E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that progressively disrupt tissue structure and impair function. |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024460 |
E.1.2 | Term | Light chain disease myeloma associated |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This trial is a phase I/IIa study to assess the use of a [90Y]-labelled anti-CD66 as the sole conditioning prior to autologous stem cell transplant conditioning in patients with AL-amyloidosis.
The main objective will be to determine the safety and toxicity associated with the use of the [90Y]-labelled anti-CD66 as measured by CTCAE version 4.0 criteria and stem cell engraftment and hence establish the maximum tolerated radiation dose (MTD) over three infused radiation activity levels. |
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E.2.2 | Secondary objectives of the trial |
In addition the study will allow the assessment of clonal response (as measured by serial FLC assay) and by using established, validated methods of FLOW cytometry to measure the change in malignant plasma cell population. Disease response, cardiac recovery, time to progression and overall survival will also be reviewed, whilst determining the engraftment status of patients. Finally the study will allow the assessment of the dosimetry model previously developed in Phase I and II trials in this patient group.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The main inclusion criteria is patients with systemic AL-amyloidosis with an indication for treatment who satisfy all standard transplant inclusion criteria (good organ function, no significant heart involvement, good performance status).
• Aged ≥18 years. • Have a diagnosis of systemic AL-amyloidosis, either as a new diagnosis or recurrent disease. • Measurable clonal plasma cell dyscrasia. • Amyloid related organ dysfunction or organ syndrome. • Estimated life expectancy of at least 6 months (as defined at trial entry). • Sufficient stem cells for two transplant procedures . • Bone Marrow (BM) cellularity >20%. • Eligible for ASCT in AL amyloidosis defined as fulfilling all of the following criteria : o ECOG Performance Status of 0 or 1 o Cardiac troponin-T <0.07 µg/L o NYHA heart failure class of <3 o No more than 3 organs involved by amyloidosis by consensus guidelines. o Creatinine clearance or isotope GFR ≥30ml/min. o Bilirubin ≤1.5 times and alkaline phosphatase ≤3 x upper limit of normal. o AST or ALT <2.5 x upper limit of normal range. o Mean left ventricular wall thicknesses of <16mm by echocardiography. o Absence of clinically important amyloid related autonomic neuropathy . o Absence of clinically important amyloid related gastro intestinal haemorrhage. • Capable of providing written, informed consent. • Women of child bearing potential should use adequate forms of contraception. o Intrauterine Device (IUD) o Hormonal based contraception (pill, contraceptive injection etc.) o Double Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap with spermicide) o True abstinence
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E.4 | Principal exclusion criteria |
Patients with poor performance, advanced organ involvement or significant cardiac involvement will be excluded from the study.
Patients with the following characteristics are ineligible for this study: • Overt symptomatic multiple myeloma. • Amyloidosis of unknown or non AL type. • Localised AL-amyloidosis (in which amyloid deposits are limited to a typical single organ, for example the bladder or larynx, in association with a clonal proliferative disorder within that organ). • Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome). • NYHA Class III or IV heart failure (appendix 1). • Liver involvement by amyloid causing bilirubin >1.5 times upper limit of normal. • Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas. • Pregnant, lactating or unwilling to use adequate contraception as listed above • Intolerance / sensitivity to any of the study drugs. • Known positive Human anti-murine antibodies (HAMA). • Unable to provide written informed consent • Involved in another IMP trial
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary objective is: Safety and toxicity of using [90Y]-anti-CD66 as the sole conditioning prior to autologous stem cell transplantation for AL-amyloidosis. Primary Outcome measure is: Specific organ toxicity as defined in CTCAE ver 4.0. Overall number of Serious Adverse Events, Serious Unexpected Adverse Events determined as causally related to the radiolabelled anti-CD66. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Disease response as determined by changes in the free light chain assay (FLCa) pre and post [90Y]-labelled anti-CD66 and post transplantation. 2. Clonal plasma cell population as determined by FLOW cytometry pre and post transplantation (D100) 3. NT-proBNP levels pre and post (D100) therapy 4. Assessment of TTP and OS. 5. Comparison of organ dosimetry from previous trials using the same antibody vector. 6. Tablation of platelet and neutrophil engraftment.
HAMA assay results from samples taken at defined intervals post transplantation
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description |
Orchard et al have reported targeting with the anti-CD66 in previous Phase I |
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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 | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | No |
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 |
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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
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Patient recruitment into the trial will end after the last patient reaches the day +100 post transplant time-point. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |