion cohort) | Drug: BMS-936564<br> <br> * Other names: MDX-1338;Drug: Cytarabine<br> <br> |
| Experimental: Ulocuplumab Dose B + low dose Cytarabine<br>Ulocuplumab Dose B + low dose Cytarabine Phase 2 (expansion cohort) | Drug: BMS-936564<br> <br> * Other names: MDX-1338;Drug: Cytarabine<br> <br> |
| Other: low dose Cytarabine only<br>Low Dose Cytarabine only Phase 2 (expansion cohort) | Drug: BMS-936564<br> <br> * Other names: MDX-1338;Drug: Cytarabine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLTs) in Treatment Cycle 1 - Phase 1 | Safety data evaluated for DLTs. DLTs and all other toxicities were defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). DLTs were defined based upon events that were considered to be related to ulocuplumab in combination with LDAC and that occurred during the first cycle of drug administration (28 days). | From first dose to end of cycle 1 (28 days) | 
| Number of Participants With Adverse Events (AEs) - Phase 1 | The number of participants with an on-study adverse event (AE). Safety data are evaluated for AEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose to 30 days post last dose | 
| Number of Participants With >= Grade 3 AEs - Phase 1 | The number of participants with an on-study adverse event >= Grade level 3. Safety data are evaluated for >= Grade 3 AEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose to 30 days post last dose | 
| Number of Participants With AEs Leading to Discontinuation - Phase 1 | The number of participants with an on-study adverse event (AE) leading to discontinuation. Safety data are evaluated for AEs leading to discontinuation, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose to 30 days post last dose | 
| Number of Participants With Serious Adverse Events (SAEs) - Phase 1 | The number of participants with an on-study serious adverse event (SAE). Safety data are evaluated for SAEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose to 30 days post last dose | 
| Number of Deaths - Phase 1 | The number of participants who died. | From first dose to 30 days post last dose | 
| Number of Participants With Laboratory Abnormalities - Phase 1 | The number of participants with an on-study laboratory abnormality. Safety data are evaluated for laboratory abnormalities, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). grades 1, 2, 3, 4, 5, unknown, with 5 being the worst outcome | From first dose to 30 days post last dose | 
| Best Overall Response (BOR) - Phase 2 | The phase 2 primary endpoint was based on the rate of Complete Remission (CR/CRi) prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 primary analysis was conducted after all participants had an opportunity for 6 months of follow-up. Complete remission rate: CR + CRi, confidence interval based on the Clopper and Pearson method. CR = complete response CRi = complete response, incomplete blood count | From first dose until a minimum follow-up of up to 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) - Phase 1 | Investigator assessed best overall response prior to the initiation of any alternative therapy for Phase 1 participants. | From first dose until a minimum follow-up of up to 2 months | 
| Number of Participants With AEs - Phase 2 | The number of participants with an on-study adverse event (AE). Safety data are evaluated for AEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose until a minimum follow-up of up to 2 months | 
| Number of Participants With AEs Leading to Discontinuation - Phase 2 | The number of participants with an on-study adverse event (AE) leading to discontinuation. Safety data are evaluated for AEs leading to discontinuation, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose until a minimum follow-up of up to 2 months | 
| Number of Participants With SAEs - Phase 2 | The number of participants with an on-study serious adverse event (SAE). Safety data are evaluated for SAEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose until a minimum follow-up of up to 2 months | 
| Number of Deaths- Phase 2 | The number of participants who died. Safety data are evaluated for deaths, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose until a minimum follow-up of up to 2 months | 
| Number of Participants With Laboratory Abnormalities - Phase 2 | The number of participants with an on-study laboratory abnormality, assessed from Grade 1-4 Serum Chemistry, Electrolytes, and Hematology Laboratory Test results, with grade 4 being the worst. Safety data are evaluated for laboratory abnormalities, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). | From first dose until a minimum follow-up of up to 2 months | 
| Number of Participants With Anti-drug Antibodies (ADA) Positive for Ulocuplumab - Phases 1 and 2 | Serum samples from ulocuplumab treated participants were evaluated for the presence of anti-ulocuplumab antibodies | From first dose until a minimum follow-up of up to 2 months | 
| Maximum Observed Serum Concentration (Cmax) - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration EOT = end of treatment Measure type and method of dispersion are Geometric mean and %CV, respectively | Cycle 1 Day 1 | 
| Trough Observed Serum Concentration (Ctrough) - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment Measure type and method of dispersion are Geometric mean and %CV, respectively | Days 1, 8, 15 for cycle 1; Days 8, 15 for cycle 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up) | 
| Time of Maximum Observed Ulocuplumab Serum Concentration (Tmax) - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment | Cycle 1 Day 1 | 
| Area Under the Ulocuplumab Concentration-time Curve From Time Zero to the Last Quantifiable Concentration [AUC(0-T)] - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment AUC(0-T) calculated by log- and linear-trapezoidal summation Measure type and method of dispersion are Geometric mean and %CV, respectively | Cycle 1 Day 1 | 
| Area Under the Ulocuplumab Concentration-time Curve in One Dosing Interval [AUC(TAU)] - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment Measure type and method of dispersion are Geometric mean and %CV, respectively | Cycle 1 Day 1 | 
| Area Under the Ulocuplumab Concentration-time Curve From Time Zero to Infinity [AUC(INF)] - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment AUC(INF) calculated by summing AUC(0-T) and the extrapolated area, computed by the quotient Clast/λz Measure type and method of dispersion are Geometric mean and %CV, respectively | Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up) | 
| Elimination Half-life (T-HALF) - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment T-HALF determined as 0.693/λz | Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up) | 
| Total Body Clearance of Ulocuplumab (CLT) - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment CLT calculated by dividing the total dose of ulocuplumab by its corresponding AUC(INF) value Measure type and method of dispersion are Geometric mean and %CV, respectively | Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up) | 
| Volume of Distribution at Steady State (Vss) - Phases 1 and 2 | The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment Measure type and method of dispersion are Geometric mean and %CV, respectively | Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up) | 
| Overall Rate of Remission in Participants Treated With Ulocuplumab at Two Different Dose Levels 800 mg and 1000 mg in Combination With LDAC - Phase 2 | This phase 2 secondary endpoint was based on the rate of Overall Remission (OR=PR+CR +CRi) prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 analysis was conducted after all participants had an opportunity for 6 months of follow-up. Overall remission rate: CR + CRi, + PR confidence interval based on the Clopper and Pearson method. CR = complete response CRi = complete response, incomplete blood count PR = partial remission | From first dose until a minimum follow-up of up to 2 months | 
| Duration of Response in Participants With CR/CRi Treated With Ulocuplumab at Two Different Dose Levels 800 mg and 1000 mg in Combination With LDAC - Phase 2 | This phase 2 secondary endpoint was based on the duration of complete remission prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 analysis was conducted after all participants had an opportunity for 6 months of follow-up. | From first dose until a minimum follow-up of up to 2 months | 
| Rate of Complete Remission (CR/CRi) and Overall Rate of Remission in Participants Treated With LDAC Only - Phase 2 | This phase 2 secondary endpoint was based on the rate of Complete Remission (CR/CRi) and rate of Overall Remission (OR=PR+CR +CRi) prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 analysis was conducted after all participants had an opportunity for 6 months of follow-up. Overall remission rate: CR + CRi, + PR confidence interval based on the Clopper and Pearson method. CR = complete response CRi = complete response, incomplete blood count PR = partial remission | From first dose until a minimum follow-up of up to 2 months | 
| Duration of Response in Participants With CR/CRi Treated With LDAC Only - Phase 2 | This phase 2 secondary endpoint was based on the duration of complete remission prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 analysis was conducted after all participants had an opportunity for 6 months of follow-up. | From first dose until a minimum follow-up of up to 2 months | 
| Change From Baseline of Electrocardiogram (ECG) Endpoints: Heart Rate - Phases 1 and 2 | Change from baseline of ECG endpoints Heart rate measured in beats per minute (bpm) | From first dose until a minimum follow-up of up to 2 months | 
| Change From Baseline of Electrocardiogram (ECG) Endpoints: PR Interval - Phases 1 and 2 | Change from baseline of ECG endpoints PR interval measured in milliseconds (msec) | From first dose until a minimum follow-up of up to 2 months | 
| Change From Baseline of Electrocardiogram (ECG) Endpoints: QRS Interval - Phases 1 and 2 | Change from baseline of ECG endpoints QRS interval measured in milliseconds (msec) | From first dose until a minimum follow-up of up to 2 months | 
| Change From Baseline of Electrocardiogram (ECG) Endpoints: QT Interval - Phases 1 and 2 | Change from baseline of ECG endpoints QT interval measured in milliseconds (msec) | From first dose until a minimum follow-up of up to 2 months | 
| Overall Survival (OS) - Phases 1 and 2 | OS is defined as the time between the first date of treatment and the date of death due to any cause. A participant who has not died was be censored at the last known alive date. | From first dose until a minimum follow-up of up to 2 months |