Clinical trial NCT02610062: A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Acute Myeloid Leukemia (AML)
Official title: A Phase 1 Study Evaluating Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Acute Myeloid Leukemia (AML)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Keywords: AML
Acute Myeloid Leukemia
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-11-20
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence and nature of adverse events
timeFrame: Up to 24 months
Secondary outcomes:
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Maximum observed concentration (Cmax)
timeFrame: 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
measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Maximum observed concentration (Cmax)
timeFrame: 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
measure: Pharmacokinetic parameter for Monomethyl Auristatin E (MMAE) in dose escalation part: Time to maximum concentration (Tmax)
timeFrame: 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
measure: Pharmacokinetic parameter for Monomethyl Auristatin E (MMAE) in dose expansion part: Time to maximum concentration (Tmax)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose escalation part: Systemic clearance (CL)
timeFrame: 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
measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE) in dose expansion part: Systemic clearance (CL)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Incidence of Anti-Drug Antibody (ADA) formation to the fully human monoclonal antibody (AGS67C) and antibody-drug conjugate (AGS67E)
timeFrame: Up to 24 months
measure: Complete remission (CR) rate
timeFrame: Up to 24 months
measure: Composite CR (CRc) rate
timeFrame: Up to 24 months
measure: Best overall response rate
timeFrame: Up to 24 months
measure: Duration of remission
timeFrame: Up to 24 months
measure: Duration of response
timeFrame: Up to 24 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Site US0006
state: California
city: New York
country: United States
facility: Site US0004
state: New York
city: Houston
country: United States
facility: Site US0001
state: Texas
city: Toronto
country: Canada
facility: Site CA0010
state: Ontario
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Associate Medical Director
role: STUDY_DIRECTOR
References: