A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of AGS67E in subjects with acute myeloid leukemia (AML) and determine a safe dose for future development. In addition, this study will assess the pharmacokinetics (PK), the immunogenicity, and the anti-leukemic activity of AGS67E.

Detailed Description
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The study will sequentially evaluate AGS67E given as a 30 minute intravenous (IV) infusion in two different schedules: once every 3 weeks (Q3) and then once weekly for 3 weeks. The dose escalation follows a 3 + 3 design. The Data Review Team may expand any dose level or intermediate dose level that has been deemed safe and resulted in at least one subject with a Composite Complete Remission (CRc). An expansion cohort may enroll up to 15 subjects.

Official Title
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A Phase 1 Study Evaluating Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: AGS67E


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2008) and fulfills one of the following: Refractory to at least 1 cycle of induction chemotherapy Relapsed after achieving remission with a prior therapy Patients with untreated AML who are either unwilling or unable to undergo high-dose induction/consolidation intensive chemotherapy Circulating blasts < 20,000 (cytoreduction with hydroxyurea is allowed) Eastern Cooperative Oncology Group performance score (ECOG) ≤ 2 Subject has adequate renal function: serum creatinine ≤ 2.0 mg/dL and estimated creatinine clearance of ≥ 30 mL/min by the Cockcroft-Gault equation Subject has a total bilirubin ≤ 1.5 x upper limit of normal (ULN), albumin ≥ 2.5 g/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN Negative pregnancy test in women of child bearing potential Sexually active fertile subjects, and their partners, must agree to use medically accepted double-barrier methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the study and at least 6 weeks after termination of study therapy Exclusion Criteria: Subject has a diagnosis of acute promyelocytic leukemia Subject has preexisting sensory or motor neuropathy Grade ≥ 2 at baseline Subject has received small molecule therapy, radiotherapy, immunotherapy, monoclonal antibodies, investigational drug, or chemotherapy within 14 days before first dose of study drug, with the exception of hydroxyurea P-gp inducers/inhibitors or strong CYP3A inhibitors within 14 days before the first dose of drug, with the exception of the antibiotics/ antifungals used as prophylaxis and/or supportive care Any Grade ≥ 2 persistent non-hematological toxicity related to allotransplant Graft-Versus-Host Disease (GVHD) therapy within 6 weeks before the first dose of study drug; low dose steroids (≤ 10mg) allowed Subject has known current central nervous system (CNS) disease Active angina or Class III or IV Congestive Heart Failure (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 6 months of the first dose of study drug, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by medication Subject has clinical evidence of Disseminated Intravascular Coagulation (DIC) Subject has known positivity for human immunodeficiency virus (HIV) Subject has know positivity for Hepatitis B surface antigen test or Hepatitis C Antibody Subject has an uncontrolled active infection requiring treatment and fever 38.3°C or higher 48 hours before the first dose of study drug. Controlled infections (i.e. 3 negative cultures completing antibiotics and/or stable fungal infection in therapy are allowed provided the subject has a temperature of <38.3°C within 48 hours of the first dose of study drug Subject has known sensitivity to any of the components of the investigational product AGS67E: AGS67E L-Histidine α-trehalose dihydrate or polysorbate 20 Major surgery within 28 days of the first dose of study drug Subject is pregnant or lactating Subject has a condition or situation which may put the subject at significant risk, may confound the study results, or may interfere significantly with subject's participation in the study

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGS67E 1.2 mg/kg Schedule 1<br>Participants will receive 1.2 mg/kg of AGS67E as an intravenous infusion once every three weeks (Q3). | Drug: AGS67E<br>* Intravenous (IV) infusion<br>|
| Experimental: AGS67E 1.8 mg/kg Schedule 1<br>Participants will receive 1.8 mg/kg of AGS67E as an intravenous infusion once every three weeks. | Drug: AGS67E<br>* Intravenous (IV) infusion<br>|
| Experimental: AGS67E 2.4 mg/kg Schedule 1<br>Participants will receive 2.4 mg/kg of AGS67E as an intravenous infusion once every three weeks. | Drug: AGS67E<br>* Intravenous (IV) infusion<br>|
| Experimental: AGS67E 0.6 mg/kg Schedule 2<br>Participants will receive 0.6 mg/kg of AGS67E once weekly for three weeks. | Drug: AGS67E<br>* Intravenous (IV) infusion<br>|
| Experimental: AGS67E 0.9 mg/kg Schedule 2<br>Participants will receive 0.9 mg/kg of AGS67E once weekly for three weeks. | Drug: AGS67E<br>* Intravenous (IV) infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and nature of adverse events |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Concentration at the end of infusion (CEOI) |  | Escalation Q3 weeks dosing: up to Day 15 for Cycle 1, Day 8 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Escalation weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Concentration at the end of infusion (CEOI) |  | Expansion Q3 weeks dosing: up to Day 8 for Cycle 1, Day 3 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Expansion weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Maximum observed concentration (Cmax) |  | Escalation Q3 weeks dosing: up to Day 15 for Cycle 1, Day 8 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Escalation weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Maximum observed concentration (Cmax) |  | Expansion Q3 weeks dosing: up to Day 8 for Cycle 1, Day 3 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Expansion weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for Monomethyl Auristatin E (MMAE) in dose escalation part: Time to maximum concentration (Tmax) |  | Escalation Q3 weeks dosing: up to Day 15 for Cycle 1, Day 8 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Escalation weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for Monomethyl Auristatin E (MMAE) in dose expansion part: Time to maximum concentration (Tmax) |  | Expansion Q3 weeks dosing: up to Day 8 for Cycle 1, Day 3 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Expansion weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Partial area under the serum concentration-time curve (AUC) |  | Escalation Q3 weeks dosing: up to Day 15 for Cycle 1, Day 8 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Escalation weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Partial area under the serum concentration-time curve (AUC) |  | Expansion Q3 weeks dosing: up to Day 8 for Cycle 1, Day 3 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Expansion weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Terminal or apparent terminal half-life (t1/2) |  | Escalation Q3 weeks dosing: up to Day 15 for Cycle 1, Day 8 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Escalation weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Terminal or apparent terminal half-life (t1/2) |  | Expansion Q3 weeks dosing: up to Day 8 for Cycle 1, Day 3 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Expansion weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Systemic clearance (CL) |  | Escalation Q3 weeks dosing: up to Day 15 for Cycle 1, Day 8 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Escalation weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Systemic clearance (CL) |  | Expansion Q3 weeks dosing: up to Day 8 for Cycle 1, Day 3 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Expansion weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Volume of distribution at steady state (Vss) |  | Escalation Q3 weeks dosing: up to Day 15 for Cycle 1, Day 8 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Escalation weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Volume of distribution at steady state (Vss) |  | Expansion Q3 weeks dosing: up to Day 8 for Cycle 1, Day 3 for Cycle 2, predose in subsequent cycles up to an average of 12 months. Expansion weekly dosing: up to Day 22 for Cycles 1, 2 and predose in subsequent cycles up to an average of 12 months | 
| Incidence of Anti-Drug Antibody (ADA) formation to the fully human monoclonal antibody (AGS67C) and antibody-drug conjugate (AGS67E) |  | Up to 24 months | 
| Complete remission (CR) rate |  | Up to 24 months | 
| Composite CR (CRc) rate |  | Up to 24 months | 
| Best overall response rate | Best overall response rate is defined as the percentage of subjects who experience a best overall response of CRc, partial response (PR) or morphologic leukemia-free state (MLFS) | Up to 24 months | 
| Duration of remission | Duration of remission is the duration of CRc, CR, completion remission with incomplete hematologic recovery (CRi) and completion remission with incomplete platelet recovery (CRp) | Up to 24 months | 
| Duration of response | Duration of response is CRc, PR and MLFS | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Acute Myeloid Leukemia