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Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2017 by ADC Therapeutics SARL
Sponsor:
Information provided by (Responsible Party):
ADC Therapeutics SARL
ClinicalTrials.gov Identifier:
NCT02669017
First received: January 21, 2016
Last updated: February 10, 2017
Last verified: February 2017
  Purpose
This study evaluates ADCT-402 in patients with Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL). Patients will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, patients will receive the dose level identified in Part 1.

Condition Intervention Phase
Non-Hodgkin Lymphoma
Burkitt's Lymphoma
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Follicular
Lymphoma, Mantle-Cell
Lymphoma, Marginal Zone
Waldenstrom Macroglobulinemia
Drug: ADCT-402
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 1 Adaptive Dose-escalation Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)

Resource links provided by NLM:


Further study details as provided by ADC Therapeutics SARL:

Primary Outcome Measures:
  • Assessment of Dose Limiting Toxicities (DLT) and Determination of the Maximum Tolerated Dose (MTD) of ADCT-402. [ Time Frame: 21 Day Cycle ]

Secondary Outcome Measures:
  • Evaluate the clinical activity of ADCT-402 as measured by overall response rate (ORR) [ Time Frame: Disease assessments will be conducted within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third cycle (ie, Cycles 8, 11, 14, etc.), until disease progression, and for up to 12 months after the last dose of study drug. ]
    Overall response rate will be defined as the proportion of patients with a best overall response of CR or PR at the time each patient discontinues ADCT-402.

  • Evaluate the clinical activity of ADCT-402 as measured by duration of response (DOR) [ Time Frame: Disease assessments will be conducted within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third cycle (ie, Cycles 8, 11, 14, etc.), until disease progression, and for up to 12 months after the last dose of study drug. ]
    Duration of response will be defined among responders (CR or PR) as the time from the earliest date of first response until the first date of either disease progression or death due to any cause.

  • Evaluate the clinical activity of ADCT-402 as measured by progression-free survival (PFS) [ Time Frame: Disease assessments will be conducted within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third cycle (ie, Cycles 8, 11, 14, etc.), until disease progression, and for up to 12 months after the last dose of study drug. ]
    Progression-free survival will be defined among the efficacy population as the time from first dose of study drug until the first date of either disease progression or death due to any cause.

  • Evaluate the clinical activity of ADCT-402 as measured by overall survival (OS). [ Time Frame: Disease assessments will be conducted within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third cycle (ie, Cycles 8, 11, 14, etc.), until disease progression, and for up to 12 months after the last dose of study drug. ]
    Overall survival will be defined as the time from the beginning of study drug treatment until death due to any cause.

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of Cmax [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of Cmax

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of Tmax [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of Tmax

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of AUC0 last [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0 last)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of AUC0-∞ [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of area under the concentration-time curve from time zero to infinity (AUC0-∞)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of AI [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of accumulation index (AI)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of Vss [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of volume of distribution at a steady-state (Vss)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of MRT [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of mean residence time (MRT)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of λz [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of terminal elimination phase rate constant (λz)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of T1/2 [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of terminal half-life (T1/2)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of CL [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of clearance (CL)

  • Pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199. Analysis of Vz [ Time Frame: Blood sample collection on Day 1, 2, 3, 5, 8, and 15 of 21 day cycles 1 and 2. Blood sample collection on Day 1 of each cycle starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Noncompartmental analysis of volume of distribution (Vz)

  • Evaluate anti-drug antibodies (ADAs) in blood before, during, and after treatment with ADCT 402 [ Time Frame: Blood sample collection before start of infusion in Cycles 1 and 2, and on Day 1 starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose ]
    Level of ADAs against ADCT-402 in serum.


Estimated Enrollment: 60
Study Start Date: March 2016
Estimated Study Completion Date: February 2019
Estimated Primary Completion Date: February 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ADCT-402

In Part 1 (dose escalation) patients will receive an IV infusion of ADCT-402, at escalating doses. Part 1 will continue until the maximum tolerated dose is determined.

In Part 2 (expansion), all patients will be assigned to the recommended dose level of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee.

Drug: ADCT-402
intravenous infusion

Detailed Description:

Study ADCT-402-101 is the first clinical study with ADCT-402 in patients with B-cell non-Hodgkin Lymphoma (NHL).

ADCT-402 is an antibody drug conjugate (ADC) composed of a humanized antibody directed against human cluster of differentiation 19 (CD19), stochastically conjugated via a valine-alanine cleavable, maleimide linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.

The study will be conducted in 2 parts. In Part 1 (dose escalation) patients will receive an infusion of ADCT-402, at escalating doses. Part 1 will continue until the maximum tolerated dose is determined. In Part 2 (expansion), all patients will be assigned to the recommended dose level of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee.

For each patient, the study will include a screening period (up to 28 days), a treatment period (until withdrawal), and a follow-up period to assess disease progression and survival for up to 12 months after the last dose of study drug. The total study duration will be dependent on overall patient tolerability to the study drug and response to treatment. It is anticipated that the duration of the entire study (Parts 1 and 2) could be approximately 3 years from first patient treated to last patient completed.

  Eligibility

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

Inclusion Criteria:

  • Male or female patients, ages 18 years or older with pathologically confirmed relapsed or refractory B-cell lineage NHL who have failed or are intolerant to established therapy, or for whom no other treatment options are available. Refractory or relapsed B-cell NHL (per World health Organization [WHO] Classification system)
  • Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block.
  • Measurable disease, as defined by the 2014 Lugano Classification.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
  • Absolute neutrophil count (ANC) ≥1000/μL.
  • Platelet count of ≥75000/μL.
  • Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to Day 1.
  • Serum creatinine ≤1.5 mg/dL.
  • Serum alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2 times the upper limit of normal (ULN); ≤ 5 times ULN if there is liver or bone involvement.
  • Total serum bilirubin ≤1.5 times ULN.
  • Negative serum or urine beta-human chorionic gonadotropin (β- HCG) pregnancy test within 7 days prior to Day 1 for women of childbearing potential.
  • Males, and female patients who are biologically capable of having children, must agree to use a medically acceptable method of birth control.

Exclusion Criteria:

  • Patients who have any option for other treatment for B-cell NHL at the current state of disease.
  • Active graft-versus-host disease.
  • Autologous or allogenic transplant within the 60 days prior to the Screening visit.
  • Known history of immunogenicity or hypersensitivity to a CD19 antibody.
  • Evidence of myelodysplasia or myeloid leukemia by morphology, immunostains, flow cytometry, or cytogenetics on a bone marrow aspirate or biopsy.
  • Known history of positive serum human ADA.
  • Active autoimmune disease, motor neuropathy considered of autoimmune origin, and other central nervous system (CNS) autoimmune disease.
  • Known seropositive for human immunodeficiency (HIV) virus, hepatitis B surface antigen (HbsAg), or antibody to hepatitis C virus (anti-HCV).
  • History of Steven's Johnson's syndrome or toxic epidermal necrolysis syndrome.
  • Pregnant or breastfeeding women.
  • Significant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure greater than 115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, or myocardial infarction within 6 months prior to screening, or uncontrolled atrial or ventricular cardiac arrhythmias.
  • Use of any other experimental medication(s) within 21 days prior to start of study treatment on Day 1.
  • Steroid use equivalent to greater than 20 mg of prednisone within 4 weeks (28 days) prior to Day 1.
  • Major surgery, chemotherapy, systemic therapy (excluding steroids), radiotherapy, or biotherapy targeted therapies within 21 days prior to Cycle 1, Day 1 treatment.
  • Failure to recover from acute non hematologic toxicity (except alopecia), due to previous therapy, prior to Screening.
  • Congenital long QT syndrome or a corrected QTc interval ≥450 ms at the Screening visit.
  • Active second primary malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy determined not be exclusionary.
  • Any other significant medical illness, abnormality, or condition that would make the patient inappropriate for study participation or put the patient at risk.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02669017

Contacts
Contact: Jay Feingold Jay.Feingold@adctherapeutics.com
Contact: Maria Cincotta Maria.Cincotta@adctherapeutics.com

Locations
United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Principal Investigator: Erin Reid, MD         
United States, Georgia
Winship Cancer Institute of Emory University Recruiting
Atlanta, Georgia, United States, 30322
Principal Investigator: Leonard Heffner Jr., MD         
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Principal Investigator: Brad Kahl, MD         
United States, New York
Columbia University Medical Center Herbert Irving Pavilion Recruiting
New York, New York, United States, 10032
Principal Investigator: Owen O'Connor, M.D., PhD.         
United States, Ohio
University Hospitals of Cleveland Recruiting
Cleveland, Ohio, United States, 44106
Principal Investigator: Paolo Caimi, MD         
United States, South Carolina
Greenville Health System, Institute for Translational Oncology Research, Clinical Research Unit Recruiting
Greenville, South Carolina, United States, 29605
Principal Investigator: Ki Y Chung, MD         
United States, Wisconsin
Froedtert Hospital & the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Principal Investigator: Mehdi Hamadani, MD         
Sponsors and Collaborators
ADC Therapeutics SARL
  More Information

Responsible Party: ADC Therapeutics SARL
ClinicalTrials.gov Identifier: NCT02669017     History of Changes
Other Study ID Numbers: ADCT-402-101
Study First Received: January 21, 2016
Last Updated: February 10, 2017

Additional relevant MeSH terms:
Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Waldenstrom Macroglobulinemia
Burkitt Lymphoma
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Follicular
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Leukemia
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections

ClinicalTrials.gov processed this record on March 22, 2017