Phase 2 Study of AFM13 in Combination With AB-101 in Subjects With R/R HL and CD30+ PTCL

Study Overview
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Brief Summary
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AFM13-203 is a phase 2, open-label, multi-center, multi-cohort study with a safety run-in followed by expansion cohorts. The study is evaluating the safety and efficacy of AFM13 in combination with AB-101 in subjects with R/R classical HL and CD30-positive PTCL.

Detailed Description
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The study will start with a safety run-in exploring AFM13/AB-101 combination treatment in subjects with classical HL. Two dose levels of AFM13 and AB-101, respectively, will be tested in 4 cohorts. Cohort 1 and 2 will enroll in parallel. Enrolment into Cohort 3 and 4 will start only if the combination treatment has been well tolerated. Following the safety run-in observation period, a thorough risk-benefit analysis will be performed to determine 2 of the 4 cohorts/dose levels that will be further evaluated in the main part of the study which will also include subjects with classical HL and will follow a Simon two-stage design. An additional exploratory cohort (Cohort 5) will enroll subjects with select CD30-positive PTCL subtypes after completion of the safety run-in. All subjects will be treated with AFM13/AB-101 for a maximum of 3 cycles (cycle length is 48-days).

Official Title
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A Phase 2, Open-Label, Multi-Center Study of Innate Cell Engager AFM13 in Combination With Allogeneic Natural Killer Cells (AB-101) in Subjects With Recurrent or Refractory Hodgkin Lymphoma and CD-30 Positive Peripheral T-Cell Lymphoma

Conditions
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Relapsed or Refractory Hodgkin Lymphoma, Peripheral T Cell Lymphoma

Intervention / Treatment
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* Drug: AFM13
* Drug: AB-101
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a diagnosis of FDG-avid relapsed or refractory classical HL OR select subtypes of FDG-avid CD30-positive relapsed or refractory PTCL For subjects with R/R PTCL a pre-enrollment tumor biopsy positive for CD30 locally assessed by Ber-H2 targeted immunohistochemistry at ≥1% is mandatory (PTCL subtypes: PTCL-NOS, Angioimmunoblastic T-cell lymphoma, ALCL, anaplastic lymphoma kinase (ALK)-positive, ALCL, ALK-negative) Subjects with R/R classical HL must have received at least two lines of therapy including one prior line of combination chemotherapy. Prior therapy must also have included brentuximab vedotin and a PD1 check point inhibitor. Subjects with R/R PTCL must have received at least one prior line of combination chemotherapy. Subjects with ALCL subtype of PTCL must have received or been intolerant to brentuximab vedotin. Subjects with R/R classical HL AND R/R PTCL: Prior ASCT is permitted if completed at least 3 months prior to the first dose of study treatment. Prior allogeneic stem cell transplantation will be permitted if completed at least 1 year from study enrollment and there are no signs or symptoms of GVHD. Prior CAR-T therapy is permitted if last CAR-T dose completed at least 6 months prior to the first dose of study treatment. Ability to understand and sign the ICF Exclusion Criteria: Active central nervous system (CNS) involvement (untreated or uncontrolled parenchymal brain metastasis or positive cytology of cerebrospinal fluid) Previous treatment with AFM13 or CBNK cells History of a solid organ allograft, or an inflammatory or autoimmune disease likely to be exacerbated by IL-2 (including subjects requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease that may require systemic steroids or immunosuppressive agents Treatment with any therapeutic mAb or immunosuppressive medications Known active Hepatitis B or C defined per protocol Active HIV Infection History of any other systemic malignancy, unless previously treated with curative intent and the subject has been disease free for 2 years or longer Active acute or chronic graft vs. host disease (GVHD) or GVHD requiring immunosuppressive treatment, clinically significant central nervous system (CNS) dysfunction

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety run-in in Hodgkin Lymphoma<br>4 safety run-in cohorts: Cohort 1: 200 mg AFM13 + AB-101 (2 × 10e9 cells on Day 1, Day 8, Day 15) Cohort 2: 300 mg AFM13 + AB-101 (2 × 10e9 cells on Day 1, Day 8, Day 15) Cohort 3: 200 mg AFM13 + AB-101 (4 × 10e9 cells on Day 1; 2 × 10e9 cells on Day 8, Day 15) Cohort 4: 300 mg AFM13 + AB-101 (4 × 10e9 cells on Day 1; 2 × 10e9 cells on Day 8, Day 15) | Drug: AFM13<br>* anti-human CD30 × anti-human CD16A recombinant antibody therapy, intravenous infusion<br>Drug: AB-101<br>* NK cell therapy, intravenous infusion<br>Drug: Cyclophosphamide<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Fludarabine<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Interleukin-2<br>* Immune cytokine, subcutaneously<br>|
| Experimental: Dose Level A in Hodgkin Lymphoma<br>Randomized Simon 2-stage design in Hodgkin Lymphoma Dose Level A (selected from cohort 1-4 of Safety run-in) | Drug: AFM13<br>* anti-human CD30 × anti-human CD16A recombinant antibody therapy, intravenous infusion<br>Drug: AB-101<br>* NK cell therapy, intravenous infusion<br>Drug: Cyclophosphamide<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Fludarabine<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Interleukin-2<br>* Immune cytokine, subcutaneously<br>|
| Experimental: Dose Level B in Hodgkin Lymphoma<br>Randomized Simon 2-stage design in Hodgkin Lymphoma Dose Level B (selected from cohort 1-4 of Safety run-in) | Drug: AFM13<br>* anti-human CD30 × anti-human CD16A recombinant antibody therapy, intravenous infusion<br>Drug: AB-101<br>* NK cell therapy, intravenous infusion<br>Drug: Cyclophosphamide<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Fludarabine<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Interleukin-2<br>* Immune cytokine, subcutaneously<br>|
| Experimental: Exploratory: AFM13 + AB-101 on CD30-positive PTCL<br>AFM13 + AB-101 on select CD30-positive PTCL subtypes (Dose Level A or B) | Drug: AFM13<br>* anti-human CD30 × anti-human CD16A recombinant antibody therapy, intravenous infusion<br>Drug: AB-101<br>* NK cell therapy, intravenous infusion<br>Drug: Cyclophosphamide<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Fludarabine<br>* Lymphodepleting chemotherapy, intravenous infusion<br>Drug: Interleukin-2<br>* Immune cytokine, subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate by Independent Radiology Committee | ORR (complete response (CR) + partial response [PR]) by Independent Radiology Committee (IRC) based on positron emission tomography-computed tomography (PET-CT) as assessed by the Lugano classification | From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response by Investigator and Independent Radiology Committee | Duration of response (DOR) defined as time from first assessment of PR or CR to the first assessment of progressive disease. Response based on positron emission tomography-computed tomography (PET-CT) as assessed by the Lugano classification. | Tumor assessment performed every 6 weeks for 3 cycles, if no disease progression on completion of treatment, then every 3 months for the first 12 months and then every 6 months (up to 24 months) | 
| Complete response rate (CRR) by Investigator and Independent Radiology Committee | Complete Response Rate based on positron emission tomography-computed tomography (PET-CT) as assessed by the Lugano classification. | Tumor assessment performed every 6 weeks for 3 cycles, if no disease progression on completion of treatment, then every 3 months for the first 12 months and then every 6 months (up to 24 months) | 
| ORR by Investigator based on PET-CT as assessed by the Lugano classification | ORR (CR + PR) by Investigator based on positron emission tomography-computed tomography (PET-CT) as assessed by the Lugano classification | Tumor assessment performed every 6 weeks for 3 cycles, if no disease progression on completion of treatment, then every 3 months for the first 12 months and then every 6 months (up to 24 months) | 
| Incidence of subjects receiving subsequent transplant | The incidence of subjects receiving subsequent transplant will be assessed and summarized by percentage rates and 95% Confidence Intervals | Throughout study completion (estimated up to 24 months) | 
| Incidence of TEAEs and SAEs | Frequency of subjects with study-drug related treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | From the time of first protocol-specific intervention until 30 days after the last administration | 
| Immunogenicity assessment of AFM13 in combination with AB-101 | Frequency of subjects developing anti-drug antibodies (ADAs) against AFM13 or AB-101 | During treatment cycles (estimated up 6 months) | 
| Progression-free survival (PFS) by Independent Radiology Committee | Progression-free survival (PFS) defined as time from first treatment (AFM13/AB-101) received until PD/OS. | Throughout study completion (estimated up to 24 months) | 
| Overall survival (OS) | Overall survival rate | up to 24 months |