Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Relapsed Multiple Myeloma, Refractory Multiple Myeloma, AUTO2
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.
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.
Interventions
BIOLOGICALAUTO2
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
Sponsors
Autolus Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I - Number of Subjects With Grade 3 to 5 Toxicity During the Dose Limiting Toxicity (DLT) Period | Up to 28 days post-infusion | — |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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). |
| 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. |
| Overall Survival | Up to 2 years | Descriptive analysis based on number of patients alive at database lock (1-May-2020). |
| 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 |
| 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. |
Countries
Netherlands, United Kingdom
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 details
Screening procedures were performed up to 12 weeks before study treatment administered
Participants by arm
| Arm | Count |
|---|---|
| AUTO2 Relapsed or refractory myeloma patients | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Progressive disease | 8 |
Baseline characteristics
| Characteristic | AUTO2 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment Netherlands | 1 participants |
| Region of Enrollment United Kingdom | 11 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 6 / 11 |
Outcome results
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
Time frame: Up to 2 years
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUTO2 | Number of Infused Patients With Best Overall Response | 4 Participants |
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.
Time frame: Up to 28 days post-infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUTO2 | Phase I - Number of Subjects With a Dose Limiting Toxicity (DLT) | 0 Participants |
Primary
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
Population: Patients who received at least 1 dose (complete or partial) of AUTO2 therapy (infused set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUTO2 | Phase I - Number of Subjects With Grade 3 to 5 Toxicity During the Dose Limiting Toxicity (DLT) Period | 0 Participants |
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
Time frame: Up to 2 years
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUTO2 | Clinical Benefit Rate | 4 Participants |
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.
Time frame: Up to 2 years
Population: 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.
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.
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUTO2 | Number of Patients With Expansion Followed by Persistence of RQR8/APRIL CAR Positive T Cells in the Peripheral Blood | 9 Participants |
Secondary
Overall Survival
Descriptive analysis based on number of patients alive at database lock (1-May-2020).
Time frame: Up to 2 years
Population: All patients who receive at least 1 dose (complete or partial dose) of AUTO2 therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUTO2 | Overall Survival | 3 Participants |
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
Time frame: Up to 2 years
Population: 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.
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).
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUTO2 | Proportion of Patients for Whom an AUTO2 Product Can be Generated | 12 Participants |
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.
Time frame: Up to 2 years
Population: 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.