Back to resultsA Study of Alpharadin With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer (CRPC)
Primary Purpose
Bone Metastases, Castration-Resistant Prostate Cancer
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Radium-223 dichloride (Xofigo, BAY88-8223)
Docetaxel
Sponsored by
About this trial
This is an interventional treatment trial for Bone Metastases focused on measuring The target population is patients with bone metastasis from castration-resistant prostate cancer intended for treatment with docetaxel
Eligibility Criteria
Inclusion Criteria:
- Histologically or cytologically confirmed adenocarcinoma of the prostate.
- Two or more bone metastases (hot spots) confirmed by bone scintigraphy within 8 weeks prior to study entry
- Known castration-resistant disease
- Karnofsky Performance Status (KPS): ≥70% within 14 days before start of study treatment (ECOG 1)
- Life expectancy at least 6 months.
- Acceptable hematology and serum biochemistry screening values
- Eligible for use of docetaxel according to the product information (package insert or similar).
Exclusion Criteria:
- Has received an investigational therapeutic drug within the last 4 weeks prior to start of study treatment, or is scheduled to receive one during the treatment period.
- Has received external radiotherapy within the last 4 weeks prior to start of study treatment.
- Has an immediate need for radiotherapy.
- Has received prior hemibody external radiotherapy .
- Has received systemic radiotherapy (e.g. samarium, strontium etc.) for the treatment of bone metastases.
- Has received cytotoxic chemotherapy within the last 4 weeks prior to start of study treatment, or has not recovered to grade 1 or 0 from adverse events due to cytotoxic chemotherapy administered more than 4 weeks earlier.
- Has received more than ten previous infusions of docetaxel.
- Previous known experience of grade ≥ 3 docetaxel related toxicities or docetaxel toxicity related dose interruption or discontinuation.
- Previous use of G-CSF for persistent neutropenia after docetaxel treatment.
- Has received blood transfusion or erythropoietin (EPO) within the last 4 weeks prior to start of study treatment.
- Has received prior treatment with Alpharadin.
- Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.
- Symptomatic nodal disease, i.e. scrotal, penile or leg edema.
- Visceral metastases from CRPC (>2 lung and/or liver metastases [size ≥2cm]), as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to start of study treatment.
- Uncontrolled loco-regional disease.
- Other primary tumor (other than CRPC) including haematological malignancy present within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer).
- Has imminent or established spinal cord compression based on clinical findings and/or MRI.
- Unmanageable fecal incontinence
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Radium-223 dichloride (Xofigo, BAY88-8223) + docetaxel
Docetaxel
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01106352
Brief Title
A Study of Alpharadin With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer (CRPC)
Official Title
A Phase I/IIa Study of Safety and Efficacy of Alpharadin® With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
November 2016
Overall Recruitment Status
Completed
Study Start Date
July 2010 (undefined)
Primary Completion Date
June 2015 (Actual)
Study Completion Date
June 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
Detailed Description
The trial was initially conducted and submitted by Algeta ASA. After acquiring Algeta, Bayer is now the sponsor.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bone Metastases, Castration-Resistant Prostate Cancer
Keywords
The target population is patients with bone metastasis from castration-resistant prostate cancer intended for treatment with docetaxel
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
70 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Radium-223 dichloride (Xofigo, BAY88-8223) + docetaxel
Arm Type
Experimental
Arm Description
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.
Arm Title
Docetaxel
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Radium-223 dichloride (Xofigo, BAY88-8223)
Intervention Description
Alpharadin (Radium-223 dichloride) is administered intravenously as a bolus injection.
Intervention Type
Drug
Intervention Name(s)
Docetaxel
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of Subjects With Dose-Limiting Toxicities - Dose Escalation Part
Description
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
Title
Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Treatment-Emergent Serious Adverse Events (TESAE) With a CTCAE Grade of 3 or 4
Description
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
Title
Change From Baseline in Serum Biochemistry (Albumin, Protein, Hemoglobin) During the Treatment Period
Description
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)
Title
Change From Baseline in Serum Biochemistry (Alkaline Phosphatase [AP], Alanine Aminotransferase [AAT], Lactate Dehydrogenase [LD]) During the Treatment Period
Description
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)
Title
Change From Baseline in Serum Biochemistry (Bilirubin, Creatinine) During the Treatment Period
Description
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)
Title
Change From Baseline in Serum Biochemistry (Calcium, Chloride, Magnesium, Potassium, Phosphate, Sodium, Urea) During the Treatment Period
Description
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)
Title
Change From Baseline in Serum Biochemistry (Platelets, Leukocytes, Lymphocytes, Neutrophils, Monocytes, Eosinophils, Basophils) During the Treatment Period
Description
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)
Title
Change From Baseline in Serum Biochemistry (Erythrocytes) During the Treatment Period
Description
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)
Title
Changes From Baseline in Systolic and Diastolic Blood Pressure During the Treatment Period
Description
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)
Title
Changes From Baseline in Respiratory Rate During the Treatment Period
Description
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)
Title
Changes From Baseline in Heart Rate During the Treatment Period
Description
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)
Title
Changes From Baseline in Weight During the Treatment Period
Description
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)
Title
Number of Subjects With Physical Examination During the Treatment Period
Description
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)
Title
Number of Subjects With Signs of Long-Term Radiation Toxicity
Description
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
Other Pre-specified Outcome Measures:
Title
Exploratory Efficacy: Weighted Mean Area Under the Curve for Bone Turnover Biomarkers
Description
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)
Title
Exploratory Efficacy: Time to Prostate-specific Antigen (PSA) Progression
Description
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
Title
Exploratory Efficacy: Percent Change From Baseline in Circulating Tumor Cells at Day 85
Description
CTCs were measured to follow the evolution of the level of CTCs after treatment.
Time Frame
Baseline, Day 85, expanded safety cohort
Title
Exploratory Efficacy: Time to Clinical or Radiographic Progression
Description
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
Title
Progression Free Survival (PFS) End Point
Description
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
Title
Overall Survival Rate
Description
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
Title
Number of Subjects Who Responded to Interactive Voice Response System (IVRS) Pain
Description
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
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically or cytologically confirmed adenocarcinoma of the prostate.
Two or more bone metastases (hot spots) confirmed by bone scintigraphy within 8 weeks prior to study entry
Known castration-resistant disease
Karnofsky Performance Status (KPS): ≥70% within 14 days before start of study treatment (ECOG 1)
Life expectancy at least 6 months.
Acceptable hematology and serum biochemistry screening values
Eligible for use of docetaxel according to the product information (package insert or similar).
Exclusion Criteria:
Has received an investigational therapeutic drug within the last 4 weeks prior to start of study treatment, or is scheduled to receive one during the treatment period.
Has received external radiotherapy within the last 4 weeks prior to start of study treatment.
Has an immediate need for radiotherapy.
Has received prior hemibody external radiotherapy .
Has received systemic radiotherapy (e.g. samarium, strontium etc.) for the treatment of bone metastases.
Has received cytotoxic chemotherapy within the last 4 weeks prior to start of study treatment, or has not recovered to grade 1 or 0 from adverse events due to cytotoxic chemotherapy administered more than 4 weeks earlier.
Has received more than ten previous infusions of docetaxel.
Previous known experience of grade ≥ 3 docetaxel related toxicities or docetaxel toxicity related dose interruption or discontinuation.
Previous use of G-CSF for persistent neutropenia after docetaxel treatment.
Has received blood transfusion or erythropoietin (EPO) within the last 4 weeks prior to start of study treatment.
Has received prior treatment with Alpharadin.
Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.
Symptomatic nodal disease, i.e. scrotal, penile or leg edema.
Visceral metastases from CRPC (>2 lung and/or liver metastases [size ≥2cm]), as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to start of study treatment.
Uncontrolled loco-regional disease.
Other primary tumor (other than CRPC) including haematological malignancy present within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer).
Has imminent or established spinal cord compression based on clinical findings and/or MRI.
Unmanageable fecal incontinence
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
City
Evanston
State/Province
Illinois
ZIP/Postal Code
60201
Country
United States
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115-6013
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
City
Villejuif Cedex
ZIP/Postal Code
94805
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
31082669
Citation
Morris MJ, Loriot Y, Sweeney CJ, Fizazi K, Ryan CJ, Shevrin DH, Antonarakis ES, Pandit-Taskar N, Deandreis D, Jacene HA, Vesselle H, Petrenciuc O, Lu C, Carrasquillo JA, Higano CS. Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial. Eur J Cancer. 2019 Jun;114:107-116. doi: 10.1016/j.ejca.2019.04.007. Epub 2019 May 11.
Results Reference
derived
PubMed Identifier
26854432
Citation
Gkialas IK, Fragkoulis C. Emerging therapies targeting castration-resistant prostate cancer. J BUON. 2015 Nov-Dec;20(6):1389-96.
Results Reference
derived
Links:
URL
http://www.clinicaltrialsregister.eu/
Description
Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
Learn more about this trial
A Study of Alpharadin With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer (CRPC)
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