APRIL CAR T Cells (AUTO2) Targeting BCMA and TACI for the Treatment of Multiple Myeloma

Multiple Myeloma Clinical Trial

— APRIL  

Official title:

A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO2, a CAR T Cell Treatment Targeting BCMA and TACI, in Patients With Relapsed or Refractory Multiple Myeloma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03287804
• Other study ID #: AUTO2-MM1
• Secondary ID: 2016-003893-42
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: May 5, 2017
• Est. completion date: September 5, 2019

Study information

• Verified date: September 2020
• Source: Autolus Limited
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to test the safety and efficacy of AUTO2, a CAR T Cell Treatment Targeting BCMA and TACI, in Patients with Relapsed or Refractory Multiple Myeloma.

Description:

The study will consist of 2 phases, a Phase I/dose escalation phase and a Phase II/expansion phase. Patients with relapsed and relapsed or refractory multiple myeloma will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis in order to harvest T cells, which is the starting material for the manufacture of the autologous CAR T product AUTO2. AUTO2 has a dual target BCMA (B cell maturation antigen) and TACI (Transmembrane activator and calcium modulator and cyclophilin ligand interactor). Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO2 intravenously as a single or split dose and will then enter a 12-month follow-up period.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 12
• Est. completion date: September 5, 2019
• Est. primary completion date: September 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

1. Male or female patients, aged = 18.

2. Willing and able to give written, informed consent.

3. Confirmed diagnosis of MM.

4. Measurable disease as defined by IMWG.

5. Relapse or refractory disease and have had at least 3 different prior lines of therapy including proteasome inhibitor, alkylator and immunomodulatory therapy (IMiD), or have "double refractory" disease to a proteasome inhibitor and IMiD.

6. For females of childbearing potential, a negative serum or urine pregnancy test must be documented at screening and confirmed before receiving study treatment.

7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.

8. Peripheral blood total lymphocyte count > 0.5 x 10?/L.

Key Exclusion Criteria:

1. Women who are pregnant or lactating.

2. Prior treatment with investigational or approved gene therapy or cell therapy products.

3. Patient has previously received an allogenic stem cell transplant.

4. Clinically significant, uncontrolled heart disease or a recent (within 6 months) cardiac event.

5. Left Ventricular Ejection fraction < 50 unless the institutional lower limit of normal is lower.

6. Significant liver disease: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = 3 × ULN, or total bilirubin > 2.0 mg/dL or evidence of end stage liver disease (e.g. ascites, hepatic encephalopathy).

7. Chronic renal impairment requiring dialysis, or calculated creatinine clearance < 30 mL/min

8. Active infectious bacterial or viral disease (hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human T-lymphotropic virus or syphilis) requiring treatmenUse of rituximab within the last 3 months.

9. Active autoimmune disease requiring immunosuppression.

10. Received any anti-myeloma therapy within the last 21 days prior to preconditioning or 10 days prior to leukapheresis; steroids of up to 160 mg of dexamethasone are permitted so long as > 7 days post-dose prior to pre-conditioning or leukapheresis.

11. Known allergy to albumin, dimethyl sulfoxide (DMSO), cyclophosphamide or fludarabine.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Biological:
• AUTO2
AUTO2 (APRIL CAR T Cells) Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with doses from 15 x 106 to 350 x 106 APRIL CAR T Cells. Following Phase 2 dose determination patients will be treated with selected dose of APRIL CAR T Cells

Locations

Country	Name	City	State
Netherlands	VU University Medical Centre Amsterdam	Amsterdam
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne

Sponsors (1)

Lead Sponsor	Collaborator
Autolus Limited

Countries where clinical trial is conducted

Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase I - Number of Subjects With Grade 3 to 5 Toxicity During the Dose Limiting Toxicity (DLT) Period		Up to 28 days post-infusion
Primary	Phase I - Number of Subjects With a Dose Limiting Toxicity (DLT)	Dose limiting toxicity was defined as: Any new non-hematological AE of Grade 3 or higher toxicity using the NCI CTCAE (Version 4.03), which is probably or definitely related to AUTO2 therapy, which occurs within the DLT evaluation period, and which fails to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; A Grade 4 CRS; Any other reason for activation of the safety switch after receiving AUTO2; Any other fatal event (Grade 5) or life-threatening event (Grade 4) that cannot be managed with conventional supportive measures or which in the opinion of the SEC necessitates dose reduction or other modification to trial treatment to avoid a similar hazard in future patients. Effort should be made to perform an autopsy in case of fatal event where the aetiology is unclear; Any event that in the opinion of treating investigators and/or Medical Monitor puts the patient at undue risk may also be considered a DLT.	Up to 28 days post-infusion
Primary	Number of Infused Patients With Best Overall Response	Best overall response was defined as stringent complete response + complete response + very good partial response + partial response following treatment with AUTO2. Response Criteria Per IMWG Consensus Recommendations	Up to 2 years
Secondary	Proportion of Patients for Whom an AUTO2 Product Can be Generated	Feasibility of product generation was examined by assessing the number of AUTO2 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients registered).	Up to 2 years
Secondary	Clinical Benefit Rate	Number of subjects exhibiting stringent complete response, complete response, very good partial response, partial response or minor response following treatment with AUTO2	Up to 2 years
Secondary	Duration of Response	Calculated from the date of first observation of sCR, CR, VGPR or PR to the date of disease progression, relapse or death, for patients who were considered responders (achieved at least PR). Patients who had not progressed, relapsed or died will be censored at the last adequate disease assessment.	Up to 2 years
Secondary	Time to Disease Progression	Calculated from the date of AUTO2 treatment to the date of progression. Patients who had not progressed, relapsed or died without progression/relapse will be censored at the last adequate disease assessment.	Up to 2 years
Secondary	Progression-free Survival	Calculated from the date of AUTO2 treatment to the date of progression or death. Patients who have not progressed or relapsed was censored at the last adequate disease assessment	Up to 2 years
Secondary	Overall Survival	Descriptive analysis based on number of patients alive at database lock (1-May-2020).	Up to 2 years
Secondary	Number of Patients With Expansion Followed by Persistence of RQR8/APRIL CAR Positive T Cells in the Peripheral Blood	Expansion and persistence of RQR8/APRIL CAR positive T cells as determined by quantitative polymerase chain reaction and/or flow cytometry.	Up to 2 years