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A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies

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ClinicalTrials.gov Identifier: NCT02175433
Recruitment Status : Active, not recruiting
First Posted : June 26, 2014
Last Update Posted : October 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, tolerability and pharmacokinetics of AGS67E both without and with myeloid growth factor (GF) in subjects with refractory or relapsed lymphoid malignancies. Immunogenicity and anticancer activity of AGS67E will also be assessed.

Condition or disease Intervention/treatment Phase
Relapsed Lymphoid Malignancy Refractory Lymphoid Malignancy Drug: AGS67E Phase 1

Detailed Description:

The dose escalation study will have two parts:

  1. Dose Escalation of AGS67E without myeloid growth factor (GF)
  2. Dose Escalation of AGS67E with myeloid growth factor (GF)

Subjects will be enrolled sequentially into dose cohorts starting with AGS67E without GF.

All subjects will receive a single 30 minute intravenous (IV) infusion of AGS67E once every three weeks. Subjects will continue treatment until disease progression, intolerability of AGS67E, investigator decision or consent withdrawal.

This dose escalation will first determine the maximum tolerated dose (MTD) of AGS67E without GF and then determine the MTD of AGS67E with GF. Once an MTD has been established, the study may enroll subjects into respective expansion cohorts of 12 subjects each at doses recommended by the data review team (DRT) (expansion cohort without GF and/or expansion cohort with GF).

During dose escalation, the Data Review Team will review cumulative unaudited data on an interim basis to review subject safety, recommend exploring additional doses and/or schedules, or the expansion of existing cohorts.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 78 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 Refractory or Relapsed Lymphoid Malignancies
Actual Study Start Date : October 14, 2014
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2019


Arm Intervention/treatment
Experimental: Dose Escalation of AGS67E
Dose escalation will first determine the maximum tolerated dose (MTD) of AGS67E without myeloid growth factor (GF) and then determine the MTD of AGS67 with GF
Drug: AGS67E
intravenous (IV) infusion

Experimental: Dose Expansion of AGS67E
Once the MTD has been established, an expansion cohort of up to 12 subjects may be enrolled
Drug: AGS67E
intravenous (IV) infusion




Primary Outcome Measures :
  1. Incidence and nature of adverse events [ Time Frame: up to 34 months ]
  2. Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Concentration at the end of infusion (CEOI) [ Time Frame: Escalation: Days 1-4, 8, 15, 22, 43-46, 50, 64 for Cycles 1-4 and predose once every 3 weeks in subsequent cycles. Expansion: Days 1, 3, 8, 22, 43, 45, 64 in Cycles 1-4 and predose once every 3 weeks in subsequent Cycles up to an average of 4 months ]
  3. Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Maximum observed concentration (Cmax) [ Time Frame: Escalation: Days 1-4, 8, 15, 22, 43-46, 50, 64 for Cycles 1-4 and predose once every 3 weeks in subsequent cycles. Expansion: Days 1, 3, 8, 22, 43, 45, 64 in Cycles 1-4 and predose once every 3 weeks in subsequent Cycles up to an average of 4 months ]
  4. Pharmacokinetic parameter for Monomethyl Auristatin E (MMAE): Time to maximum concentration (Tmax) [ Time Frame: Escalation: Days 1-4, 8, 15, 22, 43-46, 50, 64 for Cycles 1-4 and predose once every 3 weeks in subsequent cycles. Expansion: Days 1, 3, 8, 22, 43, 45, 64 in Cycles 1-4 and predose once every 3 weeks in subsequent Cycles up to an average of 4 months ]
  5. Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Partial area under the serum concentration-time curve after first dose and as appropriate (AUC0-21) [ Time Frame: Escalation: Days 1-4, 8, 15, 22, 43-46, 50, 64 for Cycles 1-4 and predose once every 3 weeks in subsequent cycles. Expansion: Days 1, 3, 8, 22, 43, 45, 64 in Cycles 1-4 and predose once every 3 weeks in subsequent Cycles up to an average of 4 months ]
  6. Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Terminal or apparent terminal half-life (t1/2) [ Time Frame: Escalation: Days 1-4, 8, 15, 22, 43-46, 50, 64 for Cycles 1-4 and predose once every 3 weeks in subsequent cycles. Expansion: Days 1, 3, 8, 22, 43, 45, 64 in Cycles 1-4 and predose once every 3 weeks in subsequent Cycles up to an average of 4 months ]
  7. Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Systemic clearance (CL) [ Time Frame: Escalation: Days 1-4, 8, 15, 22, 43-46, 50, 64 for Cycles 1-4 and predose once every 3 weeks in subsequent cycles. Expansion: Days 1, 3, 8, 22, 43, 45, 64 in Cycles 1-4 and predose once every 3 weeks in subsequent Cycles up to an average of 4 months ]
  8. Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Volume of distribution at steady state (Vss) [ Time Frame: Escalation: Days 1-4, 8, 15, 22, 43-46, 50, 64 for Cycles 1-4 and predose once every 3 weeks in subsequent cycles. Expansion: Days 1, 3, 8, 22, 43, 45, 64 in Cycles 1-4 and predose once every 3 weeks in subsequent Cycles up to an average of 4 months ]

Secondary Outcome Measures :
  1. Incidence of Anti-Drug Antibody (ADA) formation to the fully human monoclonal antibody (AGS67C) and antibody-drug conjugate (AGS67E) [ Time Frame: Up to 34 months ]
  2. Incidence of tumor response [ Time Frame: Up to 34 months ]
    Tumor response is defined as either a complete response (CR) or partial response (PR)

  3. Objective response rate (ORR) [ Time Frame: Up to 34 months ]
    ORR for a cohort is defined as the percentage of subjects who experience a best response of either complete response (CR) or partial response (PR) in that cohort.



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:

  • Refractory or relapsed chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HCL) or non-Hodgkin lymphoma (NHL) (including those of T cell origin)
  • Eastern Cooperative Oncology Group performance score (ECOG) ≤ 2
  • Negative pregnancy test (women of childbearing potential)
  • Hematologic function, as follows (no platelet transfusion within 2 weeks and no RBC transfusion within 4 days before the first dose of study drug)

    • Absolute neutrophil count (ANC) ≥ 1,000/μL
    • Platelets ≥ 75,000/μL
    • Hemoglobin ≥ 8 g/dL (may be transfused ≥ 5 days)
  • Renal function: serum creatinine ≤ 2.0 mg/dL and estimated creatinine clearance of ≥ 45 mL/min by the Cockcroft-Gault equation
  • Direct bilirubin ≤ 1.5 x upper limit of normal (ULN)
  • Serum albumin ≥ 2.5 g/dL
  • Aspartate aminotransferase (AST) ≤ 1.5 x ULN unless there is hepatic involvement, then 3 x ULN
  • Alanine aminotransferase (ALT) ≤ 1.5 x ULN unless there is hepatic involvement, then 3 x ULN
  • 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:

  • Preexisting sensory and/or motor neuropathy Grade ≥ 2
  • Small molecule therapy, radiotherapy, immunotherapy, monoclonal antibodies, or chemotherapy within 2 weeks before first dose of study drug
  • Radioimmunotherapy within 4 weeks before first dose of study drug
  • Use of any investigational drug (including marketed drugs not approved for this indication) within 14 days prior to the first dose of study drug
  • Any P-gp inducers/inhibitors or strong CYP3A inhibitors within 2 weeks before the first dose of study drug (See Appendix F for list of excluded drugs)
  • Anti Graft-Versus-Host Disease (GVHD) therapy within 12 weeks before the first dose of study drug
  • Platelet transfusion within 2 weeks and RBC transfusion within 4 days before the first dose of study drug
  • Known central nervous system (CNS) disease
  • History of other primary malignancy (including myeloid malignancy, e.g., myelodysplastic syndrome), unless

    • Curatively resected nonmelanomatous skin cancer
    • Other malignancy curatively treated with no known active disease present and no systemic treatment administered for 3 years before the first dose of study drug
  • Active angina or Class III or IV Congestive Heart Failure (CHF) (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 12 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 outpatient medication
  • Women who are pregnant or lactating
  • Known HIV positive or AIDS
  • Positive Hepatitis B surface antigen test
  • Decompensated liver disease as evidenced by clinically significant ascites refractory to diuretic therapy, hepatic encephalopathy, or coagulopathy
  • Known sensitivity to any of the components of the investigational product AGS67E:

    • AGS67E
    • L-Histidine
    • α-trehalose dihydrate or
    • polysorbate 20
  • History of thromboembolic events (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)) ≤ 2 weeks before the first dose of study drug and/or clinical diffuse intravascular coagulation (DIC)
  • Active infection requiring treatment ≤7 days before the first dose of study drug
  • 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
  • Any medical, psychiatric, addictive or other disorder which compromises the ability of the subject to give written informed consent and/or to comply with procedures.

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): NCT02175433


Locations
United States, California
Site US0006
Duarte, California, United States, 91010
Site US0002
Stanford, California, United States, 94305
United States, Kansas
Site US0004
Fairway, Kansas, United States, 66205
United States, New York
Site US0001
New York, New York, United States, 10019
Canada, British Columbia
Site CA0005
Vancouver, British Columbia, Canada, V5Z 4E6
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: NCT02175433     History of Changes
Other Study ID Numbers: AGS67E-14-1
First Posted: June 26, 2014    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: October 2018

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
Refractory or relapsed chronic lymphocytic leukemia (CLL) prolymphocytic leukemia (PLL)
Relapsed lymphoid malignancy
Refractory lymphoid malignancy
Pharmacokinetics of AGS67E
hairy cell leukemia (HCL)
AGS67C
non-Hodgkin lymphoma (NHL)
AGS67E

Additional relevant MeSH terms:
Neoplasms
Antibodies, Monoclonal
Immunoconjugates
Immunologic Factors
Physiological Effects of Drugs