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

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ClinicalTrials.gov Identifier: NCT02610062
Recruitment Status : Terminated (Business decision by sponsor)
First Posted : November 20, 2015
Last Update Posted : July 11, 2019
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Tracking Information
First Submitted Date  ICMJE November 18, 2015
First Posted Date  ICMJE November 20, 2015
Last Update Posted Date July 11, 2019
Actual Study Start Date  ICMJE March 29, 2016
Actual Primary Completion Date September 22, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 18, 2015)
Incidence and nature of adverse events [ Time Frame: Up to 24 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02610062 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2015)
  • 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Up to 24 months ]
  • Complete remission (CR) rate [ Time Frame: Up to 24 months ]
  • Composite CR (CRc) rate [ Time Frame: Up to 24 months ]
  • Best overall response rate [ Time Frame: Up to 24 months ]
    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)
  • Duration of remission [ Time Frame: Up to 24 months ]
    Duration of remission is the duration of CRc, CR, completion remission with incomplete hematologic recovery (CRi) and completion remission with incomplete platelet recovery (CRp)
  • Duration of response [ Time Frame: Up to 24 months ]
    Duration of response is CRc, PR and MLFS
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE A Phase 1 Study Evaluating Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Acute Myeloid Leukemia (AML)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia
Intervention  ICMJE Drug: AGS67E
Intravenous (IV) infusion
Study Arms  ICMJE
  • Experimental: AGS67E 1.2 mg/kg Schedule 1
    Participants will receive 1.2 mg/kg of AGS67E as an intravenous infusion once every three weeks (Q3).
    Intervention: Drug: AGS67E
  • Experimental: AGS67E 1.8 mg/kg Schedule 1
    Participants will receive 1.8 mg/kg of AGS67E as an intravenous infusion once every three weeks.
    Intervention: Drug: AGS67E
  • Experimental: AGS67E 2.4 mg/kg Schedule 1
    Participants will receive 2.4 mg/kg of AGS67E as an intravenous infusion once every three weeks.
    Intervention: Drug: AGS67E
  • Experimental: AGS67E 0.6 mg/kg Schedule 2
    Participants will receive 0.6 mg/kg of AGS67E once weekly for three weeks.
    Intervention: Drug: AGS67E
  • Experimental: AGS67E 0.9 mg/kg Schedule 2
    Participants will receive 0.9 mg/kg of AGS67E once weekly for three weeks.
    Intervention: Drug: AGS67E
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 20, 2018)
23
Original Estimated Enrollment  ICMJE
 (submitted: November 18, 2015)
110
Actual Study Completion Date  ICMJE November 21, 2017
Actual Primary Completion Date September 22, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02610062
Other Study ID Numbers  ICMJE AGS67E-15-2
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."
Responsible Party Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
Study Sponsor  ICMJE Astellas Pharma Global Development, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Associate Medical Director Astellas Pharma Global Development, Inc.
PRS Account Astellas Pharma Inc
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP