PBMC-based Leukocyte Immunotherapy

Study Overview
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Brief Summary
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This is an open-label, multicenter, dose-escalation Phase Ib trial of APN401, a suspension of viable Peripheral Blood Mononuclear Cells (PBMCs) from an individual patient that have been transfected with a small interfering ribonucleic acid (siRNA) to reduce Cbl-b expression. Twelve evaluable participants with advanced solid tumors will be assessed. The primary objective is to evaluate the safety and tolerability of APN401 and to determine the Recommended Phase 2 Dose (RP2D) of APN401. The secondary objective is to collect preliminary data on the clinical efficacy of APN401. Participants will receive up to four APN401 treatments via intravenous infusion at 3-weekly intervals. Participants, who have completed four treatment cycles and a safety follow-up, will be contacted by telephone to evaluate survival status at 6 and 12 months after start of treatment.

Detailed Description
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APN401 is a suspension of autologous Peripheral Blood Mononuclear Cells (PBMCs), transiently transfected with an siRNA to reduce Cbl-b protein levels. The administration of autologous Cbl-b silenced PBMCs to the patient will promote activation of both adaptive and innate immune mechanisms targeting tumor cells; along these lines APN401 is assumed to demonstrate significant improvement in cancer immune therapy. In addition, silencing of Cbl-b in the context of cellular therapeutics has potential to reduce mortality rates for patients with advanced cancers. This is an open-label, single-arm trial to be conducted with up to twelve patients at four hospitals in Austria, Europe. Two dose levels of APN401 are evaluated using a Bayesian Optimal Interval (BOIN) study design with accelerated titration: Dose Level/Cohort 1: 1.5x10^7 PBMCs/kg Dose Level/Cohort 2: 4.5x10^7 PBMCs/kg Dose escalation requires at least one patient to be treated and observed for at least three weeks after the first dose. The BOIN method will be used to guide the dose level assignment and estimate the MTD/RP2D based on cumulative information on DLTs in Cycle 1 of treatment (i.e. 3 weeks after first dose). Patients with advanced solid tumors first undergo screening procedures during a 28-day time window between giving consent and starting APN401 treatment. Eligible patients are treated with up to four APN401 infusions. During each treatment cycle, patients undergo leukapheresis on the first day and APN401 infusion on the second day (i.e., D0/D1; D21/D22; D42/D43; D63/D64). During the subsequent follow-up phase, patients participate a safety-follow up 3 weeks post last APN401 dose and are contacted by telephone to evaluate survival status at 6 and 12 months after start of treatment. Tumor imagings to evaluate the efficacy of APN401 treatment are scheduled during the screening phase (baseline imaging), and prior to treatment Cycle 3 and the last Safety Follow-up.

Official Title
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An Open-label, Multi-center, Dose-escalation Phase Ib Study to Determine the Recommended Phase 2 Dose of APN401 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: APN401


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of 18 years or older (all genders) Patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors and who have failed standard treatment, have no standard treatment, or are not suitable for standard treatment at this stage as determined by the investigator Progressed on or refractory to at least two prior lines of systemic therapy At least one measurable lesion according to RECIST 1.1 An Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 Life expectancy of at least 3 months Adequate organ and bone marrow function, in the absence of growth factors, defined by specific laboratory parameters. Negative serology for human immunodeficiency virus, syphilis, hepatitis B and hepatitis C No prior chemotherapy, radiation therapy (except for palliative purpose), endocrine therapy, immunotherapy or investigational agent within 3 weeks (or five half-lives) prior to Day 0 (6 weeks for nitrosoureas and mitomycin C) before treatment Toxicities from previous anti-cancer therapies or surgical procedures to grade ≤1 that have not resolved (except alopecia) Previous exposure to a checkpoint inhibitor is allowed (except exposure of Cbl-b inhibition) Women of childbearing potential must have a negative pregnancy test, should not be breastfeeding, and must be willing to use highly effective methods of contraception for at least 1 month before, while participating in this study and until 1 month after the end of the treatment Patient voluntarily agrees to participate in this study and signs an Ethics Committee approved informed consent prior to performing any of the screening visit procedures, indicating that the patient understands the purpose and procedures required for the study Patient is not participating in any other interventional clinical study within the past 30 days Exclusion Criteria: Active untreated brain metastases Use of systemic corticosteroids (> 10 mg prednisone or equivalent) within 15 days (except for prophylaxis for radiodiagnostic contrast reactions), or other immunosuppressive drugs within 30 days, prior to the first dose of APN401. Replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed Active, known, or suspected autoimmune disease except type I diabetes, vitiligo and thyroid disorders (thyroxine or insulin replacement therapy is allowed) Patients at high medical risk because of non-malignant systemic disease, active or unstable cardiac or cerebro-vascular disease, or active uncontrolled infection Any other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or APN401 administration, or may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient unsuitable for the study Any vaccination prior and/or after 7 days while on APN401 treatment

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: APN401<br>Intravenous infusion of APN401 in 3-weekly (i.e. 21 days) intervals for a maximum of 4 doses at either 1.5x10^7 PBMCs/kg (i.e., Dose Level 1) or 4.5x10^7 PBMCs/kg (i.e., Dose Level 2), depending on assigned cohort | Drug: APN401<br>* APN401 is a suspension of viable peripheral blood mononuclear cells (PBMCs) from an individual patient that have been transfected with a small interfering ribonucleic acid (siRNA) to reduce Cbl-b expression. It is administered intravenously in 3-weekly intervals (i.e. every 21 days) for a maximum of 4 treatment cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events (TEAEs) and/or Serious Adverse Events (SAEs) | The safety and tolerability of APN401 will be assessed by recording the TEAEs and SAEs using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 5.0) | Up to 30 days post last dose | 
| Occurence of Dose Limiting Toxicities (DLTs) | The safety and tolerability of APN401 will be assessed by recording DLTs | Observed from Day 1 of APN401 infusion until the end of Cycle 1 (Day 21) | 
| Determination of Recommended Phase 2 Dose (RP2D) of APN401 | RP2D will be determined on the BOIN recommendations (based on DLT and MTD) and the overall safety information | Through completion of DLT period of last evaluable patient, an average of 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Preliminary data on clinical efficacy of APN401 will be assessed according to RECIST 1.1 | Up to 12 months | 
| Disease Control Rate (DCR) | Preliminary data on clinical efficacy of APN401 will be assessed according to RECIST 1.1 | Up to 12 months | 
| Overall Survival (OS) | Preliminary data on clinical efficacy of APN401 will be assessed | Time from enrollment to death | 
| Overall Survival (OS) at 3, 6 and 12 months | Preliminary data on clinical efficacy of APN401 will be assessed | At 3, 6 and 12 months post start of treatment phase | 
| Progression Free Survival (PFS) | Preliminary data on clinical efficacy of APN401 will be assessed according to RECIST 1.1 | From date of enrollment until the date of first evidence of disease progression or date of death from any cause, whichever came first, assessed up to 12 months | 
| Progression Free Survival (PFS) Rate at 3 months | Preliminary data on clinical efficacy of APN401 will be assessed according to RECIST 1.1 | At 3 months post start of treatment phase | 
| Immune responses in circulation to monitor APN401 immune activation | Preliminary data on clinical efficacy of APN401 will be assessed using ELISA-based techniques | Prior to treatment cycles C1, C2, C3, C4 (each cycle is 21 +/- 3 days) and 21 days (+/-10 days) post last APN401 dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced solid tumor, siRNA (small interfering ribonucleic acid), cell therapy, immune checkpoint, ATMP (Advanced Therapy Medicinal Product), PBMCs (Peripheral Blood Mononuclear Cells), Cbl-b (Casitas B Lineage Lymphoma B)