E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypercalcemia of malignancy (HCM) |
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E.1.1.1 | Medical condition in easily understood language |
Hypercalcemia of malignancy |
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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 | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020588 |
E.1.2 | Term | Hypercalcemia of malignancy |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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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 |
To evaluate the potential for denosumab to treat HCM that does not respond to recent treatment with Intravenous (IV) bisphosphonates by lowering corrected serum calcium (CSC) ≤ 11.5 mg/dL (2.9 mmol/L) by study day 10. |
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E.2.2 | Secondary objectives of the trial |
• To determine the duration of the treatment effect
• To determine the time to response
• To determine the time to relapse/nonresponse
• Changes in CSC level from baseline
• To determine the safety of denosumab in this subject population |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Hypercalcemia of Malignancy (HCM) as defined as documented histologically or cytologically confirmed cancer and a CSC > 12.5 mg/dL (3.1 mmol/L) at screening by local laboratory
• Last IV bisphosphonate treatment must be ≥ 7 days and ≤ 30 days before the screening CSC
• Adults (≥ 18 years)
• Adequate organ function as defined by the following criteria:
- serum aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN)
- serum alanine aminotransferase (ALT) ≤ 5 x ULN
- serum total bilirubin ≤ 2 x ULN
• Before any study-specific procedure is performed, the appropriate written informed consent must be obtained |
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E.4 | Principal exclusion criteria |
• Evidence of benign hyperparathyroidism, hyperthyroidism, adrenal insufficiency, vitamin D intoxication, milk alkali syndrome, sarcoidosis or other granulomatous disease.
• Receiving dialysis for renal failure
• Treatment with thiazides, calcitonin, mithramycin, or gallium nitrate within their window of expected therapeutic effect (as determined by the physician) prior to the date of the screening CSC
• Treatment with cinacalcet within 4 weeks prior to the date of the screening CSC
• Thirty days or less since receiving an investigational product (other than denosumab) or device (ie, does not have marketing authorization; thalidomide use is allowed) in another clinical study
• Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products)
• Female subject is pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
• Female subject of childbearing potential is not willing to use 2 highly effective methods of contraception during treatment and for 7 months after the end of treatment
• Subject will not be available for follow-up assessment.
• Any organic or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects with a response, defined as CSC ≤ 11.5 mg/dL (2.9 mmol/L), within 10 days after the first dose of denosumab |
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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) |
• Proportion of subjects with a response (ie, CSC ≤11.5 mg/dL [2.9 mmol/L]) by visit
• Proportion of subjects with a complete response (CR) (ie, CSC ≤10.8 mg/dL [2.7 mmol/L]) by visit
• Time to response
• Time to CR
• Duration of response defined as the number of days from the first day of CSC ≤ 11.5 mg/dL (2.9 mmol/L) to the last day of CSC ≤11.5 mg/dL (2.9 mmol/L)
• Duration of CR defined as the number of days from the first day of CSC ≤ 10.8 mg/dL (2.7 mmol/L) to the last day of CSC ≤10.8 mg/dL (2.7 mmol/L)
• Time to relapse/nonresponse of HCM
• Changes in CSC from baseline
• Type, frequency, and severity of adverse events
• Changes in laboratory values |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Efficacy endpoints: Months 3, 9 and 15
• Safety endpoints: Months 3 and 9 |
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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 | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
European Union |
Canada |
United States |
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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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The end of study will occur 4 weeks after the last dose of denosumab. |
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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 | 9 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |