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

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

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.

Study Overview

• Status: Completed
• Conditions: Relapsed Lymphoid Malignancy; Refractory Lymphoid Malignancy
• Intervention / Treatment: Drug: AGS67E

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
• Enrollment (Actual): 71
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Site CA0005
• United States
  • California
    • Duarte, California, United States, 91010
      • Site US0006
    • Stanford, California, United States, 94305
      • Site US0002
  • Kansas
    • Fairway, Kansas, United States, 66205
      • Site US0004
  • New York
    • New York, New York, United States, 10019
      • Site US0001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation of AGS67E 0.05 mg/kg Without GF; Participants will receive 0.05 milligram per kilogram (mg/kg) AGS67E without growth factor (GF) by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 0.1 mg/kg Without GF; Participants will receive 0.1 mg/kg AGS67E without GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 0.3 mg/kg Without GF; Participants will receive 0.3 mg/kg AGS67E without GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 0.6 mg/kg Without GF; Participants will receive 0.6 mg/kg AGS67E without GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 0.9 mg/kg Without GF; Participants will receive 0.9 mg/kg AGS67E without GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 1.2 mg/kg Without GF; Participants will receive 1.2 mg/kg AGS67E without GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Expansion of AGS67E 0.9 mg/kg Without GF; Participants will receive 0.9 mg/kg AGS67E without GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 1.2 mg/kg With GF; Participants will receive 1.2 mg/kg AGS67E with GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 1.5 mg/kg With GF; Participants will receive 1.5 mg/kg AGS67E with GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Escalation of AGS67E 1.8 mg/kg With GF; Participants will receive 1.8 mg/kg AGS67E with GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion
Experimental: Dose Expansion of AGS67E 1.5 mg/kg With GF; Participants will receive 1.5 mg/kg AGS67E with GF by intravenous infusion once every three weeks.	Drug: AGS67E; intravenous (IV) infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence and nature of adverse events	up to 34 months
Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Concentration at the end of infusion (CEOI)	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
Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Maximum observed concentration (Cmax)	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
Pharmacokinetic parameter for Monomethyl Auristatin E (MMAE): Time to maximum concentration (Tmax)	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
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)	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
Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Terminal or apparent terminal half-life (t1/2)	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
Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Systemic clearance (CL)	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
Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Volume of distribution at steady state (Vss)	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

Outcome Measure	Measure Description	Time Frame
Incidence of Anti-Drug Antibody (ADA) formation to the fully human monoclonal antibody (AGS67C) and antibody-drug conjugate (AGS67E)		Up to 34 months
Incidence of tumor response	Tumor response is defined as either a complete response (CR) or partial response (PR)	Up to 34 months
Objective response rate (ORR)	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.	Up to 34 months

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Investigators: Study Director: Associate Medical Director, Astellas Pharma Global Development, Inc.

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website.

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2014
• Primary Completion (Actual): October 29, 2019
• Study Completion (Actual): October 29, 2019

Study Registration Dates

• First Submitted: June 24, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimated): June 26, 2014

Study Record Updates

• Last Update Posted (Actual): November 1, 2024
• Last Update Submitted That Met QC Criteria: October 30, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: non-Hodgkin lymphoma (NHL); Refractory or relapsed chronic lymphocytic leukemia (CLL) prolymphocytic leukemia (PLL); Relapsed lymphoid malignancy; Refractory lymphoid malignancy; Pharmacokinetics of AGS67E; hairy cell leukemia (HCL); AGS67C; AGS67E
• Additional Relevant MeSH Terms: Neoplasms; Immunologic Factors; Physiological Effects of Drugs; Immunoconjugates; AGS67E
• Other Study ID Numbers: AGS67E-14-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR