Autologous CD30.CAR-T in Combination With Nivolumab in cHL Patients After Failure of Frontline Therapy

Study Overview
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Brief Summary
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This is a Phase 1b, multicenter, open-label, single arm study to evaluate the safety and efficacy of the combination therapy, CD30.CAR-T and the programmed cell death protein-1 (PD-1) checkpoint inhibitor, nivolumab, in patients aged 12 years of age and above with relapsed or refractory classical Hodgkin lymphoma (cHL) following failure of standard frontline therapy.

Detailed Description
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Upon successful leukapheresis to produce CD30.CAR-T cells, patients will enter the treatment phase of the study. Treatments will include 4 cycles of nivolumab and CD30.CAR-T infusion (preceded by lymphodepletion chemotherapy). Patients will then enter the post-treatment follow-up phase of the study, whereby patients will undergo either autologous stem cell transplant or continue to receive up to 6 additional treatment cycles of nivolumab. Patients will be followed for response assessments and safety monitoring until end of study (EOS); approximately 3 years after leukapheresis. Long-term follow-up will continue with additional safety monitoring and survival for up to 15 years after Leukapheresis.

Official Title
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Phase 1b Study Evaluating the Safety and Efficacy of Autologous CD30.CAR-T in Combination With PD-1 Checkpoint Inhibitor (Nivolumab) in Relapsed or Refractory Classical Hodgkin Lymphoma Patients After Failure of Frontline Therapy (ACTION)

Conditions
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Classical Hodgkin Lymphoma, Hodgkin Disease Refractory, Hodgkin Disease Recurrent

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Autologous CD30.CAR-T
* Drug: Fludarabine
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed ICF Male or female patients who are 12 years of age and above Relapsed or refractory CD30+ cHL following failure of a standard frontline chemotherapy At least 1 lesion, which must be fluordeoxyglucose positron emission tomography (FDG-PET) avid and measurable by PET-CT scan Adequate laboratory parameters including hematologic, renal, hepatic, and coagulation function Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, or equivalent either Karnofsky performance status (for patients ≥ 16 years of age) or Lansky performance status (for patients < 16 years of age) Anticipated life expectancy > 12 weeks No active infections including COVID 19 at Screening Exclusion Criteria: Evidence of lymphomatous involvement of the central nervous system (CNS) Presence of clinically relevant or active seizure disorder, stroke, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement Symptomatic cardiovascular disease: Class III or IV according to the New York Heart Association (NYHA) Functional Classification Active uncontrolled bleeding or a known bleeding diathesis Inadequate pulmonary function defined as oxygen saturation by pulse oximetry < 90% on room air Echocardiogram (ECHO) or Multi-gated Acquisition (MUGA) scan with left ventricular ejection fraction (LVEF) < 45% Prior receipt of salvage therapy, for relapsed or refractory cHL, including allogeneic or ASCT Prior receipt of investigational CD30.CAR-T cells Receiving any investigational agents or any tumor vaccines Receiving any live/attenuated vaccines Ongoing treatment with immunosuppressive drugs or chronic systemic corticosteroids Unresolved > Grade 1 non-hematologic toxicity associated with any prior treatments Previous history of known or suspected autoimmune disease within the past 5 years Active interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity Evidence of human immunodeficiency virus (HIV) infection Evidence of active viral infection with hepatitis B virus (HBV) Evidence of active viral infection with hepatitis C virus (HCV) Active second malignancy or history of another malignancy within the last 3 years History of hypersensitivity reactions to murine protein-containing products or other product excipients Any allergic or adverse reaction to nivolumab, fludarabine, or bendamustine that precludes treatment with these agents History of a significant irAE from prior immune checkpoint inhibitor therapy

Ages Eligible for Study
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Minimum Age: 12 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
Interventional Model Description: Upon successful leukapheresis to produce CD30.CAR-T cells, patients will enter the treatment phase of the study. Treatments will include 4 cycles of nivolumab and CD30.CAR-T infusion (preceded by lymphodepletion chemotherapy). Patients will then enter the post-treatment follow-up phase of the study, whereby patients will undergo either autologous stem cell transplant or continue to receive up to 6 additional treatment cycles of nivolumab. Patients will be followed for response assessments and safety monitoring until end of study (EOS); approximately 3 years after leukapheresis. Long-term follow-up will continue with additional safety monitoring and survival for up to 15 years after Leukapheresis.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab and CD30.CAR-T<br>Study treatment will include 4 cycles of nivolumab and a single CD30.CAR-T infusion (preceded by lymphodepletion chemotherapy of Fludarabine and Bendamustine). | Drug: Nivolumab<br>* Dose: 480 mg or 6 mg/kg Q4W<br>* Other names: Opdivo;Drug: Autologous CD30.CAR-T<br>* Dose: 2 x 10e8 cells/m2<br>* Other names: CD30-directed CAR-T cells;Drug: Fludarabine<br>* Dose: 30 mg/m2/day x 3 days<br>* Other names: Fludara;Drug: Bendamustine<br>* Dose: 70 mg/m2/day x 3 days<br>* Other names: Treanda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of autologous CD30.CAR-T in combination with nivolumab | DLT | From first dose of nivolumab (Cycle 1) to end of nivolumab Cycle 4 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity using CR rate of autologous CD30.CAR-T in combination with nivolumab | CR rate | Up to end of 10 weeks post-CD30.CAR-T treatment | 
| Overall response rate | ORR | Through study completion, an average of 3 years from Leukapheresis | 
| Duration of response | DOR | Through study completion, an average of 3 years from Leukapheresis | 
| Progression-free survival | PFS | Through study completion, an average of 3 years from Leukapheresis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cHL