E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Breast cancer with painful bone metastases. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
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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 |
The primary objective of the phase I study will be to investigate the maximum tolerated dose of Re-188-HEDP for the combined use with Capecitabine.The primary objective of the phase II part of the study will be to investigate the efficacy of Re-188-HEDP combined with Capecitabine, as determined by pain. |
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E.2.2 | Secondary objectives of the trial |
Secondary aims:- to determine the biodistribution of Re-188-HEDP when combined with Capecitabine- to study haematological toxicity- to monitor objective tumor response (RECIST)- to monitor analgesic consumption- to monitor HRQOL (Quality of life) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Related to breast cancer: Histologically documented carcinoma of the breast, resistant to both taxanes and Anthracycline-containing chemotherapy regimen or resistant to taxanes and for whom further Anthracycline therapy is not indicated. Bone pain and/or pain medication is required for phase II testing. Presence of more than one osteoblastic bone metastasis confirmed by 99mTc-labeled bisphosphonates bone scan performed within 8 weeks prior to study entry. Presence of bidimensionally measurable disease as reflected by at least one measurable soft tissue lesion on CT-scan performed within 4 weeks prior to study entry. Karnofsky performance status >60% (Appendix: IV). Life expectancy of at least 3 months. Patients with lower urinary tract obstruction or incontinence must consent to catheterization of the bladder for up to 8 hours after administration of Re-188-HEDP.
Related to the patient: Age >18 years. Ability to understand and willingness to sign a written informed consent document.
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E.4 | Principal exclusion criteria |
Related to breast cancer: 1. Patients with pathologic long-bone fractures (unless surgically stabilized), imminent pathologic long-bone fracture (cortical erosion on radiography > 50%), or clinical evident spinal cord compression. 2. Patient known to have a malignancy other than breast cancer (but not including basal cell carcinoma of the skin or carcinoma-in-situ of the uterine cervix).
Related to previous or concomitant therapies: 3. Previous chemotherapy within 4 weeks prior to screening. 4. Any other medicine taken with the intension to treat the disease. 5. Use of Interferon-alpha, Allopurinol, Sorivudine and analogues and Folinic acid. 6. Prior treatment with a systemic radiotherapeutic bone agent (only 153Sm-EDTMP, Re 186-HEDP or Re-188-HEDP) within 3 months. Prior treatment with other radiotherapeutic bone agents (e.g., 89Sr-chloride, 32P -phosphate) within 6 months. 7. Patients receiving bisphosphonate therapy must be discontinued for at least 2 weeks prior to treatment with Re-188-HEDP. 8. Receipt of any other investigational drug within 4 weeks of study entry. 9. Previous hemi-body external radiation therapy. 10. Receipt of external beam radiation for bone metastases with irradiation of bone marrow more than 25%, within 6 months of study entry.
Related to the patient: 10. Known hypersensitivity to 5-FU, Re-188-HEDP, Capecitabine or any of the excipients, or phosphate compounds. 11. Patients whose medical history includes clinically significant bleeding disorders which might be exacerbated by study medication. 12. Known deficiency of dihydropyrimidine dehydrogenase (DPD). 13. Patients with concurrent illnesses or treatments that might preclude study completion or interfere with study results. 14. Patients with a history of dementia, seizures, central nervous system disorders, or psychiatric disability thought to be clinically significant in the opinion of the investigator and adversely affecting patient compliance with drug intake. 15. Patients with active CNS (grade 2 or higher) or epidural brain metastasis. 16. Clinical diagnosis of disseminated intravascular coagulation. 17. Absolute neutrophil count, ANC < 2 109/L. 18. Platelet count < 150 109/L. 19. Haemoglobin < 6 mmol/L. 20. Serum creatinine clearance < 50 ml/min (Cockroft and Gault). 21. Bilirubin > 1,5 x ULN. 22. SGOT/ASAT > 2.5 x ULN or SGPT/ALAT 2.5 x ULN.
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohorts of three successive patients will be treated with a combination of Capecitabine and and increasing dose of Re-188-HEDP. If one or two DLT’s occur in the cohort of 3 patients then the cohort will be increased to 6 patients. If maximum 2 out of 6 patients have a DLT then the next cohort will be tested. If at least 3 out of 3 patients, or 3 out of 6 patients have a DLT then the MTD can be determined. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
dose escalation, dose finding |
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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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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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When the MTD of Re-188-HEDP has been defined in the Phase I part of the study, a Phase II study will be performed with a minimum of 15 patients. All patients will start treatment at the MTD level defined in the Phase I study. Duration of participation will be 9 weeks. Follow-up will be continued after end of study for unresolved AE’s, that might be related to one or both of the study drugs. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |