Breast Cancer, Colon Cancer, Endocrine Cancer, Head and Neck Cancer, Hodgkin's Lymphoma, Hypercalcemia of Malignancy, Kidney Cancer, Lung Cancer, Lymphoma, Metastatic Cancer, Multiple Myeloma, Non-Hodgkin's Lymphoma, Non-Small Cell Lung Cancer, Parathyroid Neoplasms, Renal Cancer, Thyroid Cancer
Conditions
Keywords
hypercalcemia, calcium, bisphosphonates, denosumab, amgen, malignancy, 20070315, HMC, oncology, hematology
Brief summary
The purpose of this study is to determine the potential of denosumab to treat Hypercalcemia of Malignancy in patients with elevated serum calcium who do not respond to recent treatment with intravenous bisphosphonates by lowering corrected serum calcium \</= 11.5 mg/dL (2.9 millimoles /L) by day 10.
Interventions
DRUGdenosumab
120 mg subcutaneously (SC) every 4 weeks with a loading dose of 120 mg SC on study days 8 and 15.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Hypercalcemia of Malignancy (HCM) as defined as documented histologically or cytologically confirmed cancer and a corrected serum calcium (CSC) \> 12.5 mg/dL (3.1 millimoles /L) at screening by local laboratory * Last IV bisphosphonate treatment must be \>/= to 7 days and \</= to 30 days before the screening corrected serum calcium * 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 upper limit of normal * serum total bilirubin \</= 2 x upper limit of normal
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Response Within 10 Days of First Dose of Denosumab | 10 days | Response is defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL, within 10 days after the first dose of denosumab. For all CSC values, if albumin was \< 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium \[mg/dL\] + (0.8 x (4 - serum albumin \[g/dL\])) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Complete Response by Visit | Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57 | Response is defined as corrected serum calcium (CSC) ≤ 10.8 mg/dL (2.7 mmol/L). For all CSC values, if albumin was \< 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium \[mg/dL\] + (0.8 x (4 - serum albumin \[g/dL\])). |
| Time to Response | From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months. | Time to Response was defined as the time period from study Day 1 to the first time post-baseline corrected serum calcium (CSC) ≤ 11.5 mg/dL. Participants were censored on the last CSC assessment day if no response was observed. If there was no post-baseline CSC assessment, time to response was censored on study Day 1. Time to response was analyzed using Kaplan-Meier methods. |
| Time to Complete Response | From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months. | Time to complete response was defined as the time period from study Day 1 to the first time post-baseline corrected serum calcium (CSC) was ≤ 10.8 mg/dL (2.7 mmol/L). Participants were censored on the last CSC assessment day if no complete response was observed. If there was no post-baseline CSC assessment, time to complete response was censored on study Day 1. Time to complete response was analyzed using Kaplan-Meier methods. |
| Percentage of Participants With a Response by Visit | Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57 | Response is defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL, within 10 days after the first dose of denosumab. For all CSC values, if albumin was \< 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium \[mg/dL\] + (0.8 x (4 - serum albumin \[g/dL\])) |
| Duration of Complete Response | From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months. | Duration of complete response is defined as the number of days from the first day of of corrected serum calcium ≤ 10.8 mg/dL (2.7 millimoles/L) to the last day of corrected serum calcium ≤ 10.8 mg/dL. Participants were censored on the last CSC assessment day if their CSC level never reached \> 10.8 mg/dL after the complete response. If a participant had no CSC assessment after the complete response, duration of complete response was set to zero and censored. Duration of complete response was summarized for participants who achieved a complete response using the Kaplan-Meier method. |
| Time to Relapse/Nonresponse of Hypercalcemia of Malignancy | From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months. | Time to relapse/nonresponse was defined as the number of days from study Day 1 until the last day of CSC ≤ 11.5 mg/dL for all particiipants with relapse after the first response. Participants were censored on the last CSC assessment day if their CSC level never reached \> 11.5 mg/dL after first response. For participants who never achieved response, time to relapse/nonresponse was set to zero. Otherwise, if there was no post-baseline CSC assessment, time to relapse/nonresponse was censored on study Day 1. Time to relapse/nonresponse was estimated using the Kaplan-Meier method. |
| Change From Baseline in Corrected Serum Calcium | Baseline and Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57 | — |
| Duration of Response | From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months. | Duration of response is defined as the number of days from the first day of corrected serum calcium ≤ 11.5 mg/dL (2.9 millimoles/L) to the last day of corrected serum calcium ≤ 11.5 mg/dL. Participants were censored on the last CSC assessment day if their CSC level never reached \> 11.5 mg/dL after the first response. If a participant had no CSC assessment after the first response, duration of response was set to zero and censored. Duration of response was summarized for participants who achieved a response using the Kaplan-Meier method. |
Countries
Canada, France, Italy, Poland, United States
Participant flow
Recruitment details
First patient was enrolled on 16 November 2009 and the last patient enrolled on 02 July 2012. Data are reported as of the primary analysis cut-off date of 13 September 2012.
Participants by arm
| Arm | Count |
|---|---|
| Denosumab Participants received denosumab at a dose of 120 mg subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study Days 8 and 15. | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Death | 10 |
| Overall Study | Disease Progression | 5 |
| Overall Study | Ongoing in study | 2 |
| Overall Study | Other | 4 |
| Overall Study | Requirement for alternative therapy | 3 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Denosumab |
|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 14.8 |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Abdominal pain | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Anorexia | 5 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Confusion | 3 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Constipation | 4 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Decreased mental acuity | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Depressed level of consciousness | 2 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Dry mouth | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Dyspnea | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Fatigue | 9 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms General weakness | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Insomnolence | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Lethargy | 4 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Light headedness (dizziness) | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Listlessness/muscle weakness | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Nausea | 4 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Polyuria | 2 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Polyuro-polydipsic syndrome | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Psychomotor retardation | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Retching | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Urinary frequency | 1 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Vomiting | 2 participants |
| Baseline Hypercalcemia of Malignancy (HCM) Symptoms Weight loss | 1 participants |
| Calcium (corrected) | 13.89 mg/dL STANDARD_DEVIATION 1.27 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 1 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 7 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 14 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 3 | 8 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 4 | 3 participants |
| Presence of bone metastatic disease at enrollment No | 20 participants |
| Presence of bone metastatic disease at enrollment Yes | 13 participants |
| Presence of metastatic disease at enrollment No | 3 participants |
| Presence of metastatic disease at enrollment Yes | 30 participants |
| Primary Tumor Type Bladder | 1 participants |
| Primary Tumor Type Breast | 6 participants |
| Primary Tumor Type Chronic lymphocytic leukemia | 2 participants |
| Primary Tumor Type Head and neck | 2 participants |
| Primary Tumor Type IGG kappa multiple myeloma | 1 participants |
| Primary Tumor Type Liver | 1 participants |
| Primary Tumor Type Multiple myeloma | 3 participants |
| Primary Tumor Type Myeloma | 1 participants |
| Primary Tumor Type Neuroendocrine/carcinoid | 4 participants |
| Primary Tumor Type Non-hodgkin's | 2 participants |
| Primary Tumor Type Non-small cell lung cancer | 3 participants |
| Primary Tumor Type Ovarian | 1 participants |
| Primary Tumor Type Renal | 3 participants |
| Primary Tumor Type Small cell lung cancer | 1 participants |
| Primary Tumor Type Soft tissue sarcoma | 1 participants |
| Primary Tumor Type Unknown (primary tumor) | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black or African American | 7 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants |
| Race/Ethnicity, Customized White or Caucasian | 23 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 21 Participants |
| Time from initial cancer diagnosis to enrollment | 56.9 months STANDARD_DEVIATION 68.8 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 26 / 33 |
| serious Total, serious adverse events | 29 / 33 |
Outcome results
Primary
Percentage of Participants With a Response Within 10 Days of First Dose of Denosumab
Response is defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL, within 10 days after the first dose of denosumab. For all CSC values, if albumin was \< 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium \[mg/dL\] + (0.8 x (4 - serum albumin \[g/dL\]))
Time frame: 10 days
Population: Response Analysis Subset including all participants who received at least 1 dose of denosumab and had a screening CSC (from local lab) \> 12.5 mg/dL (3.1 mmol/L).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Denosumab | Percentage of Participants With a Response Within 10 Days of First Dose of Denosumab | 63.6 percentage of participants |
Secondary
Change From Baseline in Corrected Serum Calcium
Time frame: Baseline and Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57
Population: Efficacy Analysis Subset included all participants who received at least 1 dose of denosumab. n = Number of participants who had non-missing data at Baseline and the time point of interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 2 (n = 32) | -0.13 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 4 (n = 32) | -0.25 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change form Baseline to Day 8 (n = 27) | -0.43 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 10 (n = 28) | -0.54 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 15 (n = 24) | -0.51 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 19 (n = 22) | -0.64 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 23 (n = 21) | -0.60 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 29 (n = 22) | -0.53 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 36 (n = 20) | -0.61 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 43 (n = 19) | -0.75 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 50 (n = 15) | -0.83 mmol/L |
| Denosumab | Change From Baseline in Corrected Serum Calcium | Change from Baseline to Day 57 (n = 17) | -0.73 mmol/L |
Secondary
Duration of Complete Response
Duration of complete response is defined as the number of days from the first day of of corrected serum calcium ≤ 10.8 mg/dL (2.7 millimoles/L) to the last day of corrected serum calcium ≤ 10.8 mg/dL. Participants were censored on the last CSC assessment day if their CSC level never reached \> 10.8 mg/dL after the complete response. If a participant had no CSC assessment after the complete response, duration of complete response was set to zero and censored. Duration of complete response was summarized for participants who achieved a complete response using the Kaplan-Meier method.
Time frame: From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
Population: Participants with a complete response in the Response Analysis Subset
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denosumab | Duration of Complete Response | 34.0 days |
Secondary
Duration of Response
Duration of response is defined as the number of days from the first day of corrected serum calcium ≤ 11.5 mg/dL (2.9 millimoles/L) to the last day of corrected serum calcium ≤ 11.5 mg/dL. Participants were censored on the last CSC assessment day if their CSC level never reached \> 11.5 mg/dL after the first response. If a participant had no CSC assessment after the first response, duration of response was set to zero and censored. Duration of response was summarized for participants who achieved a response using the Kaplan-Meier method.
Time frame: From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
Population: Participants with a response in the Response Analysis Subset
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denosumab | Duration of Response | 104.0 days |
Secondary
Percentage of Participants With a Complete Response by Visit
Response is defined as corrected serum calcium (CSC) ≤ 10.8 mg/dL (2.7 mmol/L). For all CSC values, if albumin was \< 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium \[mg/dL\] + (0.8 x (4 - serum albumin \[g/dL\])).
Time frame: Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57
Population: Response Analysis Subset
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 2 | 3.0 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 4 | 15.2 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 8 | 27.3 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 10 | 36.4 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 15 | 45.5 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 19 | 45.5 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 23 | 51.5 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 29 | 51.5 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 36 | 60.6 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 43 | 63.6 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 50 | 63.6 percentage of participants |
| Denosumab | Percentage of Participants With a Complete Response by Visit | By Day 57 | 63.6 percentage of participants |
Secondary
Percentage of Participants With a Response by Visit
Response is defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL, within 10 days after the first dose of denosumab. For all CSC values, if albumin was \< 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium \[mg/dL\] + (0.8 x (4 - serum albumin \[g/dL\]))
Time frame: Days 2, 4, 8, 10, 15, 19, 23, 29, 36, 43, 50 and 57
Population: Response Analysis Subset
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Denosumab | Percentage of Participants With a Response by Visit | By Day 2 | 9.1 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 4 | 24.2 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 8 | 48.5 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 10 | 63.6 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 15 | 63.6 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 19 | 69.7 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 23 | 69.7 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 29 | 69.7 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 36 | 69.7 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 43 | 69.7 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 50 | 69.7 percentage of participants |
| Denosumab | Percentage of Participants With a Response by Visit | By Day 57 | 69.7 percentage of participants |
Secondary
Time to Complete Response
Time to complete response was defined as the time period from study Day 1 to the first time post-baseline corrected serum calcium (CSC) was ≤ 10.8 mg/dL (2.7 mmol/L). Participants were censored on the last CSC assessment day if no complete response was observed. If there was no post-baseline CSC assessment, time to complete response was censored on study Day 1. Time to complete response was analyzed using Kaplan-Meier methods.
Time frame: From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
Population: Response Analysis Subset
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denosumab | Time to Complete Response | 23.0 days |
Secondary
Time to Relapse/Nonresponse of Hypercalcemia of Malignancy
Time to relapse/nonresponse was defined as the number of days from study Day 1 until the last day of CSC ≤ 11.5 mg/dL for all particiipants with relapse after the first response. Participants were censored on the last CSC assessment day if their CSC level never reached \> 11.5 mg/dL after first response. For participants who never achieved response, time to relapse/nonresponse was set to zero. Otherwise, if there was no post-baseline CSC assessment, time to relapse/nonresponse was censored on study Day 1. Time to relapse/nonresponse was estimated using the Kaplan-Meier method.
Time frame: From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
Population: Response Analysis Subset
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denosumab | Time to Relapse/Nonresponse of Hypercalcemia of Malignancy | 19.0 days |
Secondary
Time to Response
Time to Response was defined as the time period from study Day 1 to the first time post-baseline corrected serum calcium (CSC) ≤ 11.5 mg/dL. Participants were censored on the last CSC assessment day if no response was observed. If there was no post-baseline CSC assessment, time to response was censored on study Day 1. Time to response was analyzed using Kaplan-Meier methods.
Time frame: From Day 1 until the end of study date or primary data cutoff date (13 September 2012), whichever occured first; median time on study was 1.8 months.
Population: Response Analysis Subset
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denosumab | Time to Response | 9.0 days |