Study to Evaluate the Efficacy and Safety of Camidanlumab Tesirine (ADCT-301) in Patients With Relapsed or Refractory Hodgkin Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the clinical efficacy and safety of Camidanlumab Tesirine (ADCT-301) in participants with relapsed or refractory Hodgkin Lymphoma (HL).

Detailed Description
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This is a phase 2, multi-center, open-label, single-arm study of efficacy and safety of Camidanlumab Tesirine (ADCT-301) in participants with relapsed or refractory Hodgkin lymphoma. This study will enroll approximately 100 participants. Camidanlumab Tesirine (ADCT-301) is an antibody drug conjugate (ADC), composed of the human monoclonal antibody, HuMax®-TAC, which is directed against human CD25. The antibody is conjugated through a protease cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. For each participant the study will include a screening period (of up to 28 days), a treatment period (cycles of 3 weeks), and a follow-up period (approximately every 12-week visits) for up to 3 years after treatment discontinuation. Participants may continue treatment for up to 1 year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first. Additionally, patients benefiting clinically at 1 year may continue treatment after a case by case review with the Sponsor.

Official Title
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A Phase 2, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Camidanlumab Tesirine (ADCT-301) in Patients With Relapsed or Refractory Hodgkin Lymphoma

Conditions
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Relapsed Hodgkin Lymphoma, Refractory 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: Written informed consent must be obtained prior to any procedures. Male or female participant aged 18 years or older. (16 years or older at US based sites) Pathologic diagnosis of classical Hodgkin lymphoma (cHL). Patients with relapsed or refractory cHL, who have received at least 3 prior lines of systemic therapy (or at least 2 prior lines in HSCT ineligible patients) including brentuximab vedotin and a checkpoint inhibitor approved for cHL (e.g., nivolumab or pembrolizumab). Note 1: Receipt of HSCT to be included in the number of prior therapies needed to meet eligibility. Measurable disease as defined by the 2014 Lugano Classification. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum 10 freshly cut unstained slides if block is not available). Note 1: Any biopsy since initial diagnosis is acceptable, but if several samples are available, the most recent sample is preferred. Note 2: If a sufficient amount of tissue is not available, a fresh biopsy may be taken, provided the procedure is not deemed high-risk and is clinically feasible, and provided it is approved locally. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Adequate organ function as defined by Screening laboratory values within the following parameters: Absolute neutrophil count (ANC) ≥ 1.0 × 103/μL (off growth factors at least 72 h). Platelet count ≥ 75 × 103/μL without transfusion in the past 2 weeks. ALT, AST, or GGT ≤ 2.5 × the upper limit of normal (ULN) if there is no liver involvement; ALT or AST ≤ 5 × ULN if there is liver involvement. Total bilirubin ≤ 1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤ 3 × ULN with direct bilirubin ≤ 1.5 × ULN). Blood creatinine ≤ 3.0 × ULN or calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault equation. Note: A laboratory assessment may be repeated a maximum of two times during the Screening Period to confirm eligibility. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drug for women of childbearing potential. Women of childbearing potential (WOCBP) must agree to use a highly effective method of contraception from the time of giving informed consent until at least 9.5 months after the last dose of Camidanlumab Tesirine. Men with female partners who are of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 6.5 months after the participants receives his last dose of Camidanlumab Tesirine. Exclusion Criteria: Previous treatment with Camidanlumab Tesirine. Participation in another investigational interventional study. Being in follow-up of another investigational study is allowed. Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) to a CD25 antibody. Allogenic or autologous transplant within 60 days prior to start of study drug. Active graft-versus-host disease (GVHD), except for non-neurologic symptoms as a manifestation of mild (≤ Grade 1) chronic GVHD. Post-transplantation lymphoproliferative disorders. 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 that the Sponsor's medical monitor and Investigator agree and document should not be exclusionary. 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]) (subjects with vitiligo, type 1 diabetes mellitus, residual hypothyroidism, hypophysitis due to autoimmune condition only requiring hormone replacement may be enrolled). History of neuropathy considered of autoimmune origin (e.g., polyradiculopathy including Guillain-Barré syndrome and myasthenia gravis) or other central nervous system autoimmune disease (e.g., poliomyelitis, multiple sclerosis). History of recent infection (within 4 weeks of Cycle 1, Day 1 [C1D1]) considered to be caused by one of the following pathogens: HSV1, HSV2, VZV, EBV, CMV, measles, Influenza A, Zika virus, Chikungunya virus, mycoplasma pneumonia, Campylobacter jejuni, or enterovirus D68, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Note: An influenza test and a pathogendirected SARS CoV-2 test (such as polymerase chain reaction) are mandatory and must be negative before initiating study treatment (tests to be performed 3 days or less prior to dosing on C1D1; an additional 2 days are allowed in the event of logistical issues for receiving the results on time). Participants known to be or having been infected with human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV), and require anti-viral therapy or prophylaxis. Note: Serology testing is mandatory for patients with unknown status. History of Stevens-Johnson syndrome or toxic epidermal necrolysis. Failure to recover ≤ Grade 1 (Common Terminology Criteria for Adverse Events version 4.0 [CTCAE v4.0]) from acute non-hematologic toxicity (except ≤ Grade 2 neuropathy or alopecia), due to previous therapy, prior to screening. Hodgkin lymphoma (HL) with central nervous system involvement, including leptomeningeal disease. Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath). Breastfeeding or pregnant. Significant medical comorbidities, including uncontrolled hypertension (blood pressure [BP] ≥ 160/100 mmHg repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 3 months prior to screening, severe uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes, or severe chronic pulmonary disease. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy, within 14 days prior to start of study drug, except shorter if approved by the Sponsor. Use of any other experimental medication within 30 days prior to start of study drug. Any live vaccine within 4 weeks prior to start of study drug and planned live vaccine administration after starting study drug. Congenital long QT (measure between Q wave and T wave in the electrocardiogram) syndrome, or a corrected QTc interval of ≥ 480 ms, at screening (unless secondary to pacemaker or bundle branch block). Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the participants inappropriate for study participation or put the participant at risk.

Ages Eligible for Study
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Minimum Age: 16 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Camidanlumab Tesirine<br>Camidanlumab Tesirine is administered as a 30- minute intravenous (IV) infusion on Day 1 of each cycle (every 3 weeks). Camidanlumab Tesirine will be administered at a dose of 45 μg/kg every 3 weeks for 2 cycles, then 30 μg/kg for subsequent cycles. | Drug: Camidanlumab Tesirine<br>* Intravenous Infusion<br>* Other names: ADCT-301;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR according to the 2014 Lugano classification as determined by central review in all-treated participants.ORR will be defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR defined as the time from the first documentation of tumor response to disease progression or death. | Up to 3 years | 
| Complete Response (CR) Rate | CR rate defined as the percentage of treated participants with a best overall response (BOR) of CR. | Up to 3 years | 
| Relapse-Free Survival (RFS) | Relapse-free survival (RFS) defined as the time from the documentation of CR to disease progression or death due to any case. | Up to 3 years | 
| Progression-Free Survival (PFS) | PFS defined as the time from first dose of study drug until the first date of either disease progression or death due to any cause. | Up to 3 years | 
| Overall Survival (OS) | OS defined as the time from first dose of study drug until death due to any cause. | Up to 3 years | 
| Fraction of Participants Who Receive Hematopoietic Stem Cell Transplant (HSCT) |  | Up to 3 years | 
| Number of Participants Who Experience At Least One Treatment-Emergent Adverse Event (TEAE) | An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation where participants are administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an AE that occurs or worsens in the period extending from the first dose of study drug to 30 days after the last dose of study drug in this study or start of a new anticancer therapy/procedure, whichever comes earlier. | Day 1 (post-dose) until 30 days after last dose of study drug | 
| Number of Participants Who Experience At Least One Serious Adverse Event (SAE) | An SAE is defined as any adverse event (AE) that: results in death. is life threatening. requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance is not considered an SAE). results in persistent or significant disability/incapacity. is a congenital anomaly/birth defect. important medical events that do not meet the preceding criteria but based on appropriate medical judgement may jeopardize the participant or may require medical or surgical intervention to prevent any of the outcomes listed above. | Day 1 (post-dose) until 30 days after last dose of study drug | 
| Number of Participants Who Experience a Clinically Significant Change From Baseline in Clinical Laboratory Results | Parameters measured will include clinical hematology, coagulation panel, biochemistry, and urinalysis. | Day 1 to end of treatment (maximum 30 days after last dose of study drug) | 
| Number of Participants Who Experience a Clinically Significant Change From Baseline in Vital Sign Measurements | Vital signs include the measurements of arterial blood pressure (systolic and diastolic), heart rate (HR), respiratory rate, and body temperature. | Day 1 to end of treatment (maximum 30 days after last dose of study drug) | 
| Number of Participants Who Experience a Clinically Significant Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status | The ECOG Performance Status is a scale used to asses a person's level of functioning in terms of their ability to care for themselves, daily activity, and physical ability. The scale consists of 6 grades, ranging from 0 to 5. A grade of 0 indicates the person is fully active and able to carry on as normal, and a grade of 5 indicates death. | Day 1 to end of treatment (maximum 30 days after last dose of study drug) | 
| Number of Participants Who Experience a Clinically Significant Change From Baseline in Electrocardiogram (ECGs) Results |  | Day 1 to end of treatment (maximum 30 days after last dose of study drug) | 
| Maximum Observed Plasma Concentration (Cmax) of Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) For Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Area Under the Plasma Concentration-Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) For Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUCinf) For Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Apparent Terminal Elimination Half-Life (T1/2) For Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Clearance (CL) For Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Volume of Distribution (Vd) For Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Accumulation Index (AI) For Camidanlumab Tesirine Total Antibody, PBD-Conjugated Antibody, and Unconjugated Warhead SG3199 |  | Cycle 1 and 2: Day 1 (pre-dose, EOI and post-dose), Day 8 and Day 15. Cycles 3 to 6: Day 1 (pre-dose and EOI). For remaining cycles: Day 1 (pre-dose) of each cycle until EOT, maximum of 30 days after the last dose of study drug. Each cycle is 21 days. | 
| Number of Participants With Confirmed Positive Anti-Drug Antibody (ADA) Responses | Measurement of Anti-drug antibodies to ADCT-301 before, during and after treatment with Camidanlumab Tesirine | Day 1 until end of treatment, a maximum of 30 days after last dose of study drug | 
| Number of Participants With At Least One ADA Titer |  | Day 1 until end of treatment, a maximum of 30 days after last dose of study drug | 
| Number of Participants With Neutralizing Antibodies To Camidanlumab Tesirine Following Treatment With Camidanlumab Tesirine |  | Day 1 until end of treatment, a maximum of 30 days after last dose of study drug | 
| Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) | The EQ-5D-5L is a tool for evaluating quality of life (QoL). The instrument consists of 2 parts: the descriptive system and the visual analog scale (VAS). The 1st part comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The participant evaluates each dimension by ticking the box next to the most appropriate level (1-5). This decision results in a 1-digit number that represents the level selected for that dimension. A high level indicates a negative rating. These digits are combined into a 5-digit number that describes the participant's health state. The 2nd part involves the participant indicating their health state on that day on a VAS (by placing an 'X'), where the endpoints are labelled 'the best health you can imagine' (100) and 'the worst health you can imagine' (0). A low score indicates a negative result. | Day 1 of each 21 day cycle until end of treatment, a maximum of up to 30 days after last dose of study drug. Each cycle is 21 days. | 
| Change from Baseline in HRQoL as Measured by Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) | The FACT-Lym is a lymphoma-specific subscale for the Functional Assessment of Cancer Therapy (FACT) questionnaire. The questionnaire consists of 15 specific items that are used together with the core 27-item questionnaire FACT-G. The participant is asked to give each item a score of between 0-4 (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = very much). A higher score indicates a worse level of QoL. | Day 1 of each 21 day cycle until end of treatment, a maximum of up to 30 days after last dose of study drug. Each cycle is 21 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Camidanlumab Tesirine; Relapsed or Refractory Hodgkins Lymphoma; Classical Hodgkins Lymphoma; Lymphoma