Phase II Study to Assess AFM13 in Patients With R/R CD30-positive T-cell Lymphoma or Transformed Mycosis Fungoides

Study Overview
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Brief Summary
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This is a phase II study to evaluate the antitumor activity and safety of AFM13 given as monotherapy in patients with CD30-positive T-cell lymphoma. The investigational medicinal product AFM13 is a tetravalent bispecific chimeric (anti-human CD30 x anti-human CD16A) recombinant antibody construct which is being developed to treat CD30-positive malignancies. Patients who suffer from peripheral T-cell lymphoma or transformed mycosis fungoides, whose tumor expresses the surface marker CD30, and who have relapsed after an earlier treatment or have refractory disease will be enrolled into this study if all of the study entry criteria are fulfilled. Dependent on their disease type and the magnitude of CD30 expression, study participants will be assigned to one of 3 study cohorts, each cohort receiving the same treatment of weekly AFM13 infusions (a 200mg dose per infusion). The main goal of the study is to assess the efficacy of AFM13 treatment as judged by the rate of overall responses. Further goals are to assess the safety of AFM13 treatment, the immunogenicity of AFM13 (as measured by the potential formation of anti-AFM13 antibodies) and the concentration of AFM13 in the blood. Approx. 1 month after the last dose of AFM13 there will be a final study visit to assess the patients' health status after therapy, followed by quarterly phone contacts to check on their overall health status and long-term survival.

Official Title
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A Phase II Open-label Multicenter Study to Assess the Efficacy and Safety of AFM13 in Patients With Relapsed or Refractory CD30-positive Peripheral T-cell Lymphoma or Transformed Mycosis Fungoides (REDIRECT)

Conditions
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Peripheral T Cell Lymphoma, Transformed Mycosis Fungoides

Intervention / Treatment
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* Drug: AFM13


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Histologically confirmed CD30-positive PTCL (most subtypes allowed) or TMF per the revised World Health Organization 2016 classification (Swerdlow, 2016) by central assessment. Cohorts A and B (PTCL cohorts): measurable by the modified Lugano Classification (Cheson, 2014); measurable disease of ≥1.5 cm diameter by computed tomography (CT), assessed locally for eligibility. Note: fluorodeoxyglucose (FDG) avid disease by positron emission tomography (PET) recommended, if possible. Cohort C (TMF cohort): measurable by the Olsen Criteria (Olsen, 2011) including at least 1 cutaneous lymphoma lesion ≥2 cm in diameter, assessed locally for eligibility. Patients must have relapsed or refractory disease AND the following: Cohorts A and B (PTCL): patients must have received at least 1 prior line of systemic therapy. For patients with systemic ALCL, patients must have failed or be intolerant to brentuximab vedotin [BV]; Adcetris® Cohort C (TMF): patients must have received at least 1 prior line of systemic therapy; and have exhausted systemic therapies with regular approval for their disease Main Exclusion Criteria: Patients with the following subtypes of lymphoma: T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; Chronic lymphoproliferative disorder of NK cells; Aggressive NK-cell leukemia; Extranodal NK-/T-cell lymphoma; Indolent T-cell lymphoproliferative disorder of the GI tract: Has had an allogenic tissue hematopoietic cell/solid organ transplant within the last 3 years. Note: Patients who have had a transplant >3 years ago are eligible as long as there are no signs/symptoms of graft versus host disease (GvHD). Requirement for systemic immunosuppressive therapy, e.g. GvHD therapy, <12 weeks prior to the first dose of study drug. Prior treatment with AFM13

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Subjects with Relapsed or Refractory CD30 positive Peripheral T-cell Lymphoma (PTCL). | Drug: AFM13<br>* weekly intravenous infusions of 200mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Assessed by Independent Review Committee Based on PET-CT | Overall response by Positron Emission Tomography-Computed Tomography (PET-CT) as defined by achieving complete response and/or partial response assessed by an Independent Review Committee (IRC) utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014). | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Assessed by Investigator Based on PET-CT | Overall response by Positron Emission Tomography-Computed Tomography (PET-CT) as defined by achieving complete response and/or partial response assessed by the investigator utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014). | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months). | 
| Overall Response Rate Assessed by Investigator Based on CT | Overall response by Computed Tomography (CT) as defined by achieving complete response and/or partial response assessed by the investigator utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014). | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months). | 
| Complete Response Rate and Partial Response Rate Assessed by Independent Review Committee Based on PET-CT | Complete response and/or partial response by Positron Emission Tomography-Computed Tomography (PET-CT) assessed by an Independent Review Committee (IRC) utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014). | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months). | 
| Complete Response Rate, Partial Response Rate and Overall Response Rate Assessed by Independent Review Committee Based on CT | Overall response by Computed Tomography (CT) as defined by achieving complete response and/or partial response assessed by an Independent Review Committee (IRC) utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014). | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months). | 
| Duration of Overall Response Assessed by Independent Review Committee Based on PET-CT | Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Positron Emission Tomography-Computed Tomography (PET-CT) by Independent Review Committee (IRC). | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months). | 
| Duration of Overall Response Assessed by Independent Review Committee Based on CT | Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Computed Tomography (CT) by Independent Review Committee (IRC). | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months). | 
| Duration of Overall Response Assessed by Investigator Based on PET-CT | Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Positron Emission Tomography-Computed Tomography (PET-CT) by the investigator. | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months). | 
| Duration of Overall Response Assessed by Investigator Based on CT | Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Computed Tomography (CT) by the investigator. | Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months). | 
| Number of Subjects With Treatment Related Adverse Event | Number of subjects who had treatment (AFM13) related Adverse Events. | From the date of first treatment until the date of the last treatment + 37 days, up to 138 weeks. | 
| Maximum Measured Concentration (Cmax) of AFM13 | Maximum measured concentration (Cmax) of the AFM13 in plasma. | Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1 and Day 29. | 
| Area Under the Concentration-Time Curve of AFM13 From 0 to Infinity (AUC 0-∞) | Area under concentration (AUC) versus time curve of the AFM13 in plasma over time interval from 0 extrapolated to infinity. | Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1 and Day 29. | 
| Volume of Distribution at Steady State (Vss) of AFM13 | Volume of distribution at steady state (Vss) of the AFM13. | Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1 and Day 29. | 
| The Terminal Half-life (t1/2) of AFM13 | The terminal half-life (t1/2) of the AFM13. | Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1 and Day 29. | 
| European Quality of Life 5-dimensional Pain/Discomfort Score (EQ-5D) | Quality of Life (QoL) as measured by the European QoL 5-dimensional questionnaire (EQ-5D) for Cohorts A. The EQ-5D comprises asks for the current health state in the five dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Pain/discomfort scores assessed based on questionnaire. The categories of the response offer three levels pain/discomfort score: no pain or discomfort (score of 1), moderate pain or discomfort (score of 2), and extreme pain and discomfort (score of 3). Scores are presented from baseline to each visit for Cohort A. | At baseline and final study visit, up to 138 weeks. | 
| European Quality of Life 5-dimensional Visual Analogue Scale Scores (EQ-5D) | Quality of Life (QoL) as measured by the European Quality of Life 5-dimensional questionnaire (EQ-5D) for Cohorts A. Visual Analogue Scale scores assessed based on drawn scale from 0(worst imaginable state) to 100(best imaginable state). Subjects chose their health state on scale based on their situation by themselves. | From baseline until final study visit, up to 138 weeks. |