A Study of Alpharadin With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer (CRPC)

Study Overview
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Brief Summary
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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
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The trial was initially conducted and submitted by Algeta ASA. After acquiring Algeta, Bayer is now the sponsor.

Official Title
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A Phase I/IIa Study of Safety and Efficacy of Alpharadin® With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer

Conditions
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Bone Metastases, Castration-Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 dichloride (Xofigo, BAY88-8223) + docetaxel<br>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)<br>* Alpharadin (Radium-223 dichloride) is administered intravenously as a bolus injection.<br>Drug: Docetaxel<br>* 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.<br>|
| Active Comparator: Docetaxel<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | From start of study treatment upto 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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The target population is patients with bone metastasis from castration-resistant prostate cancer intended for treatment with docetaxel