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

• ClinicalTrials.gov Identifier: NCT02175433
• Recruitment Status: Completed
• First Posted: June 26, 2014
• Last Update Posted: December 1, 2020
• Sponsor: Astellas Pharma Global Development, Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential 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
• Actual Primary Completion Date: October 29, 2019
• Actual Study Completion Date: October 29, 2019

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

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.

More Information

Additional Information:

Link to results on the Astellas Clinical Study Results website. 

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT02175433
• Other Study ID Numbers: AGS67E-14-1
• First Posted: June 26, 2014
• Last Update Posted: December 1, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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 compounds 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. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• 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.
• 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.
• URL: https://www.clinicalstudydatarequest.com/

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