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

• Sponsor: Autolus Limited (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03287804
• Collaborator: (none)
• Enrollment: 12
• Locations: 4
• Arm: 1
• Actual Duration (Months): 28
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Biological: AUTO2	Phase 1/Phase 2

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 5, 2017
• Actual Primary Completion Date: Sep 5, 2019
• Actual Study Completion Date: Sep 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AUTO2 Relapsed or refractory Myeloma patients	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

Outcome Measures

Primary Outcome Measures

1. Phase I - Number of Subjects With Grade 3 to 5 Toxicity During the Dose Limiting Toxicity (DLT) Period [Up to 28 days post-infusion]

2. Phase I - Number of Subjects With a Dose Limiting Toxicity (DLT) [Up to 28 days post-infusion]

   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.

3. Number of Infused Patients With Best Overall Response [Up to 2 years]

   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

Secondary Outcome Measures

1. Proportion of Patients for Whom an AUTO2 Product Can be Generated [Up to 2 years]

   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).

2. Clinical Benefit Rate [Up to 2 years]

   Number of subjects exhibiting stringent complete response, complete response, very good partial response, partial response or minor response following treatment with AUTO2

3. Duration of Response [Up to 2 years]

   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.

4. Time to Disease Progression [Up to 2 years]

   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.

5. Progression-free Survival [Up to 2 years]

   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

6. Overall Survival [Up to 2 years]

   Descriptive analysis based on number of patients alive at database lock (1-May-2020).

7. Number of Patients With Expansion Followed by Persistence of RQR8/APRIL CAR Positive T Cells in the Peripheral Blood [Up to 2 years]

   Expansion and persistence of RQR8/APRIL CAR positive T cells as determined by quantitative polymerase chain reaction and/or flow cytometry.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 10⁹/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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VU University Medical Centre Amsterdam	Amsterdam		Netherlands
2	University College London Hospitals NHS Foundation Trust	London		United Kingdom
3	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
4	Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne		United Kingdom

Sponsors and Collaborators

• Autolus Limited

Investigators

• Study Director: Autolus Limited, Sponsor GmbH

Study Documents (Full-Text)

• Study Protocol - Jun 27, 2018
• Statistical Analysis Plan - Apr 21, 2020

More Information

Publications

None provided.

• Responsible Party: Autolus Limited
• ClinicalTrials.gov Identifier: NCT03287804
• Other Study ID Numbers: AUTO2-MM1; 2016-003893-42
• First Posted: Sep 19, 2017
• Last Update Posted: Oct 23, 2020
• Last Verified: Sep 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Autolus Limited: Multiple Myeloma; Relapsed Multiple Myeloma; Refractory Multiple Myeloma; AUTO2
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Recruitment Details	Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients were treated with doses from 15 x 10⁶ to 350 x 10⁶ APRIL CAR T Cells.
Pre-assignment Detail	Screening procedures were performed up to 12 weeks before study treatment administered

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Period Title: Overall Study
STARTED	12
Leukaperesed	12
Started Pre-conditioning Therapy	11
Received Study Treatment	11
COMPLETED	1
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	9 75%
>=65 years	3 25%
Sex: Female, Male (Count of Participants)
Female	3 25%
Male	9 75%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	12 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 16.7%
White	10 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Netherlands	1 8.3%
United Kingdom	11 91.7%

Outcome Measures

1. Primary Outcome

Title	Phase I - Number of Subjects With Grade 3 to 5 Toxicity During the Dose Limiting Toxicity (DLT) Period
Time Frame	Up to 28 days post-infusion

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 dose (complete or partial) of AUTO2 therapy (infused set)

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients
Measure Participants	11
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Phase I - Number of Subjects With a Dose Limiting Toxicity (DLT)
Description	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.
Time Frame	Up to 28 days post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Measure Participants	11
Count of Participants [Participants]	0 0%

3. Primary Outcome

Title	Number of Infused Patients With Best Overall Response
Description	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
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose (complete or partial) of AUTO2 therapy in Phase I of the study were included in this analysis. No patients were enrolled in Phase II as the study was early terminated in Phase I. 2 patients were retreated; their best overall response is presented for this endpoint

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Measure Participants	11
Count of Participants [Participants]	4 33.3%

4. Secondary Outcome

Title	Proportion of Patients for Whom an AUTO2 Product Can be Generated
Description	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).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients
Measure Participants	12
Count of Participants [Participants]	12 100%

5. Secondary Outcome

Title	Clinical Benefit Rate
Description	Number of subjects exhibiting stringent complete response, complete response, very good partial response, partial response or minor response following treatment with AUTO2
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose (complete or partial) of AUTO2 therapy in Phase I of the study were included in this analysis. 2 patients were retreated; their best overall response is presented for this endpoint

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Measure Participants	11
Count of Participants [Participants]	4 33.3%

6. Secondary Outcome

Title	Duration of Response
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Analysis was not performed due to not enough patients who had a response (VGPR, PR) to justify the duration of response. The study was terminated early and Phase 2 was not started.

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Measure Participants	0

7. Secondary Outcome

Title	Time to Disease Progression
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Analysis was not performed due to not enough patients who had a response (VGPR, PR) to justify the time to disease progression. The study was terminated early and Phase 2 was not started.

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Measure Participants	0

8. Secondary Outcome

Title	Progression-free Survival
Description	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
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Analysis was not performed due to not enough patients who had a response (VGPR, PR) to justify the progression-free survival. The study was terminated early and Phase 2 was not started.

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Measure Participants	0

9. Secondary Outcome

Title	Overall Survival
Description	Descriptive analysis based on number of patients alive at database lock (1-May-2020).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All patients who receive at least 1 dose (complete or partial dose) of AUTO2 therapy

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients.
Measure Participants	11
Count of Participants [Participants]	3 25%

10. Secondary Outcome

Title	Number of Patients With Expansion Followed by Persistence of RQR8/APRIL CAR Positive T Cells in the Peripheral Blood
Description	Expansion and persistence of RQR8/APRIL CAR positive T cells as determined by quantitative polymerase chain reaction and/or flow cytometry.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients
Measure Participants	11
Count of Participants [Participants]	9 75%

Adverse Events

Time Frame	From Day 0 until Day 60 post last AUTO2 infusion.
Arm/Group Title	AUTO2
Arm/Group Description	Relapsed or refractory myeloma patients
All Cause Mortality
	AUTO2
	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)
Serious Adverse Events
	AUTO2
	Affected / at Risk (%)	# Events
Total	6/11 (54.5%)
Cardiac disorders
Acute myocardial infarction	1/11 (9.1%)	1
General disorders
Pyrexia	2/11 (18.2%)	5
Infections and infestations
Lung infection	1/11 (9.1%)	1
Investigations
Neutrophil count decreased	1/11 (9.1%)	1
Metabolism and nutrition disorders
Hypocalcaemia	1/11 (9.1%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metaplastic breast carcinoma	1/11 (9.1%)	1
Nervous system disorders
Hedache	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	AUTO2
	Affected / at Risk (%)	# Events
Total	11/11 (100%)
Blood and lymphatic system disorders
Anaemia	9/11 (81.8%)	31
Febrile neutropenia	1/11 (9.1%)	1
Neutropenia	3/11 (27.3%)	29
Thrombocytopenia	2/11 (18.2%)	7
Ear and labyrinth disorders
Ear disorder	1/11 (9.1%)	1
Gastrointestinal disorders
Constipation	2/11 (18.2%)	3
Diarrhoea	5/11 (45.5%)	6
Dry mouth	1/11 (9.1%)	1
Haematochezia	1/11 (9.1%)	1
Nausea	2/11 (18.2%)	3
Stomatitis	3/11 (27.3%)	3
General disorders
Catheter site bruise	1/11 (9.1%)	1
Chills	4/11 (36.4%)	4
Fatigue	6/11 (54.5%)	10
Oedema peripheral	3/11 (27.3%)	4
Pyrexia	6/11 (54.5%)	8
Immune system disorders
Haemophagocytic lymphohistiocytosis	1/11 (9.1%)	1
Infections and infestations
Enterovirus infection	1/11 (9.1%)	1
External ear cellulitis	1/11 (9.1%)	1
Metapneumovirus infection	1/11 (9.1%)	2
Parvovirus B19 infection	1/11 (9.1%)	1
Pseudomonal bacteraemia	1/11 (9.1%)	1
Rhinovirus infection	1/11 (9.1%)	1
Upper respiratory tract infection	2/11 (18.2%)	2
Urinary tract infection enterococcal	1/11 (9.1%)	1
Investigations
ALT increased	1/11 (9.1%)	1
AST increased	1/11 (9.1%)	1
Blood ALP increased	1/11 (9.1%)	1
Blood creatinine phosphokinase increased	1/11 (9.1%)	1
Gamma-glutamyltransferase increased	1/11 (9.1%)	2
Neutrophil count decreased	7/11 (63.6%)	71
Platelet count decreased	2/11 (18.2%)	12
Respiratory syncytial virus test positive	1/11 (9.1%)	1
Serum ferritin increased	1/11 (9.1%)	3
Metabolism and nutrition disorders
Decreased appetite	1/11 (9.1%)	1
Dehydration	1/11 (9.1%)	1
Fluid overload	1/11 (9.1%)	1
Hypophosphataemia	1/11 (9.1%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	3/11 (27.3%)	6
Back pain	1/11 (9.1%)	1
Bone pain	4/11 (36.4%)	6
Muscular weakness	1/11 (9.1%)	1
Musculoskeletal chest pain	2/11 (18.2%)	2
Musculoskeletal discomfort	1/11 (9.1%)	1
Myalgia	3/11 (27.3%)	3
Pain in extremity	1/11 (9.1%)	1
Nervous system disorders
Dizziness	1/11 (9.1%)	1
Dysgeusia	1/11 (9.1%)	1
Headache	3/11 (27.3%)	6
Paraesthesia	2/11 (18.2%)	2
Tension headache	1/11 (9.1%)	1
Psychiatric disorders
Hallucination	1/11 (9.1%)	1
Renal and urinary disorders
Micturition urgency	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/11 (18.2%)	2
Dyspnoea	4/11 (36.4%)	5
Epistaxis	1/11 (9.1%)	2
Oropharyngeal pain	3/11 (27.3%)	3
Tachypnoea	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/11 (9.1%)	1
Pruritus	1/11 (9.1%)	1
Rash	2/11 (18.2%)	2
Vascular disorders
Haematoma	2/11 (18.2%)	2
Hypotension	1/11 (9.1%)	1

Limitations/Caveats

Early termination leading to small numbers of patients analyzed

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.