Cancer, Prostate
Conditions
Keywords
Cancer, Prostate, IL-6, Mitoxantrone, Metastatic prostate cancer
Brief summary
The purpose of this study is to assess the safety and efficacy of siltuximab administered in combination with mitoxantrone and prednisone in participants with metastatic (spread of cancer cells from one part of the body to another) hormone-refractory (not responding to treatment) prostate cancer (abnormal tissue that grows and spreads in the body) (HRPC).
Detailed description
This is a 2-part, open-label (all people know the identity of the intervention) multicenter (when more than 1 hospital or medical school team work on a medical research study), Phase 2 study to evaluate the safety and efficacy of the combination of siltuximab plus mitoxantrone versus mitoxantrone in participants with metastatic HRPC who have received 1 prior Docetaxel-based chemotherapy (treatment of disease, usually cancer, by chemical agents) regimen (pattern of giving treatment). Part 1 of the study is single arm where participants will receive mitoxantrone, prednisone and siltuximab. Part 2 of the study is randomized portion (the study drug is assigned by chance), consisting of 2-arms. The experimental arm will consist of treatment with mitoxantrone, prednisone and siltuximab. The control arm will consist of treatment with mitoxantrone and prednisone. Mitoxantrone will be administered at a dose of 12 milligram per square meter (mg/m\^2) intravenously (into a vein) as a 30-minute infusion (a fluid or a medicine delivered into a vein by way of a needle) on Day 1 of each 3-week cycle, until disease progression or unacceptable toxicity (any harmful effect of a drug) or up to 10 cycles (a maximum total dose of approximately 120 mg/m\^2). Siltuximab will be administered at a dose of 6 mg/kilogram intravenously as a 2-hour infusion, starting Day 1 of Cycle 1 to continue every 2 weeks until disease progression or unacceptable toxicity or up to a maximum of 1 year. All participants will receive prednisone 5 mg twice daily starting with the first administration of Mitoxantrone. The duration of treatment will be a maximum of 12 months for cumulative dose. Radiologic assessments will be performed on Week 12 after the first study agent dosing, then every 9 weeks until the end of treatment and then once every 3 months until documented disease progression. Tumor (a mass in a specific area) response will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. There will be short-term follow-up visits (conducted monthly for 2 months), followed by long-term follow-up visits (conducted once every 3 months). Participants' safety will also be monitored throughout the study.
Interventions
DRUGMitoxantrone
Mitoxantrone 12 mg/m\^2 intravenously as a 30 minute infusion on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity or up to 10 cycles (a maximum cumulative dose of approximately 120 mg/m\^2)
DRUGSiltuximab
Siltuximab 6 mg/kg intravenously as a 2 hour infusion every 2 weeks until disease progression or unacceptable toxicity or up to a maximum of 1 year
DRUGPrednisone
Prednisone 5 mg orally twice daily
Sponsors
Centocor, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically (the study of tissue under the microscope) or cytologically (the study of cells) confirmed adenocarcinoma (a malignant epithelial tumor with a glandular organization) of the prostate * Radiologically (Gamma and Computed Topography \[CT\] scans) documented metastatic disease * At least 6 weeks of treatment with 1 prior docetaxel-based chemotherapy for metastatic Hormone Refractory Prostate Cancer (HRPC) * Disease progression, during or within 6 months of stopping of prior docetaxel-based therapy, based on one of the following: serum Prostate Specific Antigen (PSA) progression, defined as a rise in at least 2 consecutive serum PSA values, each obtained at least 1 week apart or radiologic disease progression: if disease progression is shown by bone scan only, then disease progression is defined by the appearance of 2 or more new bone lesions (abnormal area of tissue, such as a wound, sore, rash, or boil) * Orchiectomy (surgery to remove one or both testicles) or testosterone less than 50 nanogram per decilliter (ng/dL) by means of pharmacological/chemical castration
Exclusion criteria
* No evidence of a brain tumor * No more than 1 line of chemotherapy for metastatic prostate cancer * No prior mitoxantrone treatment * Prior malignancy (other than prostate cancer) except adequately treated superficial bladder cancer, basal cell or squamous cell carcinoma (type of cancer) of the skin, or other cancer for which the subject has been disease-free for atleast 3 years * No Human Immunodeficiency Virus (HIV) (a life-threatening infection that you can get from an infected person's blood or from having sex with an infected person) seropositivity or hepatitis (inflammation of the liver) B or C infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to 12 weeks after last dose administration | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. An SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. |
| Part 2: Progression Free Survival (PFS) | Randomization, Week 12, then every 9 weeks until 1 month after last dose administration, then every 3 months until disease progression or death, up to 2 years | The PFS is the time from the date of randomization until the first documented sign of progression (at least a 20 percent increase in the sum of the longest diameter \[LD\] of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new target or non-target lesions as per Response Evaluation Criteria in Solid Tumors \[RECIST\] or 3 or more new skeletal lesions on bone scan with confirmation of second bone scan or with clinical deterioration) or death, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Deterioration (TtCD) | Start of treatment (Part 1)/Randomization (Part 2), Week 1 of each cycle up to 1 month after last dose administration, and thereafter every 3 months until clinical deterioration or death, up to 2 years | The TtCD is defined as the time from the start of treatment (for participants in Part 1) or randomization (for participants in Part 2) until the first documented clinical deterioration (consists of pain requiring palliative (intended to relieve pain) intervention (a treatment given during the course of a research study), or death due to any cause, whichever occurs earlier. |
| Number of Participants With Palliative Response | Start of treatment (Part 1)/Randomization (Part 2), Week 1 of each cycle up to 1 month after last dose administration, and thereafter every 3 months up to 2 years | Palliative response was defined as a 2-point or greater reduction from baseline pain, without a categorical increase in prescribed disease-related analgesic (drug used to control pain) use or at least a categorical decrease in disease-related analgesic use without a concomitant (given at the same time) increase in pain. Each component required confirmation at least 3 weeks later. |
| Number of Participants With Prostate Specific Antigen (PSA) Response | Start of treatment (Part 1)/Randomization (Part 2), Week 1 of each cycle up to 1 month after last dose administration, and thereafter every 3 months until disease progression, up to 2 years | The PSA response is defined as at least a 50% reduction in PSA from the Baseline value, confirmed by a second PSA value at least 3 weeks after initial documentation of PSA response. |
| Overall Survival (OS) | Start of treatment (Part 1)/Randomization (Part 2) until death, up to 2 years | The OS is defined as the time from the date of start of treatment (for participants in Part 1) or randomization (for participants in Part 2) to death due to any cause. For participants who were alive at the time of analysis, OS was censored at the last contact date. |
Countries
Austria, Belgium, France, Germany, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Mitoxantrone + Prednisone + Siltuximab Participants received mitoxantrone 12 milligram per square meter (mg/m\^2) intravenously (into a vein) as a 30-minute infusion (a fluid or a medicine delivered into a vein by way of a needle) on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity or up to 10 cycles (a maximum cumulative dose of approximately 120 mg/m\^2) along with siltuximab (CNTO 328) 6 milligram per kilogram (mg/kg) intravenously as a 2-hour infusion every 2 weeks until disease progression or unacceptable toxicity or up to a maximum of 1 year; and prednisone 5 milligram (mg) orally twice daily starting with the first administration of mitoxantrone. | 9 |
| Part 2: Mitoxantrone + Prednisone Participants received mitoxantrone 12 mg/m\^2 intravenously as a 30-minute on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity or up to 10 cycles (a maximum cumulative dose of approximately 120 mg/m\^2) along with prednisone 5 mg orally twice daily starting with the first administration of mitoxantrone. | 49 |
| Part 2: Mitoxantrone + Prednisone + Siltuximab Participants received mitoxantrone 12 mg/m\^2 intravenously as a 30-minute infusion on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity or up to 10 cycles (a maximum cumulative dose of approximately 120 mg/m\^2) along with siltuximab 6 mg/kg intravenously as a 2-hour infusion every 2 weeks until disease progression or unacceptable toxicity or up to a maximum of 1 year; and prednisone 5 mg orally twice daily starting with the first administration of mitoxantrone. | 48 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1 | Adverse Event | 1 | 0 | 0 |
| Part 1 | Death | 2 | 0 | 0 |
| Part 1 | Lack of Efficacy | 5 | 0 | 0 |
| Part 1 | Other | 1 | 0 | 0 |
| Part 2 | Adverse Event | 0 | 6 | 10 |
| Part 2 | Death | 0 | 0 | 2 |
| Part 2 | Lack of Efficacy | 0 | 14 | 13 |
| Part 2 | Other | 0 | 11 | 21 |
| Part 2 | Randomized but not treated | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Part 1: Mitoxantrone + Prednisone + Siltuximab | Part 2: Mitoxantrone + Prednisone | Part 2: Mitoxantrone + Prednisone + Siltuximab | Total |
|---|---|---|---|---|
| Age, Continuous | 69.4 years STANDARD_DEVIATION 7.89 | 67.8 years STANDARD_DEVIATION 7.83 | 67.9 years STANDARD_DEVIATION 9.28 | 68 years STANDARD_DEVIATION 8.46 |
| Region of Enrollment AUSTRIA | 0 participants | 1 participants | 2 participants | 3 participants |
| Region of Enrollment BELGIUM | 0 participants | 6 participants | 6 participants | 12 participants |
| Region of Enrollment FRANCE | 0 participants | 15 participants | 12 participants | 27 participants |
| Region of Enrollment GERMANY | 0 participants | 4 participants | 5 participants | 9 participants |
| Region of Enrollment SPAIN | 0 participants | 7 participants | 4 participants | 11 participants |
| Region of Enrollment UNITED KINGDOM | 0 participants | 5 participants | 6 participants | 11 participants |
| Region of Enrollment UNITED STATES | 9 participants | 11 participants | 13 participants | 33 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 49 Participants | 48 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 42 / 47 | 46 / 46 |
| serious Total, serious adverse events | 5 / 9 | 18 / 47 | 18 / 46 |
Outcome results
Primary
Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. An SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above.
Time frame: Baseline up to 12 weeks after last dose administration
Population: Safety population in Part 1 included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Mitoxantrone + Prednisone + Siltuximab | Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 9 participants |
| Part 1: Mitoxantrone + Prednisone + Siltuximab | Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 5 participants |
Primary
Part 2: Progression Free Survival (PFS)
The PFS is the time from the date of randomization until the first documented sign of progression (at least a 20 percent increase in the sum of the longest diameter \[LD\] of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new target or non-target lesions as per Response Evaluation Criteria in Solid Tumors \[RECIST\] or 3 or more new skeletal lesions on bone scan with confirmation of second bone scan or with clinical deterioration) or death, whichever occurs first.
Time frame: Randomization, Week 12, then every 9 weeks until 1 month after last dose administration, then every 3 months until disease progression or death, up to 2 years
Population: Intent-to-treat (ITT) population in Part 2 included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Mitoxantrone + Prednisone + Siltuximab | Part 2: Progression Free Survival (PFS) | 228.0 days |
| Part 2: Mitoxantrone + Prednisone + Siltuximab | Part 2: Progression Free Survival (PFS) | 97.0 days |
Secondary
Number of Participants With Palliative Response
Palliative response was defined as a 2-point or greater reduction from baseline pain, without a categorical increase in prescribed disease-related analgesic (drug used to control pain) use or at least a categorical decrease in disease-related analgesic use without a concomitant (given at the same time) increase in pain. Each component required confirmation at least 3 weeks later.
Time frame: Start of treatment (Part 1)/Randomization (Part 2), Week 1 of each cycle up to 1 month after last dose administration, and thereafter every 3 months up to 2 years
Population: Data for this outcome measure was not analyzed because minimal efficacy analysis (primary and key secondary endpoints) was done due to early termination of study.
Secondary
Number of Participants With Prostate Specific Antigen (PSA) Response
The PSA response is defined as at least a 50% reduction in PSA from the Baseline value, confirmed by a second PSA value at least 3 weeks after initial documentation of PSA response.
Time frame: Start of treatment (Part 1)/Randomization (Part 2), Week 1 of each cycle up to 1 month after last dose administration, and thereafter every 3 months until disease progression, up to 2 years
Population: Analysis population included all participants who received at least one dose of study drug in Part 1 and all randomized participants in Part 2. Here, 'N' (Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Mitoxantrone + Prednisone + Siltuximab | Number of Participants With Prostate Specific Antigen (PSA) Response | 4 participants |
| Part 2: Mitoxantrone + Prednisone + Siltuximab | Number of Participants With Prostate Specific Antigen (PSA) Response | 12 participants |
| Part 2: Mitoxantrone + Prednisone + Siltuximab | Number of Participants With Prostate Specific Antigen (PSA) Response | 7 participants |
Secondary
Overall Survival (OS)
The OS is defined as the time from the date of start of treatment (for participants in Part 1) or randomization (for participants in Part 2) to death due to any cause. For participants who were alive at the time of analysis, OS was censored at the last contact date.
Time frame: Start of treatment (Part 1)/Randomization (Part 2) until death, up to 2 years
Population: Analysis population included all participants who received at least one dose of study drug in Part 1 and all randomized participants in Part 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Mitoxantrone + Prednisone + Siltuximab | Overall Survival (OS) | 368.0 days |
| Part 2: Mitoxantrone + Prednisone + Siltuximab | Overall Survival (OS) | 394.0 days |
| Part 2: Mitoxantrone + Prednisone + Siltuximab | Overall Survival (OS) | 311.0 days |
Secondary
Time to Clinical Deterioration (TtCD)
The TtCD is defined as the time from the start of treatment (for participants in Part 1) or randomization (for participants in Part 2) until the first documented clinical deterioration (consists of pain requiring palliative (intended to relieve pain) intervention (a treatment given during the course of a research study), or death due to any cause, whichever occurs earlier.
Time frame: Start of treatment (Part 1)/Randomization (Part 2), Week 1 of each cycle up to 1 month after last dose administration, and thereafter every 3 months until clinical deterioration or death, up to 2 years
Population: Analysis population included all participants who received at least one dose of study drug in Part 1 and all randomized participants in Part 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Mitoxantrone + Prednisone + Siltuximab | Time to Clinical Deterioration (TtCD) | 199.0 days |
| Part 2: Mitoxantrone + Prednisone + Siltuximab | Time to Clinical Deterioration (TtCD) | 298.0 days |
| Part 2: Mitoxantrone + Prednisone + Siltuximab | Time to Clinical Deterioration (TtCD) | 183.0 days |