A Phase I/II Trial of ALETA-001 for the Treatment of Participants With B-cell Malignancies

Study Overview
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Brief Summary
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This is a Phase I/II multicentre, open-label trial designed to evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of a novel chimeric antigen receptor (CAR) T-cell engager, ALETA-001, administered by intravenous (IV) infusion as a single agent every 2 weeks in patients with relapsed non-Hodgkin lymphoma (NHL) who have failed to optimally respond to prior treatment with anti-CD19 CAR T-cell therapy. This first in human study is divided into 2 parts: a safety lead-in phase (Phase I) and a dose expansion phase (Phase II). Different dose levels of ALETA-001 will be evaluated in Phase I in order to define a recommended dosing level and schedule for Phase II. Phase II will further evaluate the safety, PK and therapeutic activity of ALETA-001.

Official Title
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A Cancer Research Phase I/ II Trial of ALETA-001 in Participants Who Do Not Achieve or Maintain an Optimal Response to Anti-CD19 CAR T-cell Therapy for the Treatment of B-cell Malignancies

Conditions
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Lymphoma, Non-Hodgkin, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Lymphoma, Follicular, Lymphoma, B-Cell

Intervention / Treatment
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* Drug: ALETA-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 16 years or over. Written informed consent and capable of co-operating with ALETA-001 administration and follow-up. Confirmed diagnosis of NHL according to World Health Organization (WHO) 2016 criteria. Received an approved anti-CD19 CAR T-cell therapy. Objectively evaluable or measurable disease at 4 weeks post CAR T, which demonstrates inadequate or incomplete response or progressive disease if there is a reasonable expectation of deriving benefit from trial treatment, or- initial response followed by relapse within 9 months assessed according to Lugano criteria. Eastern Cooperative Oncology Group performance status of 0, 1 or 2 following anti-CD19 CAR T-cell treatment. Haematological and biochemical indices within protocol specified ranges. Exclusion Criteria: Concurrent radiotherapy (except for palliative reasons). Potential participants who experienced any of the following because of the initial CAR T-cell treatment: Grade 4 ICANs, Grade >=3 ICANs persisting beyond 7 days and despite optimal supportive therapy. Grade 4 CRS, Grade 3 CRS persisting beyond 7 days and despite optimal supportive therapy, any Grade 2 ICANs or CRS must be fully resolved. Any ongoing toxic manifestation of previous anti-cancer treatment that, in the opinion of the Investigator, should exclude the participant. Active or previous malignancies of other types that, in the opinion of the Investigator, should exclude the participant. Exceptions include adequately treated cone biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin and patients with asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or who require only hormonal therapy and have had normal prostate specific antigen for >1 year prior to the start of therapy. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 2 years or more and are deemed at negligible risk for recurrence, are eligible for the trial. Ongoing need for systemic immunosuppressive therapy other than replacement dose of corticosteroids. Intermittent topical, inhaled or intra-nasal corticosteroids are permitted. Presence of active infections and/ or inflammatory disease requiring active management. Documented current central nervous system involvement by lymphoma. Women of childbearing potential (or are already pregnant or lactating) unless willing to adhere to protocol-defined contraceptive requirements. Male patients with partners of childbearing potential unless willing to adhere to protocol-defined contraceptive requirements. Major thoracic or abdominal surgery from which the participant has not yet recovered. At high medical risk because of non-malignant systemic disease including active uncontrolled infection. Hypersensitivity to any of the ingredients/excipients in ALETA-001 Participation in another interventional clinical trial, whilst taking part in this trial of ALETA-001. Participation in an observational trial or interventional clinical trial that does not involve administration of an IMP and that would not place an unacceptable burden on the participant, in the opinion of the Investigator and CDD, would be acceptable. Participants with any congenital or acquired immunodeficiency syndrome or who are receiving immunosuppressive therapy (including any dose of systemic corticosteroids), or who are immunosuppressed post organ transplant. However, participants receiving inhaled corticosteroids and participants with a history of allergy (other than anaphylaxis) are eligible, as are participants with a history of autoimmune disease. Any other condition that, in the Investigator's opinion, would mean that the trial is not in the best interests of the participant.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-In Phase<br> | Drug: ALETA-001<br>* ALETA-001 will be administered intravenously (IV) every two weeks.<br>|
| Experimental: Dose Expansion Phase<br> | Drug: ALETA-001<br>* ALETA-001 will be administered intravenously (IV) every two weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose level of ALETA-001 for use in Dose Expansion (Safety Lead-in Phase). | Determine a dose level that is deemed tolerable based on available safety and pharmacodynamic data. | Day 1 to Day 28. | 
| Number of Participants who experience dose limiting toxicities (DLTs). | DLTs will be assessed up to Day 28 and are defined as toxicities that meet pre-defined severity criteria and assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, intercurrent illness, or concomitant medications that occurs within the 28 days of the first dose of ALETA-001. | Up to Day 28. | 
| Number of Participants who experience Grade 3, 4 or 5 related adverse event (AEs). | Related AEs are those considered by the investigator to be possibly, probably or highly probably related to ALETA-001. Events of cytokine release syndrome (CRS) and immune effector cell mediated neurotoxicity (ICANS) are graded according to the American Society for Transplantation and Cellular Therapy grading criteria. All other AEs are graded according to the Common Terminology Criteria for AEs (CTCAE) Version 5.0. | Safety data will be collected from the time of informed consent until 95 days after the last dose of ALETA-001. The average time from consent to the end of follow up will be presented. | 
| Best Overall Response (Dose Expansion Phase). | Best Overall Response according to Lugano criteria (Cheson, Journal of Clinical Oncology, 2014), the number of participants taking part in the Dose Expansion Phase with best overall response of complete response (CR), partial response (PR), no response or stable disease (SD/NR), and progressive disease (PD). | Radiological assessment from within 28 days before starting ALETA-001 and up to 12 months after. | 
| Progression-Free Survival (PFS) (Dose Expansion Phase). | Median PFS measured from first dose of ALETA-001 to date of progression according to Lugano criteria or date of death without a previous progression recorded. | From date of first dose of ALETA-001 up to 12 months. | 
| Time to Progression (TTP) (Dose Expansion Phase). | Median TTP measured from first dose of ALETA-001 to date of progression according to Lugano criteria. Participants who die without recorded progression will be censored. | From date of first dose of ALETA-001 up to 12 months. | 
| Overall Survival (OS) (Dose Expansion Phase). | Median OS measured from first dose of ALETA-001 to date of death due to any cause or to the date of censoring at the last time the participant was known to be alive. | Follow-up until end of trial, estimated to be up to 48 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (Safety Lead-in Phase). | Best Overall Response according to Lugano criteria, the number of participants taking part in the Safety Lead-in Phase with best overall response of complete response (CR), partial response (PR), no response or stable disease (SD), and progressive disease (PD). | Radiological assessment from within 28 days before starting ALETA-001 and up to 12 months after. | 
| Progression-Free Survival (PFS) (Safety Lead-in Phase). | Median PFS measured from first dose of ALETA-001 to date of progression according to Lugano criteria or date of death without a previous progression recorded. | From date of first dose of ALETA-001 up to 12 months. | 
| Time to Progression (TTP) (Safety Lead-in Phase). | Median TTP measured from first dose of ALETA-001 to date of progression according to Lugano criteria. Participants who die without recorded progression will be censored. | From date of first dose of ALETA-001 up to 12 months. | 
| Overall Survival (OS) (Safety Lead-in Phase). | Median OS measured from first dose of ALETA-001 to date of death due to any cause or to the date of censoring at the last time the participant was known to be alive. | Follow-up until end of trial, estimated to be up to 48 months. | 
| Maximum observed plasma concentration (Cmax) of ALETA-001. | Measurement of Cmax of ALETA-001 as appropriate. | Day 1 to Day 7. | 
| Terminal elimination half-life (t1/2) of ALETA-001. | Measurement of t1/2 of ALETA-001 as appropriate. | Day 1 to Day 7. | 
| Area under the concentration-time curve (AUC) of ALETA-001. | Measurement of AUC of ALETA-001 as appropriate. | Day 1 to Day 7. | 
| Volume of distribution (Vss) of ALETA-001. | Measurement of Vss of ALETA-001 as appropriate. | Day 1 (before first ALETA-001 infusion) to Day 7. | 
| Clearance (CL) of ALETA-001. | Measurement of CL of ALETA-001 as appropriate. | Day 1 to Day 7. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, Receptors, Antigen, T-Cell, Antigens, CD19