TERAGNOSTIC METHOD FOR CANCER PATIENTS

Abstract

A radiopharmaceutical composition is here described comprising as the active ingredient copper-64 in ionic form (64Cu++), in combination with suitable excipients, and/or diluents, having radioconcentration comprised between 50 and 3,500 MBq/mL at calibration time. Such radiopharmaceutical composition is useful in a method for treating a subject affected by a neoplasia. Such method may comprise a step for evaluating the eligibility of a patient for the treatment, in which 64Cu++ cellular uptake is detected. In case no uptake is detectable, the treatment is not advisable. In case radioactive copper uptake from cancer lesions is detectable, this has a predictive value of response to treatment and the subject is selected for the treatment. If the patient is eligible for the treatment and is selected for the treatment, the method further comprises a step of treating cancer in said subject by administering a therapeutically effective amount of the same 64Cu++ salt.

Claims

1.-47. (canceled)

48. A method of treatment of a neoplasm comprising the administration of a radiopharmaceutical composition comprising as the active ingredient copper-64 in ionic form (.sup.64Cu.sup.++), in combination with suitable excipients and/or diluents in a saline solution, having a radioconcentration comprised between 50 and 3,500 MBq/mL, optionally equal to, lower or higher than 925 MBq/ml at calibration time.

49. The method of treatment according to claim 48, wherein the method is preceded by a phase of evaluation of the eligibility of the patient for the treatment.

50. The method of treatment according to claim 48, wherein the evaluation comprises PET/MRI or PET/CT of said patient to confirm copper-64 uptake by the neoplasm.

51. The method of treatment according to claim 49, wherein the evaluation is performed by method that includes an output from a computer.

52. The method of treatment according to claim 51, wherein the output from the computer does not require the interpretation from a medical doctor.

53. The method of treatment according to claim 48, wherein the treatment is followed by a phase of monitoring the response of the patient to the treatment.

54.-59 (canceled)

60. A method of treatment of a neoplasm comprising the administration of a radiopharmaceutical composition comprising as the active ingredient copper-64 in ionic form (.sup.64Cu.sup.++), in combination with suitable excipients and/or diluents in a saline solution, having a radioconcentration comprised between 50 and 3,500 MBq/mL, wherein radiopharmaceutical composition is used at a dose from 7 MBq/kg to 210 MBq/kg, and wherein the administration is intravenous by infusion.

61. The method of treatment according to claim 60, wherein the radiopharmaceutical composition is used at a dose from 13 MBq/kg to 105 MBq/kg.

Description

DESCRIPTION OF THE DRAWINGS

[0138] FIG. 1Impact of different radioconcentrations on tumor cell uptake .sup.64CuCl.sub.2 cell uptake in different tumor cell lines U87MG, PC-3, CAMA1, C8161, HT-29. Cell uptake was evaluated treating cells at the same dosage (15 MBq/dish 100 mm), but at three different radioconcentrations C1=925 MBq/mL, C2=1,850 MBq/mL, C3=2,775 MBq/mL. Values are expressed as mean SEM.

[0139] FIG. 2Impact of different radioconcentrations on tumor cell survival

[0140] Survival curve of U87MG treated with the same dosage range but at three different concentrations C1=925 MBq/mL, C2=1,850 MBq/mL, C3=2,775 MBq/mL. Value are expressed as mean SEM. (**p0.01 ***p0.001 compared to cell treated with C1). D0=No treatment, D1=0.0034 MBq, D2=0.034 D3=0.34, D4=1.7 MBq, D5=3.4MBq. C3 let to have at D4 and D5 an improved cell killing-effect of about 30% compared to C1.

[0141] FIG. 3Tumor volume reduction after .sup.64CuCl.sub.2 treatment

[0142] Graphic representation of tumor volume reduction of the lesion of a single glioblastoma patient evaluated by MRI. The volume was evaluated at day 0 (before treatment beginning), at day 42 (after 7 treatments of .sup.64CuCl.sub.2) and at day 90 (3 months follow up). This patient was treated with a fixed dose of 4,810 MBq for 7 weeks, 1 treatment per week. X axis: MRI examination day 0=before treatment beginning, day 42=after 7 treatments, day 90=3 months after the end of treatment, day 180=6 months after the end of treatment. Y axis: sum of products of perpendicular diameters of all measurable enhancing lesion

[0143] FIG. 4Pre- and Post-treatment MRI

[0144] MRI of a glioblastoma patient treated with 7 fixed doses of .sup.64CuCl.sub.2 (4,810 MBq) once a week. On the left the MRI performed before starting treatment, on the right the MRI performed 90 days after the start of treatment. The patient resulted responder to the treatment indeed MRI showed a tumor volume reduction after treatment>50%.

EXAMPLES

Example 1Compositions to be Used in the Selection Step

[0145] In the selection step an efficient amount of .sup.64CuCl.sub.2 is administered as a contrast agent for PET/CT or PET/MRI imaging. The composition of the medicinal product .sup.64CuCl.sub.2 for the selection step is a ready-to-use solution for injection (intravenous use) at a radioconcentration from 930 MBq/mL to 3,500 MBq/mL, preferably of 2,775 MBq/mL at date and time of calibration as a single dose product or as a multidose doses product. The volume of the solution for injection varies from 0.5 to 20 mL for single dose.

[0146] Drug synthesis steps are performed in a closed-system synthesis module which is automated and remotely controlled by GMP compliant software with automated monitoring and recording of the process parameters. In consideration of the nature of the product (radioactive) a natural decay of the radionuclide occurs, which is a property of radiopharmaceuticals, therefore the radio concentration change over time and this is the reason why the above mentioned raioconcentrations refers to a calibration time.

Example 2Composition to be Used in the Treatment Step

[0147] The composition of the medicinal product .sup.64CuCl.sub.2 for the treatment step is a ready-to-use solution for injection (intravenous use) at a radioconcentration from 930 MBq/mL to 3,500 MBq/mL, at date and time of calibration as a single dose product or as a multidose doses product. The volume of the solution for injection varies from 0.5 to 20 mL for single dose. The solution can be diluted before administration with NaCl 0.9%.

[0148] Alternatively, the composition of the medicinal product .sup.64CuCl.sub.2 for the treatment step is a ready-to-use solution for infusion at a radioconcentration comprised between 50 MBq/mL and 925 MB/mL, at calibration time. The volume of the solution for infusion varies from 5 to 30 mL for single dose.

[0149] Drug synthesis steps are performed in a closed-system synthesis module which is automated and remotely controlled by GMP compliant software with automated monitoring and recording of the process parameters. In consideration of the nature of the product (radioactive) a natural decay of the radionuclide occurs, which is a property of radiopharmaceuticals, therefore the radio concentration change over time and this is the reason why the above mentioned radioconcentrations refers to a calibration time.

Example 3Protocol for Treating a Human Patient With .SUP.64.CuCl.SUB.2

[0150] In the present protocol the medicinal product used is .sup.64CuCl.sub.2 at a radioconcentration from 930 MBq/mL to 3,500 MBq/mL as solution for injection and as a single dose product. Copper-64 has a half-life of 12.7 hours.

Step a: Administering an Efficient Amount of .sup.64CuCl.sub.2 as a Contrast Agent for PET/CT or PET/MRI Imaging

[0151] Patients with tumor received .sup.64CuCl.sub.2 at a dose between 370-925 MBq to ensure appropriate image quality. The mean effective dose for .sup.64CuCl.sub.2 calculated is 20 mSv per exam, which is aligned with the ones from the conventional PET imaging.

Step b: Acquiring Images PET/CT or PET/MRI Imaging With .sup.64CuCl.sub.2 and Selecting Patients for the Treatment

[0152] The imaging PET/CT or PET/MRI is performed 1 h after .sup.64CuCl.sub.2 injection. In case an imaging PET/CT is acquired, the parameters for the CT (AC/AL): 100 mAs (adjustments will be possible according to body mass), 130 kVa, contiguous slices of 5 mm. Once the CT acquisition is completed, the PET acquisition includes 2 number of iterations, 8 number of subsets, 128 acquisition matrix. Each PET bad position is acquired for 3-4 minutes, providing a total scan time of 15-20 minutes. After performing the PET/CT or PET/MRI scan, the imaging is evaluated to identify lesions and see the uptake of .sup.64CuCl.sub.2 in the cancer lesion of the patient. SUV.sub.max of the lesion and the SUV.sub.background for the specific background tissue is measured to calculate the Target to background ratio (TBR). Patient's lesion is determined as positive for .sup.64CuCl.sub.2 uptake (i.e. evidencing an uptake of .sup.64CuCl.sub.2), if TBR results equal or higher than 5. In this case the subject, showing copper-64 uptake, is eligible and can proceed with treatment.

Step c: Treatment With .sup.64CuCl.sub.2

[0153] The treatment can start from the same day of the diagnostic administration up to 30 days after diagnostic administration. The patients identified with positive tumor lesions according to step b) receives a therapeutic dose in the range 1,850 MBq-4,810 MBq of .sup.64CuCl.sub.2 in 1-7 doses via parental administration.

[0154] According to nuclear medicine clinical practice a range of 10% is accepted for each administered dose without any risk for the safety of the patient.

[0155] The treatment can be monitored during the course, the day of injection of the therapeutic dose a PET/CT or a PET/MRI can be acquired.

Example 4Selection of Cancer Patients for the Treatment With TBR

[0156] According to the dosimetry evaluations from two different phase I clinical trials, evaluating the preliminary capability of .sup.64CuCl.sub.2 to be a theragnostic agent respectively in 16 patients affected by glioblastoma and 16 patients affected by prostate cancer, the TBR obtained from the PET/CT scan performed in the selection/eligibility step was also correlated to the response to copper chloride treatment. These results showed that the TBR of the non-responder patient was higher compared to the responder ones, in particular on the basis of the clinical data, TBR value >25 resulted in non-responder patients and TBR from 5 to 25 resulted in patients classified as responders. Therefore TBR, in addition to represent an index of tumor uptake in patients, it can be a predictive index of .sup.64CuCl.sub.2 treatment response. The PET/CT or PET/MRI results essential to select the proper patient that can start .sup.64CuCl.sub.2 treatment avoiding to expose the patient to the risk to start an unsuccessful treatment.

Example 5Pharmacokinetic profile of the composition

[0157] Six glioblastoma patients were evaluated for safety profile and the study of biodistribution was conducted including evaluation of PET/CT scans after first daily dose administration of radiopharmaceutical composition having a radioconcentration of 2,775 MBq/mL (day 0), at different time points 1 h, 4 h, 24 h, 48 h after injection and pharmacokinetic (PK) radioactivity on blood samples at different time points of administration.

[0158] The .sup.64Cu pharmacokinetic profile in the present study showed that the .sup.64Cu uptake increases up to 4 h post-injection and decreased thereafter, indicating the in vivo stability of the theragnostic radiopharmaceutical. Data revealed a significant uptake in the liver (as expected) followed by kidney and L2-L4 regions. No treatment related toxicities were registered associated to liver/kidney and red marrow distribution. The effective dose ranged from 0.27 to 45.44 mSv with a median of 26.08 mSv. These values were considered acceptable for a theragnostic application.

Example 6Response to .SUP.64.CuCl.SUB.2 .Treatment in Glioblastoma Patients

[0159] A glioblastoma patient of 70 kg that belongs to the class of recurrent glioblastoma. The patient underwent surgery, radiotherapy and chemotherapy and after that experienced recurrence. Standard treatment are not effective in this setting therefore the patient received a diagnostic dose of .sup.64CuCl.sub.2 equal to 925 MBq. After 1 h from administration a PET/CT scan is performed. The patient resulted positive for copper lesion at the diagnostic dose and started treatment

[0160] The treatment with .sup.64CuCl.sub.2 (2,775 MBq/mL) for intravenous use by injection followed this scheme and the patient received once a week: [0161] 1st dose=4,810 MBq, 2nd dose=4,810 MBq, 3rd dose=4,810 MBq, 4th dose=4,810 MBq, 5th dose=4,810 MBq, 6th dose=4,810 MBq, 7th dose=4,810 MBq

[0162] Where the total activity administered is equal to 33,670 MBqcycle.

[0163] The efficacy of this radiopharmaceutical composition, at these dose ranges and dose intervals is shown in FIG. 3. The radiopharmaceutical composition tested with this dosage regimen showed the capability to induce a tumor volume reduction. In particular, standard imaging (MRI) showed a tumor volume reduction after 3 months (day 90) from treatment beginning over 50% (FIG. 4).

Example 7Treatment of a Prostate Cancer Patient That Belongs to the Class of Metastatic Prostate Cancer

[0164] The patient at initial diagnosis had local tumor, and after surgery (radical prostatectomy) he underwent radiotherapy and chemotherapy. However, he experienced local recurrence plus a bone metastatic lesion. After receiving all standard treatments, the patient received a diagnostic dose of .sup.64CuCl.sub.2 equal to 925 MBq. After 1 h from administration a PET/CT scan is performed. The patient resulted positive for copper lesion at the diagnostic dose and started treatment.

[0165] The treatment with the composition .sup.64CuCl.sub.2 (2,775 MBq/mL) as solution for injection followed this scheme and the patient received once a week: [0166] 1st dose=4,810 MBq, 2nd dose=4,810 MBq, 3rd dose=4,810 MBq, 4th dose=4,810 MBq, 5th dose=4,810 MBq, 6th dose=4,810 MBq 7th dose=4,810 MBq

[0167] Where the total activity administered is equal to 33,670 MBqcycle.

[0168] After the treatment the analysis of the PET/CT before and after treatment showed a reduction of the tumor lesions on the bone, indicating a therapeutic effect of this composition.

Example 8Treatment of a Glioblastoma Patient That Belongs to the Class of Recurrent Glioblastoma

[0169] The patient (71 Kg) underwent surgery, radiotherapy and chemotherapy and after that experienced recurrence. Standard treatments are not effective in this setting therefore the patient received a diagnostic dose of .sup.64CuCl.sub.2 equal to 925 MBq. After 1 h from administration a PET/CT scan is performed. The patient resulted positive for copper lesion at the diagnostic dose and started treatment (.sup.64CuCl.sub.2 277 MBq/mL for intravenous by infusion).

[0170] The treatment followed this scheme and the patient received once a week: [0171] 1.sup.st dose=1,850 MBq, 2.sup.nd dose=2,460 MBq, 3.sup.rd dose=2,922 MBq, 4.sup.th dose=3,292 MBq, 5.sup.th dose=3,606 MBq, 6.sup.th dose=3,865 MBq, 7.sup.th dose=4,068 MBq.

[0172] The total activity administered is equal to 22,063 MBq per cycle.

[0173] The patient resulted responder to the treatment.

Example 9Treatment of a Paediatric Patient Affected by High Grade Glioma

[0174] The patient (25 kg) received a diagnostic dose of .sup.64CuCl.sub.2 equal to 132,5 MBq. After 1 h from administration a PET/CT scan is performed. The child resulted positive for copper lesion at the diagnostic dose and the treatment started.

[0175] The patient received the following treatment scheme with 3 treatments per week: [0176] 1st dose=1,700 MBq, 2nd dose=1,700 MBq, 3rd dose=1,700 MBq, 4th dose=1,700 MBq, 5th dose=1,700 MBq, 6th dose=1,700 MBq 7th dose=1,700 MBq

[0177] Where the total activity administered is equal to 11,900 MBqcycle.

[0178] The composition was .sup.64CuCl.sub.2 925 MBq/mL for intravenous administration by infusion.

Example 10Treatment response after 7 doses of .SUP.64.CuCl.SUB.2

[0179] The phase I clinical trial on glioblastoma is the first study evaluating preliminary efficacy of .sup.64CuCl.sub.2 2,775 MBq/mL as therapeutic agent. This determination was performed on 10 patients, at the end of the 7th therapy dose, at 90th day (after 3 months of the last treatment) and whenever possible at 180th day to obtain a wider evaluation of the disease status. Data cut-off was performed after 5 patients. The response to treatment, in term of anti-tumor activity of .sup.64CuCl.sub.2, was measured by MRI, assessed according to the RANO criteria (Response Assessment in Neuro-Oncology, see Wen PY et al.) and defined as complete response (disappearance of tumor) partial response (reduction) and stable disease (non-progression of GBM). Among these patients 4 resulted responders and 1 non-responder. All patients were evaluated after 7 treatments with .sup.64CuCl.sub.2 and MRI assessment of the responder patients showed, at day 42 evaluation, stable disease in 3 patients and a reduction of tumor volume 50% compared to baseline MRI examination in one patient. Tumor volume reduction 50% was also shown in two cases after three months from the last treatment, and in one patient after 6 months from the last treatment. Furthermore 2 patients resulted at day 90 with stable disease and one showed stable disease up to six months after treatment.

Example 11Monitoring to Response to Treatment

[0180] The PET/CT (or PET/MRI) can be used to monitor response to the treatment without the necessity to inject another tracer but acquiring the PET/CT after the administration. Infact in 10 patients affected by glioblastoma treated with 7 doses of .sup.64CuCl.sub.2 a PET/CT was acquired at the end of the 7.sup.th therapeutic doses. At the same timepoint a standard imaging, an MRI examination was performed. The response to treatment, in term of anti-tumor activity of .sup.64CuCl.sub.2, was measured by MRI, assessed according to the RANO criteria and defined as complete response (disappearance of tumor) partial response (reduction) and stable disease (non-progression of GBM). Two external revisors analyzed the PET/CT imaging for number of lesions, localization of lesion, SUVmax lesion, SUVbackground, TBR. The response to treatment was also measured by PET/CT. The analysis obtained with the standard imaging MRI were compared with the analysis obtained by PET/CT imaging, the results show coincidence in localization of tumor lesion and a superimposable classification of response to treatment, indicating the .sup.64CuCl.sub.2 PET/CT a technique useful to monitor the response to treatment over due course. This method can be applied to all the tumor lines that are able to have an uptake of Copper-64.

Example 12Treatment Response After 4 Doses of .SUP.64.CuCl.SUB.2

[0181] Five patients affected by prostate cancer showed treatment response after 4 injections of therapeutic administration of .sup.64CuCl.sub.2 2,775 MBq/mL solution for injection. The PET/CT acquired the same day of the 4.sup.th therapeutic administration and the PET/CT acquired before treatment beginning were analyzed by two independent observers (a third observer expressed another evaluation only in case of discrepancies). After 4 administrations the volume of lesions showed a reduction or a non-progression indicating the efficacy of the treatment.

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