Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This study evaluates camidanlumab tesirine in participants with relapsed/refractory Non-Hodgkin or Hodgkin lymphoma.

Detailed Description
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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).

Official Title
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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

Conditions
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Hodgkin Lymphoma, Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Camidanlumab tesirine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age 18 years or older. Refractory or relapsed lymphoma (per World Health Organization (WHO) Classification system) Pathologically confirmed relapsed or refractory lymphoma Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block. Measurable disease, defined by the 2014 Lugano Classification Criteria and Global Response Score Grading Scales for cutaneous T-cell lymphoma (CTCL) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Absolute neutrophil count ≥1500/µL. Criterion not applicable to adult T cell leukemia/lymphoma (ATLL) patients. Platelet count of ≥75000/µL. Criterion not applicable to ATLL patients. Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to Day 1. 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 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. Total serum/plasma bilirubin ≤1.5 times ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 times ULN) Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin pregnancy test within 7 days prior to Day 1. 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: Participants who have an option for any treatment with proven clinical benefit for their lymphoid malignancy at current state of disease. Active graft-versus-host disease. Autologous or allogenic transplant within the 60 days prior to Cycle 1 Day 1 (C1D1) 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 anti-drug antibody (ADA) or known allergy to any component of ADCT-301. 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]) 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). 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. 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. 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 > 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 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. 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. 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. Congenital long QT syndrome or a corrected QT interval (QTc)≥ 450 ms at screening (unless secondary to pacemaker or bundle branch block). 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (3 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 2 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 5 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (5 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 4 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 8 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (8 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 3 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 13 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (13 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 15 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 20 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (20 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 3 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 30 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (30 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 10 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 45 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (45 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 10 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 60 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (60 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 8 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 80 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (80 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 7 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 100 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (100 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 5 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 150 μg/kg<br>Participants received an intravenous (IV) infusion of camidanlumab tesirine (150 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 2 cycles. | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|
| Experimental: 300 μg/kg<br>A single participant received by error an intravenous (IV) infusion of camidanlumab tesirine (300 μg/kg) on Day 1 of Cycle 1 (planned dose was 30 μg/kg). Dosing in the subsequent cycles was 30 μg/kg (for 2 more cycles). | Drug: Camidanlumab tesirine<br>* Intravenous (IV) infusion.<br>* Other names: Cami;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | A DLT defined as any of the following, except those that are clearly due to underlying disease or extraneous causes: A hematologic DLT is defined as (different considerations for Adult T-Cell Leukemia/Lymphoma (ATLL) participants): Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 febrile neutropenia or neutropenic infection CTCAE Grade 4 neutropenia lasting >7 days CTCAE Grade 4 thrombocytopenia CTCAE Grade 3 thrombocytopenia with clinically significant bleeding, or Grade 3 thrombocytopenia requiring a platelet transfusion CTCAE Grade 4 anemia A non-hematologic DLT is defined as: CTCAE Grade 4 tumor lysis syndrome CTCAE Grade 3 or higher AE (including nausea, vomiting, diarrhea, electrolyte imbalances lasting ≥ 48 hours despite optimal therapy; excluding all grades of alopecia) CTCAE Grade 3 or higher hypersensitivity reaction CTCAE Grade 2 or higher skin ulceration CTCAE Grade 2 or higher peripheral sensory or motor neuropathy | Cycle 1 Day 1 to end of Cycle 1 or 2 (21 day cycle length) | 
| Recommended Dose of Camidanlumab Tesirine for Part 2 | The recommended dose was established by the dose escalation steering committee and based on safety findings during Part 1 of the study. | Cycle 1 Day 1 to end of Cycle 1 or 2 (21 day cycle length) | 
| Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE) | 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 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. | Day 1 up to 84 days after last dose (median time on treatment was 43 days [min 1 day; max 354 days]) | 
| Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE) | 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. | Day 1 up to 84 days after last dose (median time on treatment was 43 days [min 1 day; max 354 days]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the number of participants with a best overall response of complete response (CR) or partial response (PR) at the time each participant discontinued treatment with camidanlumab tesirine. Tumor response was assessed using the 2014 Lugano Classification. CR is defined as achieving each of the following: Complete metabolic response. Complete radiologic response (target node regress to <1.5 cm, no nonmeasured lesions, no organ enlargement, no new lesions and normal bone marrow morphology). PR is defined as achieving each of the following: Partial metabolic response (findings indicate residual disease). Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of nonmeasured lesions, spleen regressed by >50% in length and no new lesions). | 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]) | 
| Duration of Response (DoR) | DoR is defined among responders (complete response [CR] 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. Tumor response was assessed using the 2014 Lugano Classification. Disease progression is defined as progressive metabolic disease and one of the follow: Target node progression. An individual extranodal lesion must be abnormal with length > 1.5cm and/or increase of length > 50%. New or clear progression of nonmeasured lesions. Regrowth of previously resolved lesions or new nodes >1.5 cm in length. New or recurrent bone marrow involvement. DoR is presented overall for all participants who were classed as responders among the efficacy analysis set. Data is pooled for all lymphoma participants for DoR as specified in protocol section 8.4. | 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]) | 
| Progression-Free Survival (PFS) | Progression-free survival (PFS) is defined among the efficacy population as the time from first dose of study drug until either disease progression or death due to any cause. Tumor response was assessed using the 2014 Lugano Classification for response. Disease progression is defined as progressive metabolic disease and one of the following: Target node progression. An individual extranodal lesion must be abnormal with length > 1.5cm and/or increase of length > 50%. New or clear progression of nonmeasured lesions. Regrowth of previously resolved lesions or new nodes > 1.5 cm in length. New or recurrent bone marrow involvement. PFS is presented overall for all participants who received camidanlumab tesirine among the efficacy analysis set. Data is pooled for all lymphoma participants for PFS as specified in protocol section 8.4 | 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]) | 
| Overall Survival (OS) | Overall survival (OS) is defined as the time from the first dose of study drug treatment until the date of death due to any cause. OS is presented overall for all participants who received camidanlumab tesirine among the efficacy analysis set. Data is pooled for all lymphoma participants for OS as specified in protocol section 8.4. | 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]) | 
| Maximum Observed Serum Concentration (Cmax) for Camidanlumab Tesirine | Cmax for HuMax-TAC, pyrrolobenzodiazepine (PBD) conjugated HuMax-TAC, and free warhead (SG3199). | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length) | 
| Time to Reach the Maximum Serum Concentration (Tmax) for Camidanlumab Tesirine | Tmax for HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead (SG3199). | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length) | 
| Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) for Camidanlumab Tesirine | AUC0-last for HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead (SG3199). | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length) | 
| Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUC0-t) for Camidanlumab Tesirine | AUC0-tau for HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead (SG3199) for Cycle 2 only. | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycle 2 (21 day cycle length) | 
| Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for Camidanlumab Tesirine | AUC∞ HuMax-TAC and PBD-conjugated HuMax-TAC for Cycle 1 only. | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycle 1 (21 day cycle length) | 
| Accumulation Index (AI) for Camidanlumab Tesirine | AI for HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead (SG3199). AI is the ratio of area under the serum concentration-time curve (AUC) from 0 to 21 days for Cycle 2 divided by AUC from 0 to 21 days for Cycle 1 (21 day cycle length). It is the increase in drug plasma concentration after multiple dosing until a steady state is reached. | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length) | 
| Volume of Distribution for Camidanlumab Tesirine | Volume of distribution for HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead (SG3199). | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length) | 
| Apparent Terminal Half-life (T1/2) of Camidanlumab Tesirine | T1/2 of HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead (SG3199). | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length) | 
| Clearance of Camidanlumab Tesirine | Clearance of HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead (SG3199). | Pre-dose on Day 1 and 1 to 336 hours post-dose of Cycles 1 and 2 (21 day cycle length) | 
| Number of Participants With Anti-drug Antibody Response (ADA) Against Camidanlumab Tesirine | An assay determines the presence of anti-ADCT-301 antibodies in human serum using a validated bridging electro chemiluminescence immunoassay (ECLIA) technique. The technique uses the drug itself to capture any anti ADCT-301 antibodies present in the serum. If anti-ADCT-301 antibodies are detected, they are confirmed to be specifically against ADCT-301 and then the level of the anti-ADCT-301 antibodies present in the serum is established using a modified version of the ECLIA technique. | 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]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Camidanlumab tesirine