Clinical trial NCT02432235: Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma
Official title: A Phase 1 Adaptive Dose-Escalation Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of ADCT-301 in Patients With Relapsed or Refractory Hodgkin Lymphoma and Non-Hodgkin Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hodgkin Lymphoma
Non-Hodgkin Lymphoma
Keywords: Camidanlumab tesirine
Lead sponsor: ADC Therapeutics S.A.
Sponsor class: INDUSTRY
First posted: 2015-05-04
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study evaluates camidanlumab tesirine in participants with relapsed/refractory Non-Hodgkin or Hodgkin lymphoma.

Detailed description: This is a Phase I, first in human clinical study with camidanlumab tesirine to evaluate the safety and tolerability and pharmacokinetics of camidanlumab tesirine in participants with relapsed/refractory lymphoma.

Camidanlumab tesirine is a human monoclonal antibody attached via a cleavable linker to a pyrrolobenzodiazepine (PBD) warhead which, when internalized by antigen expressing cells, covalently cross links deoxyribonucleic acid (DNA) preventing replication.

The study will be conducted in 2 parts: Part 1 (dose escalation) and Part 2 (expansion).

Eligibility criteria: Inclusion Criteria:

1. Male or female age 18 years or older.
2. Refractory or relapsed lymphoma (per World Health Organization (WHO) Classification system)
3. Pathologically confirmed relapsed or refractory lymphoma
4. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block.
5. Measurable disease, defined by the 2014 Lugano Classification Criteria and Global Response Score Grading Scales for cutaneous T-cell lymphoma (CTCL)
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
7. Absolute neutrophil count ≥1500/µL. Criterion not applicable to adult T cell leukemia/lymphoma (ATLL) patients.
8. Platelet count of ≥75000/µL. Criterion not applicable to ATLL patients.
9. Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to Day 1.
10. Serum/plasma creatinine ≤1.5 mg/dL, or if the participant has a creatinine \> 1.5 mg/dL, a measured creatinine clearance must be \> 80 mL/min as calculated by the Cockcroft and Gault equation
11. Serum alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase ≤2 times the upper limit of normal (ULN); ≤ 5 times ULN if there is liver or bone involvement.
12. Total serum/plasma bilirubin ≤1.5 times ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 times ULN)
13. Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin pregnancy test within 7 days prior to Day 1.
14. Women of childbearing potential must agree to use a highly effective method of contraception. Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception.

Exclusion Criteria:

1. Participants who have an option for any treatment with proven clinical benefit for their lymphoid malignancy at current state of disease.
2. Active graft-versus-host disease.
3. Autologous or allogenic transplant within the 60 days prior to Cycle 1 Day 1 (C1D1)
4. Evidence of myelodysplasia or myeloid leukemia by morphology, immunostains, flow cytometry, or cytogenetics on a bone marrow aspirate or biopsy.
5. Known history of positive serum human anti-drug antibody (ADA) or known allergy to any component of ADCT-301.
6. History of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, Sjögren's syndrome, autoimmune vasculitis \[e.g., Wegener's granulomatosis\])
7. History of neuropathy considered of autoimmune origin (e.g., polyradiculopathy including Guillain-Barré syndrome and myasthenia gravis); other central nervous system autoimmune disease (e.g., poliomyelitis, multiple sclerosis).
8. History of recent infection (within 4 weeks of C1D1) considered to be caused by one of the pathogens listed: herpes simplex virus Type 1 (HSV1), herpes simplex virus Type 2 (HSV2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), measles, Influenza A, Zika virus, Chikungunya virus, mycoplasma pneumonia, Campylobacter jejuni, or enterovirus D68.
9. Known seropositive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or antibody to hepatitis C virus (anti-HCV) with confirmatory testing and requiring anti-viral therapy. Note: testing is not mandatory to be eligible.

   If participant is at risk for having undiagnosed hepatitis C virus (HCV) (e.g., history of injection drug use), HCV testing should be considered.
10. History of Steven's Johnson's syndrome or toxic epidermal necrolysis syndrome.
11. Pregnant or breastfeeding women.
12. 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, 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.
13. 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 study treatment on Cycle 1, Day 1, except if approved by the Sponsor.
14. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy (including prednisone ≥ 40 mg/day or equivalent) within 14 days or 5 half-lives (whichever is shorter) prior to Cycle 1, Day 1 treatment, except if approved by the Sponsor.
15. Failure to recover (to Common Terminology Criteria for Adverse Events \[CTCAE Version 4.0\] Grade 0 or Grade 1) from acute non-hematologic toxicity (except all grades of alopecia or Grade 2 or lower neuropathy), due to previous therapy, prior to Screening.
16. Congenital long QT syndrome or a corrected QT interval (QTc)≥ 450 ms at screening (unless secondary to pacemaker or bundle branch block).
17. 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 that Sponsor Medical Monitor and Investigator agree, and document should not be exclusionary.
18. Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the participant inappropriate for study participation or put the participant at risk.

Primary outcomes:
measure: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
timeFrame: Cycle 1 Day 1 to end of Cycle 1 or 2 (21 day cycle length)
measure: Recommended Dose of Camidanlumab Tesirine for Part 2
timeFrame: Cycle 1 Day 1 to end of Cycle 1 or 2 (21 day cycle length)
measure: Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE)
timeFrame: Day 1 up to 84 days after last dose (median time on treatment was 43 days [min 1 day; max 354 days])
measure: Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE)
timeFrame: Day 1 up to 84 days after last dose (median time on treatment was 43 days [min 1 day; max 354 days])
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Day 1 to End of Study (a maximum of 12 months after treatment; median time on treatment was 43 days [min 1 day; max 354 days])
measure: Duration of Response (DoR)
timeFrame: Day 1 to End of Study (a maximum of 12 months after last dose; median time on treatment was 43 days [min 1 day; max 354 days])
measure: Progression-Free Survival (PFS)
timeFrame: Day 1 to End of Study (a maximum of 12 months after last dose; median time on treatment was 43 days [min 1 day; max 354 days])
measure: Overall Survival (OS)
timeFrame: Day 1 to End of Study (a maximum of 12 months after last dose; median time on treatment was 43 days [min 1 day; max 354 days])
measure: Maximum Observed Serum Concentration (Cmax) for Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length)
measure: Time to Reach the Maximum Serum Concentration (Tmax) for Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length)
measure: Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) for Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length)
measure: Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUC0-t) for Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycle 2 (21 day cycle length)
measure: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycle 1 (21 day cycle length)
measure: Accumulation Index (AI) for Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length)
measure: Volume of Distribution for Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length)
measure: Apparent Terminal Half-life (T1/2) of Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length)
measure: Clearance of Camidanlumab Tesirine
timeFrame: Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length)
measure: Number of Participants With Anti-drug Antibody Response (ADA) Against Camidanlumab Tesirine
timeFrame: Day 1 to End of Study (a maximum of 12 months after last dose; median time on treatment was 43 days [min 1 day; max 354 days])
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
state: California
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Houston
country: United States
facility: The University of Texas/MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Milwaukee
country: United States
facility: Froedtert Hospital/Medical College of Wisconsin
state: Wisconsin
city: London
country: United Kingdom
facility: Guy's and St. Thomas' Hospital NHS Trust
state: England
city: Newcastle upon Tyne
country: United Kingdom
facility: The Newcastle Upon Tyne Hospitals NHS Foundation Trust
state: England
city: Oxford
country: United Kingdom
facility: Churchill Hospital, Oxford University Hospitals NHS Foundation Trust
state: England
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: Greater Manchester
city: Southampton
country: United Kingdom
facility: Southampton General Hospital, University Hospital Southampton NHS Foundation Trust
state: Hampshire
Study officials:
affiliation: ADC Therapeutics
name: Jens Wuerthner, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Toukam M, Wuerthner J, Havenith K, Hamadani M, Caimi PF, Kopotsha T, Cruz HG, Boni JP. Population pharmacokinetics analysis of camidanlumab tesirine in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2023 Jan;91(1):13-24. doi: 10.1007/s00280-022-04486-4. Epub 2022 Nov 4.
citation: Toukam M, Boni JP, Hamadani M, Caimi PF, Cruz HG, Wuerthner J. Exposure-response analysis of Camidanlumab tesirine in patients with relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2023 Jan;91(1):1-12. doi: 10.1007/s00280-022-04487-3. Epub 2022 Nov 4.
citation: Hamadani M, Collins GP, Caimi PF, Samaniego F, Spira A, Davies A, Radford J, Menne T, Karnad A, Zain JM, Fields P, Havenith K, Cruz HG, He S, Boni J, Feingold J, Wuerthner J, Horwitz S. Camidanlumab tesirine in patients with relapsed or refractory lymphoma: a phase 1, open-label, multicentre, dose-escalation, dose-expansion study. Lancet Haematol. 2021 Jun;8(6):e433-e445. doi: 10.1016/S2352-3026(21)00103-4.