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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01106352
First received: April 16, 2010
Last updated: September 20, 2016
Last verified: September 2016
  Purpose
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.

Condition Intervention Phase
Bone Metastases
Castration-Resistant Prostate Cancer
Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
Drug: Docetaxel
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Number of Subjects With Dose-Limiting Toxicities - Dose Escalation Part [ Time Frame: From randomization until 6 weeks post-injection in all dose cohort of dose-escalation part ] [ Designated as safety issue: Yes ]
    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 [ 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 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort) ] [ Designated as safety issue: Yes ]
    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 [ 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) ] [ Designated as safety issue: Yes ]
    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 [ 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) ] [ Designated as safety issue: Yes ]
    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 [ 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) ] [ Designated as safety issue: Yes ]
    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 [ 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) ] [ Designated as safety issue: Yes ]
    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 [ 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) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From start of study treatment upto 12 months ] [ Designated as safety issue: Yes ]
    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).


Other Outcome Measures:
  • Exploratory Efficacy: Weighted Mean Area Under the Curve for Bone Turnover Biomarkers [ 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) ] [ Designated as safety issue: No ]
    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

  • Exploratory Efficacy: Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Exploratory Efficacy: Percent Change From Baseline in Circulating Tumor Cells at Day 85 [ Time Frame: Baseline, Day 85, expanded safety cohort ] [ Designated as safety issue: No ]
    CTCs were measured to follow the evolution of the level of CTCs after treatment.

  • Exploratory Efficacy: Time to Clinical or Radiographic Progression [ Time Frame: From start of study treatment to 12 months, at every 12 weeks ] [ Designated as safety issue: No ]

    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.

  • Progression Free Survival (PFS) End Point [ Time Frame: From start of study treatment to 12 months, at every 12 weeks ] [ Designated as safety issue: No ]
    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.

  • Overall Survival Rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects Who Responded to Interactive Voice Response System (IVRS) Pain [ Time Frame: From start of study treatment until 12 months ] [ Designated as safety issue: No ]
    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.


Enrollment: 70
Study Start Date: July 2010
Study Completion Date: June 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Radium-223 dichloride (Xofigo, BAY88-8223) + docetaxel
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)
Alpharadin (Radium-223 dichloride) is administered intravenously as a bolus injection.
Drug: Docetaxel
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.
Active Comparator: 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
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.

Detailed Description:
The trial was initially conducted and submitted by Algeta ASA. After acquiring Algeta, Bayer is now the sponsor.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01106352

Locations
United States, California
San Francisco, California, United States, 94115
United States, Illinois
Evanston, Illinois, United States, 60201
United States, Maryland
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Boston, Massachusetts, United States, 02115-6013
United States, New York
New York, New York, United States, 10065
United States, Washington
Seattle, Washington, United States, 98109
France
Villejuif Cedex, France, 94805
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01106352     History of Changes
Other Study ID Numbers: 15469  BC1-10  2011-000822-31 
Study First Received: April 16, 2010
Results First Received: June 14, 2016
Last Updated: September 20, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Bayer:
The target population is patients with bone metastasis from castration-resistant prostate cancer intended for treatment with docetaxel

Additional relevant MeSH terms:
Prostatic Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Bone Neoplasms
Bone Marrow Diseases
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Neoplastic Processes
Pathologic Processes
Bone Diseases
Musculoskeletal Diseases
Hematologic Diseases
Dexamethasone
Prednisone
Docetaxel
Radium Ra 223 dichloride
Succinylcholine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on December 09, 2016