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

• ClinicalTrials.gov Identifier: NCT06045910
• Recruitment Status: Recruiting
• First Posted: September 21, 2023
• Last Update Posted: March 13, 2024
• Sponsor: Cancer Research UK
• Collaborator: Aleta BioTherapeutics
• Information provided by (Responsible Party): Cancer Research UK

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Follicular; Lymphoma, B-Cell	Drug: ALETA-001	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 72 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 19, 2024
• Estimated Primary Completion Date: December 2027
• Estimated Study Completion Date: December 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Safety Lead-In Phase	Drug: ALETA-001; ALETA-001 will be administered intravenously (IV) every two weeks.
Experimental: Dose Expansion Phase	Drug: ALETA-001; ALETA-001 will be administered intravenously (IV) every two weeks.

Outcome Measures

Primary Outcome Measures :

1. Dose level of ALETA-001 for use in Dose Expansion (Safety Lead-in Phase). [ Time Frame: Day 1 to Day 28. ]
   Determine a dose level that is deemed tolerable based on available safety and pharmacodynamic data.
2. Number of Participants who experience dose limiting toxicities (DLTs). [ Time Frame: Up to Day 28. ]
   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.
3. Number of Participants who experience Grade 3, 4 or 5 related adverse event (AEs). [ Time Frame: 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. ]
   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.
4. Best Overall Response (Dose Expansion Phase). [ Time Frame: Radiological assessment from within 28 days before starting ALETA-001 and up to 12 months after. ]
   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).
5. Progression-Free Survival (PFS) (Dose Expansion Phase). [ Time Frame: From date of first dose of ALETA-001 up to 12 months. ]
   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.
6. Time to Progression (TTP) (Dose Expansion Phase). [ Time Frame: From date of first dose of ALETA-001 up to 12 months. ]
   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.
7. Overall Survival (OS) (Dose Expansion Phase). [ Time Frame: Follow-up until end of trial, estimated to be up to 48 months. ]
   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.

Secondary Outcome Measures :

1. Best Overall Response (Safety Lead-in Phase). [ Time Frame: Radiological assessment from within 28 days before starting ALETA-001 and up to 12 months after. ]
   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).
2. Progression-Free Survival (PFS) (Safety Lead-in Phase). [ Time Frame: From date of first dose of ALETA-001 up to 12 months. ]
   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.
3. Time to Progression (TTP) (Safety Lead-in Phase). [ Time Frame: From date of first dose of ALETA-001 up to 12 months. ]
   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.
4. Overall Survival (OS) (Safety Lead-in Phase). [ Time Frame: Follow-up until end of trial, estimated to be up to 48 months. ]
   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.
5. Maximum observed plasma concentration (Cmax) of ALETA-001. [ Time Frame: Day 1 to Day 7. ]
   Measurement of Cmax of ALETA-001 as appropriate.
6. Terminal elimination half-life (t1/2) of ALETA-001. [ Time Frame: Day 1 to Day 7. ]
   Measurement of t1/2 of ALETA-001 as appropriate.
7. Area under the concentration-time curve (AUC) of ALETA-001. [ Time Frame: Day 1 to Day 7. ]
   Measurement of AUC of ALETA-001 as appropriate.
8. Volume of distribution (Vss) of ALETA-001. [ Time Frame: Day 1 (before first ALETA-001 infusion) to Day 7. ]
   Measurement of Vss of ALETA-001 as appropriate.
9. Clearance (CL) of ALETA-001. [ Time Frame: Day 1 to Day 7. ]
   Measurement of CL of ALETA-001 as appropriate.

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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.

Contacts and Locations

Contacts

Contact: Emma Ingleson; 0203 469 6897; aleta@cancer.org.uk

Locations

United Kingdom

University Hospital Birmingham NHS Foundation Trust; Recruiting

Birmingham, United Kingdom

Contact: Sridhar Chaganti, Dr 01213714379 sridhar.chaganti@uhb.nhs.uk

Cambridge University Hospitals; Recruiting

Cambridge, United Kingdom

Contact: Ram Malladi, Dr 01223 217020 Ram.malladi@nhs.net

St James's University Hospital; Not yet recruiting

Leeds, United Kingdom

Contact: Cathy Burton, Dr 01132067851 cathy.burton1@nhs.net

University Hospital London Hospital; Not yet recruiting

London, United Kingdom

Contact: William Townsend, Dr 0203 447 9443 william.townsend@nhs.net

Manchester Royal Infirmary; Not yet recruiting

Manchester, United Kingdom

Contact: Jane Norman, Dr 01612764178, 01612768686 Jane.norman@mft.nhs.uk

The Christie Hospital; Not yet recruiting

Manchester, United Kingdom

Contact: Adam Gibb, Dr 0161 446 3753 adam.gibb@nhs.net

Royal Marsden Hospital; Not yet recruiting

Sutton, United Kingdom

Contact: Carlos Arias, Dr 02086613672 Carlos.gonzalezarias@rmh.nhs.uk

Sponsors and Collaborators

Cancer Research UK

Aleta BioTherapeutics

Investigators

• Principal Investigator: Sridhar Chaganti, Dr; University Hospital Birmingham NHS Foundation Trust

More Information

Additional Information:

Simple Summary of the trial on Cancer Research UK database. 

• Responsible Party: Cancer Research UK
• ClinicalTrials.gov Identifier: NCT06045910
• Other Study ID Numbers: CRUKD/23/001; IRAS ID: 1007028 ( Other Identifier: IRAS )
• First Posted: September 21, 2023
• Last Update Posted: March 13, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual de-identified patient data that underlie the results reported will be shared with researchers whose proposed use of the data is approved by a review committee of the Sponsor.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: All requests made within 5 years from the end of trial will be considered; requests made subsequently will be considered where possible.
• Access Criteria: When a request has been approved, Cancer Research UK will provide access to the de-identified individual patient-level data and appropriate supporting information. A signed Data Sharing Agreement must be in place before accessing requested information. Requests should be submitted to drugdev@cancer.org.uk.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cancer Research UK:

Neoplasms; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Antigens, CD19

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases