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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 : Suspended (Business decision by sponsor)
First Posted : November 20, 2015
Last Update Posted : March 15, 2018
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: AGS67E Phase 1

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 4, 2016
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : September 2018


Arm Intervention/treatment
Experimental: Dose Escalation of AGS67E Schedule 1
Participants will receive AGS67E as an intravenous infusion once every three weeks (Q3) to determine a safe dose for future development.
Drug: AGS67E
Intravenous (IV) infusion

Experimental: Dose Escalation of AGS67E Schedule 2
Participants will receive AGS67E as an intravenous infusion once weekly for three weeks to determine a safe dose for future development.
Drug: AGS67E
Intravenous (IV) infusion

Experimental: Dose Expansion of AGS67E Schedule 1
Participants will receive AGS67E dose level deemed safe in the dose escalation part of the study once every three weeks (Q3).
Drug: AGS67E
Intravenous (IV) infusion

Experimental: Dose Expansion of AGS67E Schedule 2
Participants will receive AGS67E dose level deemed safe in the dose escalation part of the study once weekly for three weeks.
Drug: AGS67E
Intravenous (IV) infusion




Primary Outcome Measures :
  1. Incidence and nature of adverse events [ Time Frame: Up to 24 months ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. 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 ]
  16. Complete remission (CR) rate [ Time Frame: Up to 24 months ]
  17. Composite CR (CRc) rate [ Time Frame: Up to 24 months ]
  18. 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)

  19. 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)

  20. Duration of response [ Time Frame: Up to 24 months ]
    Duration of response is CRc, PR and MLFS



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02610062


Locations
United States, California
Site US0006
Duarte, California, United States, 91010
United States, New York
Site US0004
New York, New York, United States, 10016
United States, Texas
Site US0001
Houston, Texas, United States, 77030
Canada, Ontario
Site CA0010
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
Study Director: Associate Medical Director Astellas Pharma Global Development, Inc.

Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT02610062     History of Changes
Other Study ID Numbers: AGS67E-15-2
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: March 15, 2018
Last Verified: March 2018

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
AML
Acute Myeloid Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Antibodies, Monoclonal
Immunoconjugates
Immunologic Factors
Physiological Effects of Drugs