A Phase 1/2 interventional study of Radium-223 dichloride (Xofigo, BAY88-8223) and Docetaxel in Bone Metastases and Castration-Resistant Prostate Cancer, sponsored by Bayer. Completed at 7 sites in 2 countries. Open to male participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-01-04.
Sponsored by Bayer · Phase 1/2, Interventional, and Treatment
The main purpose of this study is to establish a recommended dose of Alpharadin to be used in combination with docetaxel in patients with bone metastases from castration-resistant prostate cancer and to investigate safety and explore efficacy of the recommended dose.
The trial was initially conducted and submitted by Algeta ASA. After acquiring Algeta, Bayer is now the sponsor.
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Exclusion Criteria:
Alpharadin (Radium-223 dichloride) is administered intravenously as a bolus injection. In the randomized phase IIa part of the protocol, the dose established in the dose-escalation part of the protocol (Phase I) will be used, i.e. 5 doses of 50 kBq/kg b.w. every 6 weeks in combination with the approved step-down dose of docetaxel (60 mg/m\^2) administered intravenously every 3 weeks with 5 mg prednisone twice a day continuously and pre-medication with dexamethasone.
Drug: Radium-223 dichloride (Xofigo, BAY88-8223) · Drug: Docetaxel
Docetaxel (75 mg/m2) will be administered intravenously every 3 weeks with 5 mg prednisone twice a day continuously and pre-medication with dexamethasone. Step-down to 60 mg/m\^2 is allowed as per the approved docetaxel label.
Drug: Docetaxel
Alpharadin (Radium-223 dichloride) is administered intravenously as a bolus injection.
Docetaxel (75 mg/m\^2) will be administered intravenously every 3 weeks with 5 mg prednisone twice a day continuously and pre-medication with dexamethasone. Step-down to 60 mg/m\^2 is allowed as per the approved docetaxel label.
Number of Subjects With Dose-Limiting Toxicities - Dose Escalation Part
DLT was defined as - Absolute neutrophil count grade greater than or equal to (\>=) 4 (Common Terminology Criteria for Adverse Events \[CTCAE\], Version 4.0: less than \[\<\] 0.5 × 109 per Liter) lasting longer than 7 days without fever despite granulocyte colony-stimulating factor (G-CSF) support). Platelet count Grade \>= 4 (CTCAE, v4.0: \< 25× 109/L) lasting longer than 7 days. Diarrhea Grade \>= 3 (CTAE, v4.0: increase of \>= 7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care in activities of daily living) in spite of optimal use of antidiarrheal medication. Vomiting or constipation Grade \>= 4 (CTCAE, v4.0: life-threatening consequences; urgent intervention indicated). Febrile neutropenia Grade \>= 3 (CTCAE, v4.0).
Time frame: From randomization until 6 weeks post-injection in all dose cohort of dose-escalation part
Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Treatment-Emergent Serious Adverse Events (TESAE) With a CTCAE Grade of 3 or 4
Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An Serious Adverse Event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in patient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.
Time frame: From start of study treatment to 6 weeks after study treatment (that is maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort) and 8 weeks for serious AEs
Change From Baseline in Serum Biochemistry (Albumin, Protein, Hemoglobin) During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)
Change From Baseline in Serum Biochemistry (Alkaline Phosphatase [AP], Alanine Aminotransferase [AAT], Lactate Dehydrogenase [LD]) During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)
Change From Baseline in Serum Biochemistry (Bilirubin, Creatinine) During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)
Change From Baseline in Serum Biochemistry (Calcium, Chloride, Magnesium, Potassium, Phosphate, Sodium, Urea) During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)
Change From Baseline in Serum Biochemistry (Platelets, Leukocytes, Lymphocytes, Neutrophils, Monocytes, Eosinophils, Basophils) During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)
Change From Baseline in Serum Biochemistry (Erythrocytes) During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)
Changes From Baseline in Systolic and Diastolic Blood Pressure During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)
Changes From Baseline in Respiratory Rate During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)
Changes From Baseline in Heart Rate During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)
Changes From Baseline in Weight During the Treatment Period
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time frame: From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)
Number of Subjects With Physical Examination During the Treatment Period
Any physical examination finding that was classified by the investigator as a clinically significant change (compared with previous examination) was considered an AE, documented on the eCRF, and followed until the outcome was known. The below physical examination findings were recorded and reported. GDASC = General disorders and administration site conditions MND = Metabolism and nutrition disorders SSTD= Skin and subcutaneous tissue disorders MCTD = Musculoskeletal and connective tissue disorders IPPC = Injury, poisoning and procedural complications RTMD = Respiratory, thoracic and mediastinal disorders NBMU = Neoplasms benign, malignant and unspecified (include cysts and polyps) In the below table.
Time frame: From start of study treatment to 6 weeks after study treatment (i.e., maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)
Number of Subjects With Signs of Long-Term Radiation Toxicity
Long-term radiation toxicity included incidence of potential late toxicity, such as new primary cancers and bone marrow changes (acute myelogenous leukemia, myelodysplastic syndrome, and aplastic anemia).
Time frame: From start of study treatment upto 12 months
Exploratory Efficacy: Weighted Mean Area Under the Curve for Bone Turnover Biomarkers
Weighted mean area under the curve for the below bone turnover biomarkers were evaluated, ICTP = pyridinoline cross-linked carboxyterminal telopeptide P1NP = N-terminal peptide of procollagen type 1 uCTX-1 = urine C-telopeptide 1
Time frame: From start of study treatment to 6 weeks after study treatment (maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)
Exploratory Efficacy: Time to Prostate-specific Antigen (PSA) Progression
Serum PSA progression defined as two consecutive increases in PSA over a previous reference value within 6 months of first study treatment, each measurement at least 1 week apart.
Time frame: 12 months
Exploratory Efficacy: Percent Change From Baseline in Circulating Tumor Cells at Day 85
CTCs were measured to follow the evolution of the level of CTCs after treatment.
Time frame: Baseline, Day 85, expanded safety cohort
Exploratory Efficacy: Time to Clinical or Radiographic Progression
Time to first radiologic or clinical progression is determined by one of the following: * For soft tissue lesions, the determination is based on Response Evaluation Criteria in Solid Tumors 1.1. * For bone disease, the determination is based on Prostate Cancer Working Cohort 2 (PCWG2) definitions, which require the appearance of at least 2 new lesions with a confirmatory bone scan at least 6 or more weeks later. For clinical progression, the investigators followed the recommendations of the PCWG25 and used their clinical judgment to determine clinical progression.
Time frame: From start of study treatment to 12 months, at every 12 weeks
Progression Free Survival (PFS) End Point
PFS defined as the time from randomization (randomization referred to the date of treatment assignment) to disease progression (radiological or clinical, whichever was earlier) or death (if death occurred before progression was documented). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.
Time frame: From start of study treatment to 12 months, at every 12 weeks
Overall Survival Rate
The overall survival (OS) time in days was calculated as number of days since the day of first dose of study medication until the date of death.
Time frame: 12 months
Number of Subjects Who Responded to Interactive Voice Response System (IVRS) Pain
The subject completed the full BPI (short form) paper questionnaire, and clinical staff completed the analgesic log. The test consists of 10 questions addressing severity, location, chronicity, and amount of relief. In question 3, subjects with pain are asked to evaluate the severity of pain at worst in the past 24 hours in a 0 to 10 scale, with 0 indicating no pain, and 10 indicating the worst pain.
Time frame: From start of study treatment until 12 months
Study was conducted at seven study centers in United States and one study center in France, between 23 July 2010 (first subject first visit) and 16 June 2015 (last subject last visit).
| Milestone | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Started | 7 | 3 | 7 | 36 | 17 |
| Started dose escalation | 7 | 3 | 7 | 0 | 0 |
| Completed dose escalation | 6 | 3 | 5 | 0 | 0 |
| Started safety cohort | 0 | 0 | 0 | 36 | 17 |
| Treated safety cohort | 0 | 0 | 0 | 33 | 13 |
| Completed safety cohort | 0 | 0 | 0 | 23 | 9 |
| Completed | 6 | 3 | 5 | 23 | 9 |
| Not completed | 1 | 0 | 2 | 13 | 8 |
| Withdrew: Subjects untreated | 0 | 0 | 0 | 3 | 4 |
| Withdrew: Sponsor decision | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Too ill to come in for the visit | 0 | 0 | 1 | 0 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 1 |
| Withdrew: Death | 0 | 0 | 1 | 3 | 1 |
| Withdrew: Disease progression | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 3 | 2 |
| Withdrew: Went on hospice | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Subject entered hospice | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Home hospice since july 2013 | 0 | 0 | 0 | 1 | 0 |
DLT was defined as - Absolute neutrophil count grade greater than or equal to (\>=) 4 (Common Terminology Criteria for Adverse Events \[CTCAE\], Version 4.0: less than \[\<\] 0.5 × 109 per Liter) lasting longer than 7 days without fever despite granulocyte colony-stimulating factor (G-CSF) support). Platelet count Grade \>= 4 (CTCAE, v4.0: \< 25× 109/L) lasting longer than 7 days. Diarrhea Grade \>= 3 (CTAE, v4.0: increase of \>= 7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care in activities of daily living) in spite of optimal use of antidiarrheal medication. Vomiting or constipation Grade \>= 4 (CTCAE, v4.0: life-threatening consequences; urgent intervention indicated). Febrile neutropenia Grade \>= 3 (CTCAE, v4.0).
| Participants | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation |
|---|---|---|---|
| Number of Subjects With Dose-Limiting Toxicities - Dose Escalation Part | 0 | 0 | 0 |
Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An Serious Adverse Event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in patient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.
| Participants | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| TEAE CTCAE Grade 3 | 3 | 1 | 4 | 6 | 3 |
| TEAE CTCAE Grade 4 | 2 | 1 | 1 | 10 | 6 |
| TESAE | 4 | 0 | 2 | 7 | 4 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| gram per liter (G/L) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Albumin Baseline (n= 7,3,7,35,13) | 42 ± 3 | 43 ± 4 | 43 ± 3.56 | 42.7 ± 3.25 | 42.3 ± 4.09 |
| Albumin: Change at Day 106 (n=1,0,0,27,11) | -2 ± NA | NA ± NA | NA ± NA | -1.3 ± 2.98 | -1.2 ± 2.75 |
| Albumin: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -2.3 ± 3.33 | -0.5 ± 2.07 |
| Protein: Baseline (n= 7,3,7,35,13) | 70.3 ± 4.23 | 69.7 ± 8.5 | 70.4 ± 4.89 | 68.7 ± 4.45 | 69.1 ± 5.33 |
| Protein: Change at Day 106 (n=1,0,0,27,11 ) | 1 ± NA | NA ± NA | NA ± NA | -3.9 ± 3.79 | -3.8 ± 2.56 |
| Protein: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -5.3 ± 3.63 | -3.7 ± 4.18 |
| Hemoglobin: Baseline (n= 7,3,7,35,13) | 122.43 ± 14.581 | 120.67 ± 16.166 | 120.43 ± 8.522 | 122.82 ± 10.939 | 120.23 ± 12.05 |
| Hemoglobin: Change at Day 106 (n=1,0,0,27,11 ) | -10 ± NA | NA ± NA | NA ± NA | -8.81 ± 8.2 | -14.27 ± 9.067 |
| Hemoglobin: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -13.65 ± 10.853 | -10.67 ± 13.794 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| units per liter (U/L) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| AP: Baseline (n= 7,3,7,33,13) | 533.1 ± 656.36 | 144 ± 89.2 | 224.6 ± 115.08 | 218.2 ± 207.63 | 195.9 ± 110.86 |
| AP: Change at Day 106 (n=1,0,0,27,11) | -134 ± NA | NA ± NA | NA ± NA | -119.6 ± 153.1 | -78.9 ± 46.35 |
| AP: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -119.3 ± 112.21 | -116.8 ± 52.21 |
| AAT: Baseline (n= 7,3,7,33,13) | 17.6 ± 5.68 | 17 ± 6.56 | 18.9 ± 5.9 | 19.8 ± 9.82 | 19.8 ± 10.78 |
| AAT: Change at Day 106 (n=1,0,0,27,11 ) | 100 ± NA | NA ± NA | NA ± NA | 2.9 ± 13.54 | -2.2 ± 11.75 |
| AAT: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 1.1 ± 8.67 | -3.7 ± 13.81 |
| LD: Baseline (n= 7,3,7,33,13) | 313.3 ± 243.9 | 179 ± 22.52 | 214.4 ± 38.92 | 212.8 ± 71.07 | 203.4 ± 61.68 |
| LD: Change at Day 106 (n= 1,0,0,27,11) | 15 ± NA | NA ± NA | NA ± NA | 10.7 ± 58.14 | 45.1 ± 93.58 |
| LD: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 16.9 ± 39.74 | 17.5 ± 100.85 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| micromole(s)/litre | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Bilirubin: Baseline (n= 7,3,7,33,13) | 8.9 ± 3.8 | 6.7 ± 1.15 | 7.1 ± 3.98 | 7.5 ± 2.62 | 7 ± 2.08 |
| Bilirubin: Change at Day 106 (n= 1,0,0,27,11) | 2 ± NA | NA ± NA | NA ± NA | 0.2 ± 1.84 | -0.8 ± 1.72 |
| Bilirubin: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -0.9 ± 1.56 | 0.3 ± 1.51 |
| Creatinine: Baseline (n= 7,3,7,33,13) | 92.33 ± 33.126 | 73.67 ± 9.5 | 70.86 ± 10.938 | 70.07 ± 19.138 | 75.5 ± 11.614 |
| Creatinine: Change at Day 106 (n= 1,0,0,27,11) | 63.6 ± NA | NA ± NA | NA ± NA | 0.74 ± 12.273 | -0.7 ± 7.232 |
| Creatinine: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 0.59 ± 11.889 | -0.17 ± 13.31 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| millimole(s)/liter | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Calcium: Baseline (n= 7,3,7,33,13) | 2.231 ± 0.1523 | 2.38 ± 0.0872 | 2.309 ± 0.071 | 2.357 ± 0.1121 | 2.307 ± 0.1437 |
| Calcium: Change at Day 106 (n= 1,0,0,27,11) | 0.2 ± NA | NA ± NA | NA ± NA | -0.065 ± 0.148 | -0.019 ± 0.104 |
| Calcium: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -0.055 ± 0.1225 | -0.143 ± 0.1536 |
| Chloride: Baseline (n= 7,3,7,33,13) | 101.4 ± 3.21 | 101.7 ± 2.52 | 102 ± 2.77 | 103.2 ± 2.75 | 101.3 ± 3.99 |
| Chloride: Change at Day 106 (n= 1,0,0,27,11) | -1.9 ± NA | NA ± NA | NA ± NA | 0 ± 2.72 | 1.5 ± 2.38 |
| Chloride: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 0 ± 3.35 | 2.5 ± 1.38 |
| Magnesium: Baseline (n= 7,3,7,33,13) | 0.93 ± 0.055 | 0.86 ± 0 | 0.86 ± 0.088 | 0.85 ± 0.072 | 0.84 ± 0.073 |
| Magnesium: Change at Day 106 (n= 1,0,0,27,11) | -4.4 ± NA | NA ± NA | NA ± NA | -0.02 ± 0.058 | -0.04 ± 0.036 |
| Magnesium: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -0.01 ± 0.079 | -0.06 ± 0.045 |
| Potassium: Baseline (n= 7,3,7,33,13) | 4.34 ± 0.541 | 4.47 ± 0.306 | 4.39 ± 0.09 | 4.29 ± 0.277 | 4.3 ± 0.443 |
| Potassium: Change at Day 106 (n= 1,0,0,27,11) | 1.1 ± NA | NA ± NA | NA ± NA | 0.06 ± 0.366 | 0.11 ± 0.336 |
| Potassium: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 0.04 ± 0.422 | 0.03 ± 0.501 |
| Phosphate: Baseline (n= 7,3,7,33,13) | 1.021 ± 0.168 | 1.167 ± 0.2466 | 0.993 ± 0.369 | 1.058 ± 0.1763 | 1.145 ± 0.1844 |
| Phosphate: Change at Day 106 (n= 1,0,0,27,11) | 0 ± NA | NA ± NA | NA ± NA | 0.086 ± 0.1369 | -0.061 ± 0.2287 |
| Phosphate: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 0.128 ± 0.1734 | 0.203 ± 0.1813 |
| Sodium: Baseline (n= 7,3,7,33,13) | 136.1 ± 4.1 | 137.7 ± 3.51 | 137.4 ± 2.51 | 138.5 ± 2.49 | 137.2 ± 4.72 |
| Sodium: Change at Day 106 (n= 1,0,0,27,11) | 0 ± NA | NA ± NA | NA ± NA | -0.6 ± 2.28 | 0.8 ± 2.56 |
| Sodium: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -0.5 ± 2.41 | 2.3 ± 1.37 |
| Urea: Baseline (n= 7,3,7,33,13) | 9.14 ± 3.092 | 7.83 ± 1.041 | 6.79 ± 2.059 | 7.03 ± 2.304 | 7.78 ± 2.312 |
| Urea: Change at Day 106 (n= 1,0,0,27,11) | 1.5 ± NA | NA ± NA | NA ± NA | -0.26 ± 1.587 | -0.26 ± 1.531 |
| Urea: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -0.15 ± 1.508 | 0.7 ± 1.122 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| giga per liter (GI/L) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Platelets: Baseline (n= 7,3,7,33,13) | 214.1 ± 58.05 | 196.3 ± 51.64 | 266.6 ± 77.43 | 259.6 ± 69.39 | 240.6 ± 52.17 |
| Platelets: Change at Day 106 (n= 1,0,0,27,11) | 169 ± NA | NA ± NA | NA ± NA | -3.1 ± 51.39 | 33 ± 55.17 |
| Platelets: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -22 ± 51.04 | 32.3 ± 68.54 |
| Leukocytes: Baseline (n= 7,3,7,33,13) | 9.13 ± 4.43 | 5.83 ± 1.858 | 8.34 ± 2.783 | 7.67 ± 2.871 | 6.71 ± 2.308 |
| Leukocytes: Change at Day 106 (n= 1,0,0,27,11) | 18.7 ± NA | NA ± NA | NA ± NA | -0.1 ± 2.086 | 2.44 ± 2.263 |
| Leukocytes: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -0.12 ± 2.603 | 1.65 ± 1.946 |
| Lymphocytes: Baseline (n= 7,3,7,33,13) | 1.044 ± 0.4687 | 1.003 ± 0.45 | 0.81 ± 0.4679 | 1.001 ± 0.5902 | 1.068 ± 0.5751 |
| Lymphocytes: Change at Day 106 (n= 1,0,0,27,11) | 1.3 ± NA | NA ± NA | NA ± NA | -0.229 ± 0.5593 | -0.063 ± 0.5129 |
| Lymphocytes: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -0.395 ± 0.3917 | -0.085 ± 0.6832 |
| Neutrophils: Baseline (n= 7,3,7,33,13) | 7.809 ± 4.0998 | 4.71 ± 1.54 | 7.359 ± 2.7781 | 6.363 ± 2.8618 | 5.205 ± 2.1487 |
| Neutrophils: Change at Day 106 (n= 1,0,0,27,11) | 517.3 ± NA | NA ± NA | NA ± NA | 0.178 ± 2.2991 | 2.622 ± 2.5672 |
| Neutrophils: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | 0.341 ± 2.4734 | 2.038 ± 1.8799 |
| Monocytes: Baseline (n= 7,3,7,33,13) | 0.224 ± 0.2319 | 0.103 ± 0.085 | 0.153 ± 0.1379 | 0.243 ± 0.2466 | 0.375 ± 0.4203 |
| Monocytes: Change at Day 106 (n= 1,0,0,27,11) | 0.12 ± NA | NA ± NA | NA ± NA | -0.011 ± 0.2959 | -0.111 ± 0.4164 |
| Monocytes: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -0.014 ± 0.3185 | -0.27 ± 0.2964 |
| Eosinophils: Baseline (n= 7,3,7,33,13) | 0.04 ± 0.0622 | 0.01 ± 0.01 | 0.014 ± 0.0151 | 0.054 ± 0.0734 | 0.043 ± 0.0407 |
| Eosinophils: Change at Day 106 (n= 1,0,0,27,11) | -0.12 ± NA | NA ± NA | NA ± NA | -0.043 ± 0.0797 | -0.008 ± 0.0995 |
| Eosinophils: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -0.049 ± 0.0786 | -0.023 ± 0.0186 |
| Basophils: Baseline (n= 7,3,7,33,13) | 0.013 ± 0.0221 | 0.007 ± 0.0058 | 0.011 ± 0.0107 | 0.012 ± 0.0137 | 0.018 ± 0.0121 |
| Basophils: Change at Day 106 (n= 1,0,0,27,11) | 0.02 ± NA | NA ± NA | NA ± NA | 0.001 ± 0.0169 | -0.001 ± 0.0197 |
| Basophils: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -0.003 ± 0.0136 | -0.015 ± 0.0105 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| tetra per liter (TI/L) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Erythrocytes: Baseline (n= 7,3,7,33,13) | 3.99 ± 0.376 | 3.9 ± 0.361 | 3.9 ± 0.327 | 3.98 ± 0.378 | 4.02 ± 0.519 |
| Erythrocytes: Change at Day 106 (n= 1,0,0,27,11) | -0.4 ± NA | NA ± NA | NA ± NA | -0.25 ± 0.233 | -0.32 ± 0.429 |
| Erythrocytes: Change at Day 190 (n= 0,0,0,23,6) | NA ± NA | NA ± NA | NA ± NA | -0.39 ± 0.287 | -0.15 ± 0.653 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| millimeters of mercury (mmHg) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| SBP: Baseline (n= 7,3,7,33,13) | 137.7 ± 9.11 | 113 ± 12.12 | 131.7 ± 13.07 | 139.2 ± 17.01 | 140.1 ± 10.85 |
| SBP: Change at Day 22 (n= 6,3,7,33,13) | -2.7 ± 13.52 | 2.3 ± 5.51 | -5 ± 12.32 | -1.8 ± 19.66 | -8.5 ± 19.53 |
| SBP: Change at Day 43 (n= 6,3,7,32,13) | -8.7 ± 12.13 | -3 ± 9.54 | -0.9 ± 19.37 | 0.6 ± 18.15 | -15.3 ± 13.91 |
| SBP: Change at Day 64 (n= 6,3,6,30,13) | -9.8 ± 16.36 | -11 ± 13.45 | -4.2 ± 13.66 | -2.5 ± 21.75 | -10.1 ± 13.32 |
| SBP: Change at Day 85 (n= 0,0,0,28,13) | NA ± NA | NA ± NA | NA ± NA | -3.1 ± 16.55 | -3.8 ± 17.19 |
| SBP: Change at Day 106 (n= 0,0,0,28,12) | NA ± NA | NA ± NA | NA ± NA | -6.7 ± 21.33 | -10.4 ± 16.33 |
| SBP: Change at Day 127 (n= 0,0,0,27,8) | NA ± NA | NA ± NA | NA ± NA | -4.6 ± 19.82 | -13.4 ± 22.01 |
| SBP: Change at Day 148 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | -3.9 ± 20.09 | -8.9 ± 18.02 |
| SBP: Change at Day 169 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | -3.6 ± 16.58 | -6.3 ± 17.85 |
| SBP: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -8.1 ± 18.25 | -10 ± 16.15 |
| DBP: Baseline (n= 7,3,7,33,13) | 81.6 ± 5.68 | 62 ± 2 | 74.1 ± 8.86 | 76.1 ± 10.19 | 83 ± 11.17 |
| DBP: Change at Day 22 (n= 6,3,7,33,13) | -2.7 ± 10.67 | 8 ± 10.39 | 2.6 ± 7.57 | 0.3 ± 10.88 | -6.2 ± 16.03 |
| DBP: Change at Day 43 (n= 6,3,7,32,13) | -3.7 ± 6.65 | 2.7 ± 5.03 | 4.1 ± 8.13 | -1.8 ± 12.17 | -11.7 ± 10.89 |
| DBP: Change at Day 64 (n= 6,3,6,30,13) | -8.7 ± 7.89 | -1 ± 1.73 | -0.2 ± 15.93 | -1.4 ± 14.66 | -8.7 ± 9.21 |
| DBP: Change at Day 85 (n= 0,0,0,28,13) | NA ± NA | NA ± NA | NA ± NA | 1.1 ± 10.99 | -7.6 ± 11.2 |
| DBP: Change at Day 106 (n= 0,0,0,28,12) | NA ± NA | NA ± NA | NA ± NA | -0.8 ± 13.15 | -7.9 ± 14.13 |
| DBP: Change at Day 127 (n= 0,0,0,27,8) | NA ± NA | NA ± NA | NA ± NA | -1.4 ± 14.22 | -8 ± 9.94 |
| DBP: Change at Day 148 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | -2 ± 12.19 | -3.9 ± 8.36 |
| DBP: Change at Day 169 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | -1.2 ± 10.45 | -9 ± 8.6 |
| DBP: Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | -3.6 ± 12.8 | -12 ± 8.92 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| breaths/min | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Baseline (n= 7,3,7,33,13) | 19.3 ± 1.63 | 18.7 ± 2.31 | 19.1 ± 1.57 | 17.1 ± 2.67 | 17.5 ± 2.79 |
| Change at Day 22 (n= 6,3,7,33,13) | -1.7 ± 2.34 | -1.3 ± 2.31 | -0.7 ± 1.03 | 0.3 ± 2.1 | -0.4 ± 2.14 |
| Change at Day 43 (n= 6,3,7,32,13) | 0 ± 1.26 | 1.3 ± 4.62 | -0.3 ± 0.82 | 0 ± 3.08 | 0.7 ± 3.5 |
| Change at Day 64 (n= 6,3,6,30,13) | -0.5 ± 2.81 | 0 ± 4 | -1 ± 1.1 | 0.4 ± 2.82 | 0.8 ± 3 |
| Change at Day 85 (n= 0,0,0,28,13) | NA ± NA | NA ± NA | NA ± NA | 0 ± 3.32 | -0.3 ± 2.39 |
| Change at Day 106 (n= 0,0,0,28,12) | NA ± NA | NA ± NA | NA ± NA | -0.8 ± 3.54 | 0.5 ± 3.27 |
| Change at Day 127 (n= 0,0,0,27,8) | NA ± NA | NA ± NA | NA ± NA | 0.9 ± 3.69 | 0.4 ± 1.51 |
| Change at Day 148 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | 0.7 ± 3.38 | -0.3 ± 1.51 |
| Change at Day 169 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | -1 ± 3.11 | 0.4 ± 2.15 |
| Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 0 ± 4.79 | -0.2 ± 1.33 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| beats per min | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Baseline (n= 7,3,7,33,13) | 88.6 ± 18.84 | 58 ± 9.17 | 80 ± 9.93 | 77.9 ± 14.18 | 73.3 ± 12.01 |
| Change at Day 22 (n= 6,3,7,33,13) | -0.2 ± 6.49 | 9.7 ± 18.72 | -0.6 ± 7.76 | 2 ± 11.39 | 7.2 ± 12.17 |
| Change at Day 43 (n= 6,3,7,32,13) | -4.3 ± 9.35 | 18.3 ± 14.57 | 0.9 ± 10.32 | 2.8 ± 11.13 | 4.9 ± 11.54 |
| Change at Day 64 (n= 6,3,6,30,13) | 0.7 ± 7.28 | 13 ± 21.17 | 6.5 ± 11.47 | 3.4 ± 14.48 | 5.1 ± 9.41 |
| Change at Day 85 (n= 0,0,0,28,13) | NA ± NA | NA ± NA | NA ± NA | 2.9 ± 16.17 | 7.2 ± 10.27 |
| Change at Day 106 (n= 0,0,0,28,12) | NA ± NA | NA ± NA | NA ± NA | 0.8 ± 19.18 | 9.2 ± 11.67 |
| Change at Day 127 (n= 0,0,0,27,8) | NA ± NA | NA ± NA | NA ± NA | 2.2 ± 13.93 | 7.5 ± 5.86 |
| Change at Day 148 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | 2.2 ± 15.88 | 15.3 ± 14.38 |
| Change at Day 169 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | 3.6 ± 16.91 | 8 ± 7.72 |
| Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 2.6 ± 16.01 | 18 ± 11.31 |
In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
| kilogram(s) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Baseline (n= 7,3,7,33,13) | 89.3 ± 13.15 | 81.9 ± 21.66 | 97.1 ± 14.29 | 87.7 ± 14.81 | 92 ± 22.28 |
| Change at Day 22 (n= 6,3,7,33,13) | -1.8 ± 1.31 | -0.3 ± 1.55 | -1.4 ± 2.5 | -0.4 ± 1.42 | -0.2 ± 1.92 |
| Change at Day 43 (n= 6,3,7,32,13) | -1 ± 1.95 | 0.2 ± 2.2 | -1 ± 2.99 | 0 ± 2.2 | 0.5 ± 1.98 |
| Change at Day 64 (n= 6,3,6,30,13) | 0.1 ± 4.2 | 0.3 ± 2.04 | -1.2 ± 3.08 | 0.2 ± 2.41 | 0.3 ± 2.48 |
| Change at Day 85 (n= 0,0,0,28,13) | NA ± NA | NA ± NA | NA ± NA | -0.2 ± 3.47 | 0.4 ± 2.87 |
| Change at Day 106 (n= 0,0,0,28,12) | NA ± NA | NA ± NA | NA ± NA | -0.3 ± 3.53 | 0.4 ± 3.1 |
| Change at Day 127 (n= 0,0,0,27,8) | NA ± NA | NA ± NA | NA ± NA | -0.1 ± 4.09 | 2.1 ± 2.11 |
| Change at Day 148 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | -0.1 ± 4.45 | 1.9 ± 2.72 |
| Change at Day 169 (n= 0,0,0,25,7) | NA ± NA | NA ± NA | NA ± NA | -0.1 ± 4.53 | 1.7 ± 3.81 |
| Change at Day 190 (n= 0,0,0,24,6) | NA ± NA | NA ± NA | NA ± NA | 0.1 ± 5 | -0.7 ± 3.59 |
Any physical examination finding that was classified by the investigator as a clinically significant change (compared with previous examination) was considered an AE, documented on the eCRF, and followed until the outcome was known. The below physical examination findings were recorded and reported. GDASC = General disorders and administration site conditions MND = Metabolism and nutrition disorders SSTD= Skin and subcutaneous tissue disorders MCTD = Musculoskeletal and connective tissue disorders IPPC = Injury, poisoning and procedural complications RTMD = Respiratory, thoracic and mediastinal disorders NBMU = Neoplasms benign, malignant and unspecified (include cysts and polyps) In the below table.
| Participants | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| At day 64: GDASC | 0 | 0 | 2 | 5 | 2 |
| At day 64: MND | NA | NA | NA | 0 | 1 |
| At day 64: SSTD | NA | NA | NA | 2 | 6 |
| At day 190: GDASC | NA | NA | NA | 7 | 2 |
| At day 190: MCTD | NA | NA | NA | 1 | 0 |
| At day 190: SSTD | NA | NA | NA | 7 | 2 |
| At day 190: Vascular disorders | NA | NA | NA | 0 | 1 |
| At day 190: Gastrointestinal disorders | NA | NA | NA | 1 | 1 |
| At day 190: IPPC | NA | NA | NA | 2 | 0 |
| At day 190: RTMD | NA | NA | NA | 0 | 1 |
| At day 190: NBMU | NA | NA | NA | 2 | 0 |
| At day 190: Social circumstances | NA | NA | NA | 1 | 0 |
Long-term radiation toxicity included incidence of potential late toxicity, such as new primary cancers and bone marrow changes (acute myelogenous leukemia, myelodysplastic syndrome, and aplastic anemia).
| Participants | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| Number of Subjects With Signs of Long-Term Radiation Toxicity | 2 | 0 |
Weighted mean area under the curve for the below bone turnover biomarkers were evaluated, ICTP = pyridinoline cross-linked carboxyterminal telopeptide P1NP = N-terminal peptide of procollagen type 1 uCTX-1 = urine C-telopeptide 1
| mcg/L | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| uCTX-1 | 14 ± 16.86 | 22.6 ± 28.2 |
| P1NP | 42.9 ± 42.36 | 106.5 ± 118.93 |
| ICTP | 4.7 ± 2.43 | 7 ± 7.08 |
Serum PSA progression defined as two consecutive increases in PSA over a previous reference value within 6 months of first study treatment, each measurement at least 1 week apart.
| days | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| Exploratory Efficacy: Time to Prostate-specific Antigen (PSA) Progression | 200 (175 to 278) | 146 (86 to 169) |
CTCs were measured to follow the evolution of the level of CTCs after treatment.
| Percent Change | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| Exploratory Efficacy: Percent Change From Baseline in Circulating Tumor Cells at Day 85 | -75.3 ± 55.29 | -68.4 ± 61.4 |
Time to first radiologic or clinical progression is determined by one of the following: * For soft tissue lesions, the determination is based on Response Evaluation Criteria in Solid Tumors 1.1. * For bone disease, the determination is based on Prostate Cancer Working Cohort 2 (PCWG2) definitions, which require the appearance of at least 2 new lesions with a confirmatory bone scan at least 6 or more weeks later. For clinical progression, the investigators followed the recommendations of the PCWG25 and used their clinical judgment to determine clinical progression.
| days | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| Exploratory Efficacy: Time to Clinical or Radiographic Progression | 365 (248 to 372) | 284 (96 to 372) |
PFS defined as the time from randomization (randomization referred to the date of treatment assignment) to disease progression (radiological or clinical, whichever was earlier) or death (if death occurred before progression was documented). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.
| days | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| Progression Free Survival (PFS) End Point | 189 (85 to 267) | 146 (86 to 169) |
The overall survival (OS) time in days was calculated as number of days since the day of first dose of study medication until the date of death.
| days | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| Overall Survival Rate | 89.1 (69.8 to 96.4) | 90 (47.3 to 98.5) |
The subject completed the full BPI (short form) paper questionnaire, and clinical staff completed the analgesic log. The test consists of 10 questions addressing severity, location, chronicity, and amount of relief. In question 3, subjects with pain are asked to evaluate the severity of pain at worst in the past 24 hours in a 0 to 10 scale, with 0 indicating no pain, and 10 indicating the worst pain.
| Participants | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|
| Day 1 | 23 | 11 |
| Day 22 | 24 | 11 |
| Day 43 | 22 | 10 |
| Day 64 | 21 | 10 |
| Day 85 | 20 | 11 |
| Day 106 | 20 | 9 |
| Day 127 | 19 | 6 |
| Day 148 | 18 | 5 |
| Day 169 | 17 | 5 |
| Day 190 | 17 | 5 |
| Safety Follow-up | 18 | 9 |
| 6-Month Follow-up | 1 | 2 |
| 9-Month Follow-up | 12 | 7 |
| 12-Month Follow-up | 7 | 5 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | — | 4/7 (57.1%) | 7/7 (100%) |
| Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | — | 0/3 (0%) | 3/3 (100%) |
| Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | — | 2/7 (28.6%) | 7/7 (100%) |
| Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | — | 7/33 (21.2%) | 33/33 (100%) |
| Docetaxel 75 mg/m^2 - Safety Cohort | — | 4/13 (30.8%) | 13/13 (100%) |
| Event | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 2/7 | 0/3 | 2/7 | 0/33 | 2/13 |
| PneumoniaInfections and infestations | 0/7 | 0/3 | 0/7 | 2/33 | 2/13 |
| LeukopeniaBlood and lymphatic system disorders | 1/7 | 0/3 | 0/7 | 0/33 | 0/13 |
| NeutropeniaBlood and lymphatic system disorders | 1/7 | 0/3 | 0/7 | 0/33 | 0/13 |
| IleusGastrointestinal disorders | 1/7 | 0/3 | 0/7 | 0/33 | 0/13 |
| StomatitisGastrointestinal disorders | 1/7 | 0/3 | 0/7 | 0/33 | 0/13 |
| DehydrationMetabolism and nutrition disorders | 1/7 | 0/3 | 0/7 | 0/33 | 0/13 |
| Back painMusculoskeletal and connective tissue disorders | 1/7 | 0/3 | 0/7 | 2/33 | 0/13 |
| Spinal cord compressionNervous system disorders | 1/7 | 0/3 | 0/7 | 0/33 | 0/13 |
| SyncopeNervous system disorders | 0/7 | 0/3 | 1/7 | 0/33 | 0/13 |
| Event | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort |
|---|---|---|---|---|---|
| FatigueGeneral disorders | 5/7 | 3/3 | 4/7 | 17/33 | 9/13 |
| Peripheral sensory neuropathyNervous system disorders | 1/7 | 3/3 | 0/7 | 6/33 | 2/13 |
| NeutropeniaBlood and lymphatic system disorders | 2/7 | 2/3 | 5/7 | 10/33 | 5/13 |
| DiarrhoeaGastrointestinal disorders | 5/7 | 2/3 | 5/7 | 14/33 | 5/13 |
| NauseaGastrointestinal disorders | 3/7 | 1/3 | 2/7 | 16/33 | 8/13 |
| DysgeusiaNervous system disorders | 1/7 | 0/3 | 0/7 | 7/33 | 8/13 |
| Back painMusculoskeletal and connective tissue disorders | 4/7 | 1/3 | 1/7 | 12/33 | 4/13 |
| AlopeciaSkin and subcutaneous tissue disorders | 1/7 | 1/3 | 3/7 | 12/33 | 7/13 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 0/7 | 1/3 | 1/7 | 7/33 | 6/13 |
| VomitingGastrointestinal disorders | 3/7 | 0/3 | 2/7 | 5/33 | 2/13 |
| Age, Customized(participants) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort | Total |
|---|---|---|---|---|---|---|
| <18 years | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 2 | 2 | 3 | 11 | 7 | 25 |
| >65 years | 5 | 1 | 4 | 25 | 10 | 45 |
| Gender(Participants) | Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation | Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation | Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort | Docetaxel 75 mg/m^2 - Safety Cohort | Total |
|---|---|---|---|---|---|---|
| Female | 0 | 0 | 0 | 0 | 0 | 0 |
| Male | 7 | 3 | 7 | 36 | 17 | 70 |
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