RADIOIMMUNOCONJUGATE FOR USE IN TREATING BONE MARROW ASSOCIATED DISEASES
20220401594 · 2022-12-22
Assignee
Inventors
Cpc classification
A61K51/1048
HUMAN NECESSITIES
A61K51/1027
HUMAN NECESSITIES
A61P37/06
HUMAN NECESSITIES
A61P7/00
HUMAN NECESSITIES
A61K51/1096
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
International classification
A61K51/10
HUMAN NECESSITIES
Abstract
The present invention relates to the use of radioimmunoconjugates for the treatment of bone marrow associated diseases, particularly AL-amyloidosis.
Claims
1. A method of bone-marrow conditioning in a patient, comprising administering to the patient a radioimmunoconjugate (RIC), wherein the RIC comprises a CD66-binding component and a radionuclide and wherein the method is optionally performed preceding a stem cell transplantation.
2. A method of treating bone marrow-associated diseases in a patient, comprising administering to the patient a radioimmunoconjugate (RIC), wherein the RIC comprises a CD66-binding component and a radionuclide, and wherein optionally the bone marrow-associated diseases comprise AL-amyloidosis.
3. The method according to claim 1, wherein the radionuclide is a therapeutically effective radionuclide.
4. The method according to claim 3, wherein the therapeutically effective radionuclide is yttrium-90 (.sup.90Y).
5. The method according to claim 2, wherein the radionuclide is an imaging radionuclide.
6. The method according to claim 5, wherein the imaging radionuclide is indium-111 (.sup.111In).
7. The method according to claim 5 for determining a therapeutically effective dose of a therapeutic RIC prior to its administration.
8. The method according to claim 7, wherein the CD66-binding component of the imaging RIC and the therapeutic RIC is identical.
9. The method according to claim 7, wherein the determination comprises a calculation based on collected patient data.
10. The method according to claim 1, wherein the CD66-binding component is an antibody.
11. The method according to claim 10, wherein the antibody is BW 250/183.
12. The method according to claim 1, wherein the radionuclide is linked to the CD66-binding component via a chelating agent.
13. The method according to claim 12, wherein the chelating agent is covalently linked to the CD66-binding component.
14. The method according to claim 12, wherein the radionuclide is linked to the CD66-binding component via a structure of the formula
[(chelating agent)-(R.sup.1).sub.p—(R.sup.2—R.sup.3).sub.n].sub.m-(CD66-binding component) wherein n is 0 or 1, m is 1 to 15, p is 0 or 1, R.sup.1 and R.sup.3 are independently selected from the group consisting of —NHCSNH—, —NHCONH—, —NHCOCH.sub.2S—, —S—S—, —NH—NH—, —NH—, —S—, —CONHNH—, —SCH.sub.2CH.sub.2COONH—, —SCH.sub.2CH.sub.2SO.sub.2—, —SCH.sub.2CH.sub.2SO.sub.2NH—, —CONH—, —O—CH.sub.2CH.sub.2O—, —CO—, —COO—, —NH—O—, —CONHO—, —S—(CH.sub.2).sub.3C(NH)NH—, —NH—COO—, —O— and ##STR00004## R.sup.2 is selected from the group consisting of C1-C18 alkylene, branched C1-C18, —CH.sub.2—C.sub.6H.sub.10—, p-alkylphenylene, p-phenylene, m-phenylene, p-alkyloxyphenylene, naphthylene, —[CH.sub.2CH.sub.2O].sub.x—, —[CH.sub.2CH.sub.2SOCH.sub.2CH.sub.2].sub.x—, —[CH.sub.2CH.sub.2SO.sub.2CH.sub.2CH.sub.2].sub.x—, or —[NHCHR.sub.4CO].sub.y—, wherein x is 1 to 200, y is 1 to 20, and wherein R.sub.4 is selected from the group consisting of H—, Me-, HSCH.sub.2—, isopropyl, but-2-yl, CH.sub.3SCH.sub.2CH.sub.2—, benzyl, 1H-indol-3-yl-methyl, HOCH.sub.2—, HOOCCH.sub.2—, CH.sub.3CH(OH)—, HOOCCH.sub.2CH.sub.2—, 4-hydroxybenzyl, H.sub.2NCOCH.sub.2—, H.sub.2NCOCH.sub.2CH.sub.2—, 4-aminobut-1-yl, 2-guanidinoethyl, 1H-imidazol-5-yl-methyl and 2-methylprop-1-yl.
15. The method according to claim 12, wherein the chelating agent is selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA), 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetic acid (TETA), 1,4,7-triazonane-N,N′,N″-triacetic acid (NOTA), 2,2′-(2-(((1S,2S)-2-(bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid (cyclohexano-DTPA), 2,2′-(2-(((1R,2R)-2-(bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2′-(2-(((1S,2R)-2-(bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2′-(2-(((1R,2S)-2-(bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2′,2″,2′″-(2,2′-(1S,2S)-cyclohexane-1,2-diylbis((carboxymethyl)azanediyl)bis(ethane-2,1-diyl))bis(azanetriyl)tetraacetic acid, 2,2′,2″,2′″-(2,2′-(1 S,2R)-cyclohexane-1,2-diylbis((carboxymethyl)azanediyl)bis(ethane-2,1-diyl))bis(azanetriyl)tetraacetic acid, (1R)-1-benzyl-diethylenetriaminepentaacetic acid, (1S)-1-benzyl-diethylenetriaminepentaacetic acid, (2R)-2-benzyl-diethylenetriaminepentaacetic acid, (2S)-2-benzyl-diethylenetriaminepentaacetic acid, (2R)-2-benzyl-(3R)-3-methyl-DTPA, (2R)-2-benzyl-(3S)-3-methyl-DTPA, (2S)-2-benzyl-(3S)-3-methyl-DTPA, (2S)-2-benzyl-(3R)-3-methyl-DTPA, (2R)-2-benzyl-(4R)-4-methyl-DTPA, (2R)-2-benzyl-(4S)-4-methyl-DTPA, (2S)-2-benzyl-(4S)-4-methyl-DTPA, (2S)-2-benzyl-(4R)-4-methyl-DTPA, (1R)-1-benzyl-(3R)-3-methyl-DTPA, (1R)-1-benzyl-(3S)-3-methyl-DTPA, (1S)-1-benzyl-(3S)-3-methyl-DTPA, (1S)-1-benzyl-(3R)-3-methyl-DTPA, (1R)-1-benzyl-(4R)-4-methyl-DTPA, (1R)-1-benzyl-(4S)-4-methyl-DTPA, (1S)-1-benzyl-(4S)-4-methyl-DTPA, (1S)-1-benzyl-(4R)-4-methyl-DTPA, 2,2′-((1R,2R)-2-(((R)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2′-((1S,2S)-2-(((S)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2′-((1R,2R)-2-(((S)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2′-((1S,2S)-2-(((R)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2′-((1R,2S)-2-(((R)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2′-((1S,2R)-2-(((S)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2′-((1 S,2R)-2-(((R)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2′-((1R,2S)-2-(((S)-2-(bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, (2S)-2-benzyl-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid, (2R)-2-benzyl-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid, 6-benzyl-1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetic acid, 2-benzyl-1,4,7-triazonane-N,N′,N″-triacetic acid, benzyl-3-methyl-diethylenetriaminepentaacetic acid (2B3M-DTPA), (R)-2-amino-3-(phenyl)propyl)trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid) (Bn-CHX-A″-DTPA) and salts and derivatives thereof.
16. The method according to claim 1, wherein the radionuclide is linked to the CD66-binding component via the structure CD66-binding component-NH—CS—NH-Bn-CHX-A″-DTPA.
17. The method according to claim 1, wherein a therapeutic RIC is administered at a dose of ≥about 10 MBq/kg lean body weight (lbw), ≥about 15 MBq/kg lbw, ≥about 20 MBq/kg lbw, ≥about 25 MBq/kg lbw, ≥about 30 MBq/kg lbw, ≥about 35 MBq/kg lbw, up to 60 MBq/kg lbw or up to 45 MBq/kg lbw.
18. The method according to claim 2, further comprising stem cell transplantation, wherein the stem cell transplantation comprises autologous or allogeneic stem cell transplantation.
19. The method according to claim 2, wherein the therapeutic RIC is for administration 6-16 days or 6-12 days, before stem cell transplantation.
20. The method according to claim 2, wherein the treating of bone marrow associated diseases does not involve administering an additional anti-tumor agent or an immunosuppressive agent at least four weeks before and/or after stem cell transplantation.
21. The method according to claim 1, wherein the patient was treated with high-dose melphalan followed by stem cell transplantation but had disease progression.
22. The method according to claim 1, wherein the patient was treated with induction therapy but had disease progression or had a haematological response.
23. The method according to claim 1, wherein the patient is ineligible for treatment with HD-melphalan preceding HSCT.
24. The method according to claim 1, wherein the patient is eligible for HSCT.
25. The method according to claim 2, wherein the treating of bone marrow associated diseases comprises the steps of: (a) optionally administering an imaging RIC to a patient 2-10 days before step (b), (b) administering a therapeutic RIC to the patient 6-16 days prior to step (c), and (c) transplanting autologous or allogeneic stem cells.
26. The method according to claim 2, wherein the bone marrow-associated diseases comprise AL-amyloidosis and wherein treating the AL-amyloidosis comprises the steps of: (i) optionally administering an imaging RIC of the antibody BW 250/183 with .sup.111In to a patient 2-10 days before step (ii), (ii) administering a therapeutic RIC of the antibody BW 250/183 with .sup.90Y to the patient 6-16 days prior to step (iii), and (iii) transplanting autologous or allogeneic stem cells.
27. The method according to claim 1, wherein the bone marrow conditioning comprises immunoablation to prevent graft rejection and/or reducing a number of defective cells in the bone marrow.
28. The method according to claim 1, wherein the stem cell transplantation is autologous or allogeneic.
29. A radioimmunoconjugate (RIC) according to the following structure ##STR00005## (CD66-binding component-NH—CS—NH-Bn-CHX-A″-DTPA) and salts thereof.
Description
FIGURES
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EXAMPLES
Material
CD66-Binding Component
Molecular Weight and Formula
[0091] The murine IgG1 kappa monoclonal antibody anti-CD66 BW 250/183 is monomeric with a molecular weight (MW) of 150 kDa protein and composed of IgG heavy and light chains of the expected MW (approx. 50 and 25 kDa, respectively). The antibody is also known as the below:
[0092] INN Name: Besilesomab
[0093] Chemical name: monoclonal antibody BW 250/183
[0094] Laboratory Code Name: MAb BW 250/183
[0095] CAS Registry Number: 537694-98-7
Chelator
NCS—CHX-A″-DTPA Chelator
[0096] The synthetic bifunctional chelate used for the covalent conjugation event on the antibody is synthesized by Macrocyclics (1309 Record Crossing, Dallas, Tex. 75235, USA). The IUPAC name is 2,2′-(2-(((S)-1-(bis(carboxymethyl)amino)-3-(4-isothiocyanatophenyl)propan-2yl) (carboxy-methyl)amino)propylazanediyl)diacetic acid, also known as isothiocyanato-(R)-2-amino-3-(phenyl)propyl)trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid) (abbreviated to ITC-CHX-A″-DTPA or ITC-Bn-CHX-A″-DTPA). The low MW chelate (MW: 704 Da) has the following chemical formula C.sub.26H.sub.34N.sub.4O.sub.10S.3HCl and is presented as a solid off-white powder.
##STR00003##
Preparation of the Radioimmunoconjugate
[0097] The batch size for the CHX-A″-DTPA-anti-CD66 Drug Substance Batch No. AB012 was 122 ml (355 mg), corresponding to 152 ml working volume (426 mg) of the starting monoclonal antibody preparation anti-CD66 Mab 250/183 (Orpegen Pharma GmbH or Glycotope Biotechnology GmbH, Germany or Celonic, Germany). The batch size for the CHX-A″-DTPA-anti-CD66 Drug Substance Batch No. AB013 was 250 ml (775 mg), corresponding to 376 ml working volume (1051 mg) of the starting monoclonal antibody preparation anti-CD66 Mab 250/183 (Orpegen Pharma GmbH).
[0098] The manufacturing process and in-process controls conducted are outlined in
a) Thawing Out of Materials
[0099] The first step in the process is the thawing out of the specific number of vials of anti-CD66 Mab specified in the batch record. The Mab is thawed at room temperature in a laminar flow hood (LFH) before combining the vials into a single sterile Falcon tube. An in-process QC sample is taken for size exclusion analysis to confirm that the Mab is predominantly monomeric and the results are reported.
[0100] The chelator ITC-CHX-A″-DTPA is removed from the freezer and allowed to warm to ambient temperature for a minimum of 1 hour at room temperature.
b) Crossflow Ultrafiltration of Mab—Diafiltration into 0.1M Sodium Carbonate pH 9.0 Solution
[0101] The major processing step for the production of the Drug Substance process is the crossflow ultrafiltration/diafiltration (UF/DF) step. These cartridges are disposable, single use and available in a number of different molecular weight cut-offs for processing (Spectrum Laboratories, USA). The cartridge and UF/DF apparatus are pre-conditioned to remove glycerol as recommended by the manufacturer before sterilizing using a validated autoclaving cycle prior to use. In general, the UF/DF step is performed to filter, diafilter (buffer exchange) and concentrate the product throughout to predetermined specifications. The 50 kDa MW cut-off hollow fiber cartridge is operated within defined operating parameters (such as transmembrane pressures, velocity in a low shear manner) that allow the retention of the Mab, whilst allowing salts and other low molecular weight impurities to pass through. The cartridge and assembly is a closed process, which is operated within a grade A laminar flow hood in a grade B clean room background.
[0102] Before processing, a 1:10 vol:vol of 0.01M DTPA solution is added to the Mab solution in the LFH (i.e 1 ml of DTPA per 10 ml of Mab). The Mab is mixed gently and incubated at room temperature for 30 minutes. The Mab solution is introduced into the hollow fiber crossflow assembly in the LFH before the Mab is diafiltered with a minimum of 5 volumes of 0.1M Sodium Carbonate pH 9.0 until the pH is within the acceptable range. In-process QC samples are taken to confirm that the pH is within the 8.9-9.2 pH range required for conjugation. The Mab is recovered from the hollow fiber cartridge into a sterile Falcon tube. An in-process QC sample is taken to monitor the concentration of the Mab by OD 280 nm.
c) Conjugation of Mab with Chelate
[0103] The amount of ITC-CHX-A″-DTPA chelator required is calculated as follows—1 mg for every 5 mg of Mab to be conjugated. The chelator is carefully weighed into a sterile container before dissolving in DMSO (dissolve 1 mg of chelator per 20 μl of DMSO). The ITC-CHX-A″-DTPA chelator is added carefully by steady mixing into the Mab (a small volume of carbonate buffer is used to wash out any remaining ligand from the container for adding to the Mab). The lid is replaced on the Mab container and the solution is mixed very gently by hand rotation. The tube is labelled and left at room temperature for 2 hours before incubation overnight at +2 to 8° C.
d) Crossflow Ultrafiltration of Mab—Diafiltration/Concentration into Acetate Buffer
[0104] In an LFH, the Mab solution is diafiltered into 0.1M Ammonium acetate solution pH 6 until in-process QC radiolabeling efficiency achieves >97%.
[0105] Once the radiolabeling efficiency is >97%, the Mab is recovered from the hollow fiber crossflow apparatus into a sterile Falcon tube by releasing the transmembrane pressure. An in-process QC sample is taken to determine the Mab concentration by OD 280 nm and, if required, the Mab is further diluted with the acetate buffer to within the acceptable range of 2.5-3.3 mg/ml. The final Mab solution is stored at +2 to 8° C.
e) Sterile Filtration & Filling of Drug Substance into Cryovials
[0106] In an LFH, in a grade B background, the product is filter sterilized using a 0.22 μM filter into a sterile Falcon tube. The filter is integrity tested to ensure that it is within the acceptable bubble point range. In an LFH, in a grade B background, the product is aseptically dispensed into the sterile cryovials using an autoclaved fixed volume pipette. In processing, E.M is performed by the operators to include continuous air particle counts. The vials are closed and labelled in accordance to GMP before storage at less than −70° C.
[0107] The bifunctional chelated CHX-A″-DTPA-anti-CD66 monoclonal antibody remains as a monomeric IgG1 of the expected MW size and composition. The preparation is shown to maintain its specificity against the CD66 antigen by immunoreactivity assay.
[0108] CHX-A″-DTPA-anti-CD66 monoclonal antibody is readily soluble in water and appears as a colorless, clear solution with no visible particles when dissolved in ammonium acetate buffer pH 6.0.
Drug Product
.SUP.111.Indium Labelled CHX-A″-DTPA-Anti CD66 Drug Product
[0109] .sup.111Indium labelled CHX-A″-DTPA-Anti CD66 drug product is manufactured in single dosage units for individual patients. The drug product .sup.111Indium labelled CHX-A″-DTPA-Anti CD66 will be prepared with an excess of .sup.111Indium to a maximum of 300 MBq to allow for residual activity losses during the manufacture and delay prior to infusion. A dose of 185 MBq±10% will be administered to each patient. The volume to be administered will be calculated based on the concentration of radioactivity in the vial. Residual radiolabeled product will be re-measured and reconciled against the original activity to allow accurate recording of actual activity administered to the patient. The flow diagram of the radiolabeling process for .sup.111Indium CHX-A″-DTPA-Anti CD66 drug product is shown in
[0110] .sup.111Indium labelled CHX-A″-DTPA Anti-CD66 drug product is a monoclonal antibody conjugated to a bifunctional chelator, labelled with the radionuclide .sup.111Indium.
[0111] The two components of this radiolabeled antibody conjugate are: [0112] 1) CHX-A″-DTPA-Anti-CD66 Monoclonal antibody (the ‘Drug Substance’) [0113] 2) Radionuclide .sup.111Indium
[0114] The radiolabeling of the monoclonal antibody conjugate is prepared individually for each patient by the radiopharmacy departments at each site, following GMP guidelines, and is supplied as a sterile, pyrogen and particle-free solution for intravenous infusion containing besilesomab (1.0-1.5 mg) diluted to 8.0 ml with 0.9% sodium chloride solution BP, labelled with Indium-111 to give a final radioactive concentration of approximately 23 MBq/ml (acceptable range 20-30 MBq/ml) at the end of synthesis. The volume of each batch of drug product will be approximately 8-10 ml at the end of manufacture. The patient dose will be presented in one 10 mL syringe.
[0115] Alternatively, radiolabeling of the monoclonal antibody conjugate with In111 can be done centrally at a radiopharmaceutical manufacturing site and the Drug Product will be shipped at 4-8° C. to the respective transplantation center that treats the patient.
.SUP.90.Yttrium Labelled CHX-A″-DTPA-Anti CD66 Drug Product
[0116] .sup.90Yttrium labelled CHX-A″-DTPA-Anti CD66 drug product is manufactured in single dosage units for individual patients. The composition of each batch/single dosage unit is presented in
[0117] The radiolabeling of the monoclonal antibody conjugate is prepared individually for each patient by the radiopharmacy departments at each site, following GMP guidelines, and is supplied as a sterile, pyrogen and particle free solution for intravenous infusion containing CHX-A″-DTPA Anti-CD66 (1.0-1.5 mg) diluted to approximately 8.0 ml with 0.9% sodium chloride solution BP, labelled with .sup.90Yttrium to give a final radioactive concentration in the range of 200-500 MBq/ml at the end of synthesis.
[0118] Alternatively, radiolabeling of the monoclonal antibody conjugate with Y90 can be done centrally at a radiopharmaceutical manufacturing site and the Drug Product will be shipped at 4-8° C. to the respective transplantation center that treats the patient.
Absorption Properties
[0119] The radiolabeled .sup.111In anti-CD66 radioimmunoconjugate was administered intravenously in a buffered saline aqueous solution. Sequential gamma camera imaging demonstrates an initial blood phase and uptake by the bone marrow within 4-6 hours of infusion (
Distribution
[0120] The biodistribution in vivo in humans shows consistent uptake by the cellular component of red marrow, typically in the axial skeleton (vertebrae, pelvis), ribs, skull and proximal region of long bones. Gamma images following infusion of [.sup.111In]-anti-CD66 are shown in
Objectives of the Study
[0121] The main objective of the study is to determine the toxicity associated with the use of the [.sup.90Y]-labelled anti-CD66 as the sole conditioning prior to autologous stem cell transplant in patients with AL-amyloidosis. Toxicity determination is measured by CTCAE version 4.0 criteria and stem cell engraftment and establishes the maximum tolerated radiation dose (MTD) over three infused radiation activity levels.
[0122] In addition, the study allows the assessment of clonal response (as measured by serum FLC assay) 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 are also reviewed, whilst determining the engraftment status of patients.
[0123] Finally, the study allows the assessment of the dosimetry model previously developed in phase I and II trials in this patient group.
Outcome Measures/Endpoints
[0124] Toxicity of [.sup.90Y]-labelled anti-CD66 monoclonal antibody as the sole conditioning regime for autologous stem cell transplantation in patients with systemic AL-amyloidosis is determined using CTCAE version 4.0 criteria.
[0125] The clonal response using the [.sup.90Y]-radiolabeled anti-CD66 mAb as targeted radiotherapy is measured by serial FLC assay. Responses will be summarized as recommended in the Consensus Guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis.
[0126] Clonal response to the [.sup.90Y]-radiolabeled anti-CD66 mAb by following the change in malignant plasma cell population in bone marrow is determined using established validated methods of FLOW cytometry.
[0127] Disease response and cardiac recovery are determined by measuring NT-proBNP levels pre and post (D100) therapy.
[0128] Impact of using [.sup.90Y]-labelled anti-CD66 mAb on time to progression and overall survival is assessed.
[0129] The utility of the dosimetry model developed in previous phase I and II trials using the same radiolabeled anti-CD66 and with imaging/dosimetry post .sup.90Y-labelled anti-CD66 is determined.
[0130] The engraftment of autologous stem cells is determined by time to platelet recovery >50×10.sup.9/L and neutrophils >0.5×10.sup.9/L (EBMT criteria).
[0131] The proportion of patients that form human anti-murine antibodies or human anti-mouse immunoglobulin antibodies (HAMA) following exposure to anti-CD66 mAb in the context of an autologous stem cell transplantation for AL amyloidosis is assessed.
Trial Design
[0132] This was an open label, phase Ulla multi-center study, assessing the use of a radiolabeled anti-CD66 in patients with AL-amyloidosis with regard to [0133] 1) Safety and Toxicity [0134] 2) Disease response. Progression from one dose level to the next will be dependent on the toxicity profile demonstrated, but not based on disease response. Patients will be recruited from those attending the National Amyloidosis Centre for diagnosis and monitoring of their disease and in whom high-dose therapy would be a treatment option.
[0135] There are three treatment levels, representing increasing infused radiation activity levels: [0136] 1. 30.0 MBq/kg lean body weight [.sup.90Y]-radio-labelled murine anti-CD66 [0137] 2. 40.0 MBq/kg lean body weight [.sup.90Y]-radio-labelled murine anti-CD66 [0138] 3. 45.0 MBq/kg lean body weight [.sup.90Y]-radio-labelled murine anti-CD66
Toxicity
[0139] Patients will be recruited sequentially and receive treatment according to the dose level active at that time. As a safety factor, a gap equivalent to D+30 post-transplant must have passed before the next patient is treated at the same dose level and D+60 post-transplant between dose level changes (although patients may be recruited and consented before the previous patient reaches D+30 or D+60 post transplantation) assuming that no toxicities are recorded. If no patients show toxicity then a maximum of 3 patients will be recruited at that same dose level and the next dose level can start (after the interval equivalent to D+60). If 1 patient develops a defined toxicity, recruitment continues at the same dose level, but to a maximum of 6 patients at the same dose level. If 2 or more patients of the initial three patients treated in the same dose level develop toxicity, the study stops. If on review, the toxicities are determined by the independent data monitoring committee (IDMC) not to be directly due to the radiolabeled antibody, the trial can continue at the same dose level, but expanded to the maximum of 6 patients. If the IDMC determines that the toxicities are related directly to the radiolabeled antibody, the trial stops, the infused radiation activity level is then set as the MTD. After six patients, if more than 2 patients experience toxicities attributed by the IDMC to the radiolabeled antibody, the trial will stop, otherwise it can continue to the next dose level (as outlined above).
[0140] If, in the opinion of the IDMC, there have been no specific toxicities at any infused activity (‘dose’) level, the final infused activity level can be expanded to 6 patients to provide additional information on toxicity and disease response.
Disease Response
[0141] Disease response (change in free light chain (FLC)) will be determined in each patient over the study period. Because of the co-morbid conditions that can affect patients with AL-amyloidosis, it is not appropriate to demonstrate a clear MTD (i.e. by further increases in the infused radiation activity) if good clinical disease responses are achieved as indicated by reduction in the FLC and clonal plasma cell population post therapy and transplant. The optimal infused radiation would produce a CR rate in all patients without demonstrable toxicity. The results from the phase I study will be used to inform the format of further trials (phase II), which would be designed to determine the optimal infused radiation activity and hence estimated bone marrow radiation dose in this specific patient group. If no toxicity is demonstrated at any infused activity level, expansion of the third level to 6 patients will provide additional evidence for disease response.
Patients
[0142] All patients with systemic AL-amyloidosis who meet eligibility criteria for ASCT in amyloidosis and have an indication for autologous stem cell transplantation as the preferred treatment option will be eligible for this study.
Inclusion Criteria
[0143] Patients with the following characteristics are eligible for this study [0144] aged ≥18 years [0145] diagnosis of systemic AL-amyloidosis, either as a new diagnosis or recurrent disease [0146] measurable clonal plasma cell dyscrasia [0147] amyloid-related organ dysfunction or organ syndrome [0148] estimated life expectancy of at least 6 months (as defined at trial entry) [0149] sufficient stem cells for two transplant procedures [0150] Bone Marrow (BM) cellularity >20% [0151] eligible for ASCT in AL amyloidosis defined as fulfilling all of the following criteria: [0152] ECOG Performance Status of 0 or 1 [0153] Cardiac troponin-T<0.07 μg/L [0154] NYHA heart failure class of <3 [0155] no more than 3 organs involved by amyloidosis by consensus guidelines [0156] creatinine clearance or isotope GFR≥30 ml/min [0157] bilirubin ≤1.5 times and alkaline phosphatase ≤3× upper limit of normal [0158] AST or ALT<2.5× upper limit of normal range [0159] mean left ventricular wall thicknesses of <16 mm by echocardiography [0160] absence of clinically important amyloid-related autonomic neuropathy [0161] absence of clinically important amyloid-related gastro-intestinal haemorrhage [0162] capable of providing written, informed consent [0163] women of child-bearing potential should use adequate forms of contraception [0164] Intrauterine Device (IUD) [0165] hormonal-based contraception (pill, contraceptive injection etc.) [0166] double barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap with spermicide) [0167] true abstinence (this is defined as refraining from heterosexual intercourse after receiving [.sup.111In] at the Dosimetry and Imaging visit through to final study visit
Exclusion Criteria
[0168] Patients with the following characteristics are ineligible for this study: [0169] overt symptomatic multiple myeloma [0170] amyloidosis of unknown or non-AL type [0171] localized 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) [0172] trivial or incidental AL amyloid deposits in the absence of a significant amyloid-related organ syndrome (e.g. isolated carpal tunnel syndrome). [0173] NYHA Class III or IV heart failure [0174] liver involvement by amyloid causing bilirubin >1.5 times upper limit of normal [0175] concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas [0176] pregnant, lactating or unwilling to use adequate contraception [0177] intolerance/sensitivity to any of the study drugs [0178] known positive Human anti-murine antibodies or human anti-mouse immunoglobulin antibodies (HAMA) [0179] unable to provide written informed consent [0180] involved in another IMP trial
Trial Assessment
Treatment—Visit 1
Dosimetry and Imaging
Premedication of Patients Prior to Administration of RIC
[0181] Patients receiving antibodies of animal origin occasionally experience symptoms, such as fever, chills, myalgia, even when lacking antibodies against the specific species, e.g. HAMA. Cumulative clinical experience with anti-CD66 indicates that side-effects due to the infusion of antibody are rare, reported as occurring in 0.5-1.0 per 10,000 infusions.
[0182] Resuscitation facilities must immediately be available; this includes apparatus for respiratory support—a supply of oxygen, ventilation, mask and bag. Adrenaline must be available and ready to be administered.
[0183] All subjects will receive pre-medication 30-60 minutes prior to the infusion of radiolabeled anti-CD66 consisting of 4 mg of chlorpheniramine and 1 g of paracetamol both orally, the use of steroids (e.g. hydrocortisone) will be avoided unless significant symptoms occur, in which case 50-100 mg of hydrocortisone will be given. If the use of radiolabeled anti-CD66 is associated with symptoms in the majority of subjects, the use of steroids as part of the premedication will be reviewed.
[0184] Administration of [.sup.111In]-labelled RIC and dosimetry (2-4 weeks after stem cell harvest)—drug product A
[0185] A small imaging dose of [.sup.111In]-labelled anti-CD66, approximately 185 MBq, will be given.
Treatment—Visit 2
[0186] Administration of [.sup.90Y]-labelled RIC (Day −14)
[0187] Infusion of labelled anti-CD66 should take place at least a week after dosimetry and will be via a central venous line or, if one has not been inserted, a peripheral cannula with an initial infusion rate of 5 mg/hr for first 5 minutes; if tolerated, the rate may be increased to 10 mg/hr. The rate may need to be reduced or the infusion stopped if the subject experiences any significant symptoms, such as throat tightness, dyspnoea, severe chills or rigors. The line will be flushed with 10-20 ml of normal saline following completion of the infusion.
[0188] At these rates of infusion, the total of 2 mg of labelled antibody will take 12 minutes to infuse.
Treatment—Visit 3 (Day −7 to Day 0 Post [.SUP.90.Y])
[0189] Patients will be reviewed and commenced on prophylactic antibiotics (Ciprofloxacin 250 mg bd, Aciclovir 400 mg bd and Fluconazole 100 mg od).
Autologous Stem Cell Reinfusion (Day 0)
[0190] All patients will be transplanted at the transplant centers using either inpatient or ambulatory care facilities as appropriate. Based on the experience of the phase I and II trials using the same [.sup.90Y]-anti-CD66, patient's peripheral blood counts are anticipated to fall from D7 post [.sup.90Y]-infusion reaching a nadir at D8-10 [equivalent to D-6 to D-4 pre-transplant]. Patients will then be admitted if not already treated as in-patients. Following their stem cell transplant (Day 0), they will be assessed daily by the study team for adverse events and appropriate need for additional antibiotics or blood products. Patients will be discharged from the hospital after adequate haematopoietic engraftment and recovery from any infections and if independent of blood product support. The patient will be followed up after discharge at day 30 and day 100. Trial follow-up will finish at day 100 and follow-up will continue off trial as per standard medical practice.
[0191] Time to disease recurrence or progression and time to next treatment will not be included as part of the formal assessment within the context of the trial. However, all patients undergoing ASCT for AL-amyloidosis are routinely on long-term follow-up by their referring consultant and are also regularly reviewed.
Results
[0192] The first three AL-amyloidosis patients that had been treated with high-dose melphalan and subsequent ASCT and had a relapse were treated with 30 MBq/kg of .sup.90Y-labelled drug product after appropriate dosimetry with .sup.111In-labelled drug product.
[0193] The three patients did not show any side-effects during conditioning with .sup.90Y-labelled drug product, no Severe Adverse Reactions (SAES) or Suspected Unexpected Severe Adverse Reactions (SUSARs) were seen. In all three patients, a fall in clonal free light chain was observed. In one case a complete response with sustained normalization of FLC and improvement in clinical symptoms and disease parameters of AL-amyloidosis was seen. The trial has been given approval by the Data and Safety Committee to continue to the next infused activity level.
[0194] These findings are absolutely unique and unexpected. Induction of disease regression as indicated by the FLC reduction without any side-effects is an outstanding result, which delivers major benefit to patients suffering from AL-amyloidosis.
[0195]
[0196] The two other patients also showed a significant decrease of the FLC level after RIC treatment.