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

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.


Eligibility Criteria:
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 one of the following approved anti-CD19 CAR T-cell therapies: Kymriah, Yescarta and Tecartus.
* 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:

* Participants who have received any other anti-cancer treatment post-CAR T.
* 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.