| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Myeloma (MM) is a cancer from plasma cells, a type of white blood cell, made in the bone marrow. In MM, the plasma cells are abnormal, multiply, release paraprotein that affects immunity. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1: Assess the safety and tolerability of AUTO2, establish the recommended Phase II dose & maximum tolerated dose, where applicable.
Phase 2: To evaluate the anti-tumour effect, safety and tolerability of AUTO2.
|
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate the feasibility of generating the ATIMP
- Evaluate the clinical efficacy of AUTO2
- Assess biomarker and pharmacodynamics effects of AUTO2
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients, aged ≥ 18.
2. Willing and able to give written, informed consent for the current study protocol AUTO2-MM1.
3. Confirmed diagnosis of MM.
4. Measurable disease as defined by any 1 of the following:
- Serum M-protein ≥ 500 mg/dL;
- Urine M-protein ≥ 200 mg/24 hours;
- Involved serum free light chain level ≥ 10 mg/dL, provided serum free light chain ratio is abnormal.
5.Relapsed or refractory disease after either one of the following:
a. Relapse or refractory disease and have had at least 3 different prior lines of therapy including proteasome inhibitor (e.g. bortezomib or carfilzomib) and immunomodulatory therapy (IMiD; e.g. thalidomide, lenalidomide or pomalidomide) and alkylator or monoclonal antibody.
or
b. have "double refractory" disease to a proteasome inhibitor and IMiD, defined as progression on or within 60 days of receiving these agents.
6. For females of childbearing potential (defined as < 2 years after last menstruation or not surgically sterile), a negative serum or urine pregnancy test must be documented at screening, prior to pre-conditioning and confirmed before receiving the first dose of study treatment.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.
8. Peripheral blood total lymphocyte count > 0.5 x 10e9/L at enrolment and prior to leukapheresis |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or lactating.
2. Prior treatment with investigational or approved gene therapy or cell therapy products.
3. Clinically significant, uncontrolled heart disease (New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, sick-sinus syndrome, or electrocardiographic evidence of acute ischaemia or Grade 3 conduction system abnormalities unless the patient has a pacemaker) or a recent (within 6 months) cardiac event.
4. Left Ventricular Ejection fraction < 50 (by ECHO or MUGA) unless the institutional lower limit of normal is lower.
5. Patients with a history or evidence of deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of pre-conditioning.
6. Patients with any major surgical intervention in the last 3 months, cement augmentation for vertebral collapse is permitted.
7. Significant liver disease: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × ULN, or total bilirubin ≥25 μmol/L (1.5 mg/dL), except in patients with Gilbert’s syndrome or evidence of end stage liver disease (e.g. ascites, hepatic encephalopathy).
8. Chronic renal impairment requiring dialysis, or calculated creatinine clearance < 30 mL/min.
9. Active infectious bacterial or viral disease (hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human T-lymphotropic virus or syphilis) requiring treatment.
10. Use of rituximab (or rituximab biosimilars) within the last 3 months prior to AUTO2 infusion.
11. Active autoimmune disease requiring immunosuppression.
12. Received any anti-myeloma therapy within the last 7 days prior to pre-conditioning or leukapheresis. Growth factors should stop 10 days prior to leukapheresis.
13. Received any radiotherapy within the last 7 days prior to pre-conditioning or leukapheresis. Localised radiation to a single site, e.g. for bone pain is permitted at any time.
14. Life expectancy < 3 months.
15. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: Incidence of Grade 3-5 toxicity occurring within the dose-limiting toxicity (DLT) period (28 days post AUTO2 infusion).
Frequency of DLT and the persistence of AUTO2.
Phase 2: Best overall response post-AUTO2 infusion.
Frequency and severity of AEs and SAEs.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1: 28 days post AUTO2 infusion and 24 months post-AUTO2 administration of the last patient.
Phase 2: From patient dosing up to 26 months post-AUTO2 administration of the last patient unless in the event of death or early withdraw, which would default to the preceding patient's completion timepoint. |
|
| E.5.2 | Secondary end point(s) |
Proportion of patients for whom an AUTO2 product can be generated (feasibility).
•Determine the clinical benefit (stringent complete response + complete response + very good partial response + partial response + minor response [sCR+CR+VGPR+PR+MR ]) rate following treatment with AUTO2.
•To evaluate clinical outcomes including duration of response, time to disease progression, PFS and OS.
Quantitative PCR (qPCR) and/or flow cytometry at a range of time points in the peripheral blood .
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From patient dosing up to 24 months following AUTO2 infusion, or in the event of an earlier outcome on the last patient entered onto the study. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial will be the last patient, last vist (12 months after AUTO2 infusion) or earlier if due to earlier withdrawal or death of the the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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