Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL)

• ClinicalTrials.gov Identifier: NCT02669264
• Recruitment Status: Terminated
• First Posted: February 1, 2016
• Results First Posted: September 26, 2019
• Last Update Posted: May 24, 2021
• Sponsor: ADC Therapeutics S.A.
• Information provided by (Responsible Party): ADC Therapeutics S.A.

Study Description

Brief Summary:

This study evaluates ADCT-402 in participants with relapsed or refractory B-cell lineage acute lymphoblastic leukemia (B-ALL). Participants will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, participants will receive the dose level identified in Part 1.

Condition or disease	Intervention/treatment	Phase
Acute Lymphoblastic Leukemia	Drug: ADCT-402	Phase 1

Detailed Description:

Study ADCT-402-102 is the first clinical study with ADCT-402 in participants with B-cell lineage acute lymphoblastic leukemia (B-ALL).

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) participants will receive an infusion of ADCT-402 either on weekly administration or every 3-week administration. participants on weekly administration will receive an infusion of ADCT-402 on Days 1, 8, and 15 of each 3 week treatment cycle. Participants on 3-week administration will receive an infusion of ADCT-402 on Day 1, every 3 weeks. Dose escalation will continue until the maximum tolerated dose (MTD) is determined.

In Part 2 (expansion), all participants will be assigned to the recommended dose and/or schedule 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Adaptive Dose-escalation, Multicenter Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Anti-tumor Activity of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL)
• Study Start Date: March 2016
• Actual Primary Completion Date: July 3, 2018
• Actual Study Completion Date: July 3, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: ADCT-402 dose escalation; Weekly administration - Participants will receive an intravenous (IV) infusion of ADCT-402, on Days 1, 8, and 15 of each 3-week (21-day) cycle. 3-week administration - Participants will receive an IV infusion of ADCT-402, on Day 1 of each 3-week (21-day) cycle. The dose escalation will be conducted according to a 3+3 design.	Drug: ADCT-402; Intravenous infusion; Other Names: Loncastuximab tesirine; Zynlonta
Experimental: Part 2: ADCT-402 expansion; All participants will be assigned to the recommended dose and/or schedule of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee	Drug: ADCT-402; Intravenous infusion; Other Names: Loncastuximab tesirine; Zynlonta

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [ Time Frame: Day 1 to End of Cycle 1 (3 weeks) ]

   A DLT is defined as any of the following events, except those that are clearly due to underlying disease or extraneous causes:

   A hematologic DLT is defined as:

   - Grade 3 or higher event of neutropenia or thrombocytopenia, or a Grade 4 anemia, with a hypocellular bone marrow lasting for 6 weeks or more after the start of a cycle, in the absence of residual leukemia (i.e., with <5% blasts). In case of a normocellular bone marrow with <5% blasts, 8 weeks with ≥Grade 3 pancytopenia will be considered a DLT.

   A non-hematologic DLT is defined as:

   • Grade 4 tumor lysis syndrome (Grade 3 TLS will not constitute DLT unless it leads to irreversible end-organ damage).
   • Grade 3 or higher AE (including nausea, vomiting, diarrhea, and electrolyte imbalances lasting more than 48 hours despite optimal therapy; excluding all grades of alopecia).
   • CTCAE Grade 3 or higher hypersensitivity reaction (regardless of premedication).
   • CTCAE Grade 3 or higher skin ulceration.
2. Recommended Dose of ADCT-402 for Part 2 [ Time Frame: Day 1 to End of Cycle 1 (3 weeks) ]
   The recommended dose was to be established by the dose escalation steering committee and based on safety findings during part 1 of the study.
3. Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE) [ Time Frame: From first dose of study drug up to 12 weeks after last dose (up to 39 weeks) ]
   An adverse event (AE) is defined as any untoward medical occurrence in a participants enrolled into this study regardless of its causal relationship to study drug. A TEAE is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug.
4. Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE) [ Time Frame: From first dose of study drug up to 12 weeks after last dose (up to 39 weeks) ]
   An adverse event (AE) is defined as any untoward medical occurrence in a participant enrolled into this study regardless of its causal relationship to study drug. A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug. An SAE is defined as any event that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug ]

   ORR is defined as the number of participants with a best overall response of complete response (CR), complete response with incomplete blood count recovery (Cri) or partial response (PR) at the time each participant discontinues treatment with ADCT-402.

   CR is defined as achieving each of the following:

   • Bone marrow differential showing ≤5% blast cells.
   • Absolute neutrophil count (ANC) ≥1.0 x 10^9/L and platelet count ≥100 x 10^9/L.
   • Absence of extramedullary disease.
   • Participant is independent of red blood cell transfusions.

   Cri is defined as achieving all CR criteria except that values for ANC may be <1.0 x 10^9/L and/or values for platelets may be <100 x 10^9/L.

   PR is defined as achieving each of the following:

   • ANC ≥1.0 x 10^9/L and platelet count ≥100 x 10^9/L.
   • Bone marrow differential showing a ≥50% decrease from baseline in the percentage of bone marrow blast cells to a level >5% and ≤25%, or bone marrow differential showing <5% blast cells.
2. Duration of Response [ Time Frame: From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug ]

   Duration of response is defined among responders (complete response [CR], complete response with incomplete blood count recovery [Cri], and partial response [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.

   Disease progression is defined as:

   • For participants with CR or CRi, the first date of reappearance of blast cells in bone marrow and/or peripheral blood to a level ≥5%, or development of extramedullary disease.
   • For participants with PR, the first date of an increase in blast cells in bone marrow and/or peripheral blood such that the patient does not continue to meet the criteria for PR.
3. Overall Survival [ Time Frame: From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug ]
   Overall survival is defined as the time from the first dose of study drug treatment until the date of death due to any cause.
4. Progression-free Survival [ Time Frame: From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug ]
   Progression-free survival is 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.
5. Maximum Observed Serum Concentration (Cmax) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
   Cmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
6. Maximum Observed Serum Concentration (Cmax) for ADCT-402 Administered Every Week (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
   Cmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
7. Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
   Tmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
8. Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402 Administered Every Week (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
   Tmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
9. Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
   AUClast for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
10. Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-402 Administered Every Week (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    AUClast for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
11. Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    AUC∞ for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
12. Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for ADCT-402 Administered Weekly (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    AUC∞ for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
13. Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUC0-tau) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    AUCtau for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
14. Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUC0-tau) for ADCT-402 Administered Every Week (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    AUCtau for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
15. Accumulation Index (AI) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    AI for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. AI is the ratio of AUC 0-24 after multiple doses versus a single dose. It is the increase in drug plasma concentration after multiple dosing until a steady state is reached.
16. Accumulation Index (AI) for ADCT-402 Administered Weekly (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    AI for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. AI is the ratio of AUC 0-24 after multiple doses versus a single dose. It is the increase in drug plasma concentration after multiple dosing until a steady state is reached.
17. Volume of Distribution at Steady State for ADCT-402 [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
18. Mean Residence Time for ADCT-402 [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
19. Terminal Elimination Phase Rate Constant for ADCT-402 [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
20. Apparent Terminal Phase Elimination Half-life (T1/2) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    T1/2 for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
21. Apparent Terminal Phase Elimination Half-life (T1/2) for ADCT-402 Administered Every Week (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    T1/2 for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
22. Apparent Clearance at Steady State for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    Apparent clearance for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
23. Apparent Clearance at Steady State for ADCT-402 Administered Every Week (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    Apparent clearance for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
24. Apparent Volume of Distribution (Vd Beta) for ADCT-402 Administered Every 3 Weeks (Q3W) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    Vd beta for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts.
25. Apparent Volume of Distribution (Vd Beta) for ADCT-402 Administered Every Week (QW) [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    Vd beta for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort.
26. Number of Participants With Anti-drug Antibody Response (ADA) Against ADCT-402 [ Time Frame: Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2 ]
    Blood serum samples were collected and analysed to determine the presence or absence of ADA.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female patients, ages 12 years and older, with relapsed or refractory B-ALL who have failed, or are intolerant to, any established therapy; or for whom no other treatment options are available.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Serum/plasma creatinine ≤1.5mg/dL.
• Serum/plasma 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/plasma bilirubin ≤1.5 times ULN.
• White Blood Cell Count value of <15,000 cells/μL prior to Cycle 1 Day 1.
• Negative urine or serum beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to the Cycle 1, Day 1 visit, 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 an option for other treatment for B-ALL at the current state of disease.
• Known active central nervous system (CNS) leukemia.
• Patients with Burkitt's leukemia/lymphoma.
• Active graft-versus-host disease.
• Autologous or allogenic transplant within the 60 days prior to Screening.
• Known history of immunogenicity or hypersensitivity to a CD19 antibody.
• Known history of positive serum human ADA.
• Active autoimmune disease, motor neuropathy considered of autoimmune origin, or other central nervous system autoimmune disease.
• Known seropositive for human immunodeficiency (HIV) virus, hepatitis B surface antigen (HbsAg), or antibody to hepatitis C virus (anti-HCV).
• History of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome.
• Pregnant or breastfeeding women.
• Significant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure >115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, myocardial infarction within 6 months prior to Screening, or uncontrolled atrial or ventricular cardiac arrhythmias.
• Use of any other experimental medication(s) within 14 days or 5 half-lives, but in no case <14 days prior to the start of treatment on Cycle 1, Day 1, except if approved by the Sponsor.
• Major surgery, chemotherapy, systemic therapy (excluding hydroxyurea,steroids and any targeted small molecules or biologics), or radiotherapy, within 14 days or 5 half-lives (whichever is shorter) prior to the Cycle 1, Day 1 treatment, except if approved by the Sponsor.
• Failure to recover from acute non hematologic toxicity (except alopecia or Grade 2 or lower neuropathy), due to previous therapy, prior to Screening.
• Isolated extramedullary relapse.
• Congenital long QT syndrome or a corrected QTc interval of ≥450 ms at the Screening visit.
• Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic 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

Locations

United States, California

UC San Diego Moores Cancer Center

La Jolla, California, United States, 92093

United States, Connecticut

Smilow Cancer Hospital at Yale-New Haven

New Haven, Connecticut, United States, 06510

United States, Georgia

Emory University Hospital

Atlanta, Georgia, United States, 30322

United States, Illinois

The University of Chicago Medical Center

Chicago, Illinois, United States, 60637

United States, New Jersey

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

United States, Ohio

University Hospital of Cleveland

Cleveland, Ohio, United States, 44106

The Ohio State University Wexner Medical Center, James Cancer Hospital

Columbus, Ohio, United States, 43210

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Wisconsin

Froedtert Hospital & the Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

ADC Therapeutics S.A.

  Study Documents (Full-Text)

Documents provided by ADC Therapeutics S.A.:

Study Protocol  [PDF] April 19, 2017

Statistical Analysis Plan  [PDF] April 19, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jain N, Stock W, Zeidan A, Atallah E, McCloskey J, Heffner L, Tomlinson B, Bhatnagar B, Feingold J, Ungar D, Chao G, Zhang X, Qin Y, Havenith K, Kantarjian H, Wieduwilt MJ. Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia. Blood Adv. 2020 Feb 11;4(3):449-457. doi: 10.1182/bloodadvances.2019000767.

• Responsible Party: ADC Therapeutics S.A.
• ClinicalTrials.gov Identifier: NCT02669264
• Other Study ID Numbers: ADCT-402-102
• First Posted: February 1, 2016
• Results First Posted: September 26, 2019
• Last Update Posted: May 24, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by ADC Therapeutics S.A.:

Loncastuximab tesirine

Additional relevant MeSH terms:

Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Loncastuximab tesirine; Antineoplastic Agents, Immunological; Antineoplastic Agents