Clinical trial NCT02669264: Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL)
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Lymphoblastic Leukemia
Keywords: Loncastuximab tesirine
Lead sponsor: ADC Therapeutics S.A.
Sponsor class: INDUSTRY
First posted: 2016-02-01
Enrollment: 35
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
timeFrame: Day 1 to End of Cycle 1 (3 weeks)
measure: Recommended Dose of ADCT-402 for Part 2
timeFrame: Day 1 to End of Cycle 1 (3 weeks)
measure: Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE)
timeFrame: From first dose of study drug up to 12 weeks after last dose (up to 39 weeks)
measure: Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE)
timeFrame: From first dose of study drug up to 12 weeks after last dose (up to 39 weeks)
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 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
measure: Duration of Response
timeFrame: 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
measure: Overall Survival
timeFrame: 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
measure: Progression-free Survival
timeFrame: 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
measure: Maximum Observed Serum Concentration (Cmax) for ADCT-402 Administered Every 3 Weeks (Q3W)
timeFrame: 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
measure: Maximum Observed Serum Concentration (Cmax) for ADCT-402 Administered Every Week (QW)
timeFrame: 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
measure: Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402 Administered Every 3 Weeks (Q3W)
timeFrame: 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
measure: Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402 Administered Every Week (QW)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for ADCT-402 Administered Every 3 Weeks (Q3W)
timeFrame: 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
measure: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for ADCT-402 Administered Weekly (QW)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Accumulation Index (AI) for ADCT-402 Administered Every 3 Weeks (Q3W)
timeFrame: 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
measure: Accumulation Index (AI) for ADCT-402 Administered Weekly (QW)
timeFrame: 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
measure: Volume of Distribution at Steady State for ADCT-402
timeFrame: 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
measure: Mean Residence Time for ADCT-402
timeFrame: 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
measure: Terminal Elimination Phase Rate Constant for ADCT-402
timeFrame: 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
measure: Apparent Terminal Phase Elimination Half-life (T1/2) for ADCT-402 Administered Every 3 Weeks (Q3W)
timeFrame: 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
measure: Apparent Terminal Phase Elimination Half-life (T1/2) for ADCT-402 Administered Every Week (QW)
timeFrame: 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
measure: Apparent Clearance at Steady State for ADCT-402 Administered Every 3 Weeks (Q3W)
timeFrame: 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
measure: Apparent Clearance at Steady State for ADCT-402 Administered Every Week (QW)
timeFrame: 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
measure: Apparent Volume of Distribution (Vd Beta) for ADCT-402 Administered Every 3 Weeks (Q3W)
timeFrame: 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
measure: Apparent Volume of Distribution (Vd Beta) for ADCT-402 Administered Every Week (QW)
timeFrame: 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
measure: Number of Participants With Anti-drug Antibody Response (ADA) Against ADCT-402
timeFrame: 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
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale-New Haven
state: Connecticut
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Cleveland
country: United States
facility: University Hospital of Cleveland
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center, James Cancer Hospital
state: Ohio
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert Hospital & the Medical College of Wisconsin
state: Wisconsin
Study officials:
References:
citation: 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.