Prostate Cancer
Conditions
Brief summary
The purpose of this study is to evaluate safety and efficacy of Omnitarg (Pertuzumab) on cancerous lesions in men with castration-resistant (hormone-refractory) prostate cancer.
Interventions
DRUGrhuMAb 2C4 (pertuzumab)
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * Age \>= 18 years old * Histologically documented adenocarcinoma of the prostate, clinically refractory or resistant to hormone therapy, as assessed by progression following at least one hormonal therapy (orchiectomy or luteinizing hormone-releasing hormone \[LHRH\] agonist). Subjects must have documented progression following hormonal therapy withdrawal of \>= 4 weeks duration; nilutamide and bicalutamide require 6 weeks withdrawal. * Progression of disease after one prior chemotherapy regimen (which must have been taxane-based) for CRPC. Progression is defined as at least one of the following: A minimum of three consecutive serum PSA measurements obtained \>= 14 days apart and all within 3 months, with progressively increasing values for two consecutive measurements. The latest value must be obtained within the screening period and must be \>= 5 ng/mL; or progression of measurable disease, as defined by RECIST; or progression of bone disease, as defined by the appearance of one or more new bone lesions * Orchiectomy, or castrate levels of testosterone maintained by LHRH agonist \<70 ng/mL * Life expectancy \>= 12 weeks * ECOG performance status of 0 or 1 * Granulocyte count of \>= 1500/mL, platelet count of \>= 75,000/mL and hemoglobin of \>= 9 g/dL (hemoglobin may be supported by transfusion or erythropoietin or other approved hematopoietic growth factors; darbopoeitin \[Aranesp\] is permitted) * Serum bilirubin less than or equal to the upper limit of normal (ULN), unless due to Gilbert's disease, and alkaline phosphatase, AST, and ALT \<= 2.5 x ULN (ALT, AST, and alkaline phosphatase \<= 5 x ULN for subjects with liver metastases; no alkaline phosphatase upper limit for subjects with bone metastases) * Serum creatinine \<= 1.5 x ULN * International normalized ratio (INR) \<1.5 and activated partial thromboplastin time (aPTT) \<1.5 x ULN (except for subjects receiving warfarin) * Willing to complete serial PROSQOLI/PPI evaluations and serial diaries of analgesic use (if necessary)
Exclusion criteria
* Prior chemotherapy, radiotherapy, therapeutic radionucleotide or immunotherapy within 4 weeks of Day 1 (the day of the first rhuMAb 2C4 dose). Flutamide therapy, or other second line hormonal therapies should be withdrawn \>= 4 weeks prior to Day 1. Bicalutamide and nilutamide therapy should be withdrawn \>= 6 weeks prior to starting study medication. * Prior treatment with HER2 pathway inhibitors (e.g., Herceptin \[Trastuzumab\], Iressa \[gefitinib\], Tarceva \[erlotinib hydrochloride\], C225, CI1033, and TAK165) * Treatment with other experimental anticancer agents within 4 weeks prior to Day 1 * Prior history or clinical evidence of central nervous system or brain metastases * Ejection fraction, determined by ECHO, \<50% * Uncontrolled hypercalcemia (\>11.5 mg/dL) * Prior exposure of \>360 mg/m2 doxorubicin, \>120 mg/m2 mitoxantrone, or \>90 mg/m2 idarubicin * Ongoing corticosteroid treatment, except for subjects who are on stable doses of \<20 mg of prednisone daily (or equivalent), or who are taking corticosteroids for reasons unrelated to prostate cancer * History of other malignancies within 5 years prior to Day 1, except for adequately treated basal or squamous cell skin cancer * History of serious systemic disease, including active infection, uncontrolled hypertension (diastolic blood pressure \>100 mmHg on two consecutive occasions), unstable angina, congestive heart failure, or myocardial infarction within 6 months prior to Day 1, or unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation, paroxysmal supraventricular tachycardia, or controlled hypertension are eligible) * Ongoing liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis * Known human immunodeficiency virus infection * Major surgery or significant traumatic injury within 3 weeks prior to Day 1 * Inability to comply with study and follow-up procedures * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk for treatment complications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Best Overall Confirmed Response of Complete Response (CR) or Partial Response (PR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) and Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria | Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab | Response by tumor measurement occurred if there was documented and confirmed CR or PR. Response was assessed by both the RECIST and by PSA levels measurement, based on measurable or non-measurable disease at baseline. Per RECIST, CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. A PSA response was defined as a PSA decline of greater than or equal to (≥) 50%, which had to be confirmed by a second PSA value at least 4 weeks later. |
| Kaplan Meier Estimate of Percentage of Participants With Disease Progression at 3 Months | 3 months | Per RECIST, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of longest diameter recorded since the treatment started or the appearance of 1 or more new lesions, and/or unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Progression or Death (Progression Free Survival [PFS]) | Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab | PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment. The percentage of participants experiencing disease progression or death was calculated as the number of participants with an event divided by the number of participants analyzed, multiplied by 100. |
| Median Time of PFS | Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab | PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment. |
| Duration of Response | Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab | Duration of response was defined as the time from the initial CR or PR to the time of disease progression. |
| Percentage of Participants Who Progressed at 3, 6 and 9 Months | 3, 6, and 9 months | Per RECIST, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of longest diameter recorded since the treatment started or the appearance of 1 or more new lesions, and/or unequivocal progression of existing non-target lesions. Percentage of participants who were free from disease progression was calculated by subtracting the number of participants with disease progression at that time point from the total population at risk of disease progression, multiplied by 100. |
| Serum Concentrations of Pertuzumab | Assessed at pre-dose, 15-minutes postdose on Day 1 (Cycle 1), Day 22 (Cycle 2), Day 43 (Cycle 3), Day 85 (Cycle 5), and Day 169 (Cycle 9); pre-dose on Day 253 (Cycle 13), and on Days 8, 15, 29 and 36 | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pertuzumab All the participants received a loading dose of 840 mg of pertuzumab on Day 1 of Cycle 1, followed by 420 mg on Day 1 of each subsequent 21-day cycle. Pertuzumab was administered as an IV infusion every 3 weeks for up to 1 year (17 cycles) for participants who showed no evidence of progression. Participants with evidence of disease progression could have continued pertuzumab therapy, at the discretion of the investigator, if they had improvement in pain without an increase in narcotic use and if they had no other therapeutic options. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 24 |
| Overall Study | Physician Decision | 9 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Pertuzumab |
|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 39 / 41 |
| serious Total, serious adverse events | 11 / 41 |
Outcome results
Primary
Kaplan Meier Estimate of Percentage of Participants With Disease Progression at 3 Months
Per RECIST, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of longest diameter recorded since the treatment started or the appearance of 1 or more new lesions, and/or unequivocal progression of existing non-target lesions.
Time frame: 3 months
Population: Efficacy analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab | Kaplan Meier Estimate of Percentage of Participants With Disease Progression at 3 Months | 80 percentage of participants |
Primary
Percentage of Participants With a Best Overall Confirmed Response of Complete Response (CR) or Partial Response (PR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) and Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria
Response by tumor measurement occurred if there was documented and confirmed CR or PR. Response was assessed by both the RECIST and by PSA levels measurement, based on measurable or non-measurable disease at baseline. Per RECIST, CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. A PSA response was defined as a PSA decline of greater than or equal to (≥) 50%, which had to be confirmed by a second PSA value at least 4 weeks later.
Time frame: Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab
Population: Efficacy analysis population: All participants who received at least 1 dose of study drug and either underwent at least 1 postbaseline assessment of response or died within 30 days after the last study treatment before any evaluation of response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab | Percentage of Participants With a Best Overall Confirmed Response of Complete Response (CR) or Partial Response (PR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) and Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria | 0.0 percentage of participants |
Secondary
Duration of Response
Duration of response was defined as the time from the initial CR or PR to the time of disease progression.
Time frame: Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab
Population: No participants experienced either CR or PR.
Secondary
Median Time of PFS
PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment.
Time frame: Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab
Population: Efficacy analysis population. Five participants were censored for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab | Median Time of PFS | 9.6 weeks |
Secondary
Percentage of Participants Who Progressed at 3, 6 and 9 Months
Per RECIST, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of longest diameter recorded since the treatment started or the appearance of 1 or more new lesions, and/or unequivocal progression of existing non-target lesions. Percentage of participants who were free from disease progression was calculated by subtracting the number of participants with disease progression at that time point from the total population at risk of disease progression, multiplied by 100.
Time frame: 3, 6, and 9 months
Population: Efficacy analysis population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pertuzumab | Percentage of Participants Who Progressed at 3, 6 and 9 Months | % of participants progressed at 3 months | 66.7 percentage of participants |
| Pertuzumab | Percentage of Participants Who Progressed at 3, 6 and 9 Months | % of participants progressed at 6 months | 80.0 percentage of participants |
| Pertuzumab | Percentage of Participants Who Progressed at 3, 6 and 9 Months | % of participants progressed at 9 months | 83.3 percentage of participants |
Secondary
Percentage of Participants With Disease Progression or Death (Progression Free Survival [PFS])
PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment. The percentage of participants experiencing disease progression or death was calculated as the number of participants with an event divided by the number of participants analyzed, multiplied by 100.
Time frame: Screening, Day 1 of Cycles 1-17, and at 30 days after the last dose of pertuzumab
Population: Efficacy analysis population. Five participants were censored for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab | Percentage of Participants With Disease Progression or Death (Progression Free Survival [PFS]) | 83.3 percentage of participants |
Secondary
Serum Concentrations of Pertuzumab
Time frame: Assessed at pre-dose, 15-minutes postdose on Day 1 (Cycle 1), Day 22 (Cycle 2), Day 43 (Cycle 3), Day 85 (Cycle 5), and Day 169 (Cycle 9); pre-dose on Day 253 (Cycle 13), and on Days 8, 15, 29 and 36
Population: Pharmacokinetic evaluable participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 1, 15 minutes postdose (n=38) | 254.71 micrograms per milliliter (µg/mL) | Standard Deviation 46.85 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 8 (n=39) | 97.51 micrograms per milliliter (µg/mL) | Standard Deviation 25.93 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 15 (n=38) | 69.23 micrograms per milliliter (µg/mL) | Standard Deviation 19.13 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 22 pre-dose (n=33) | 52.41 micrograms per milliliter (µg/mL) | Standard Deviation 15.23 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 22, 15 minutes postdose (n=31) | 175.87 micrograms per milliliter (µg/mL) | Standard Deviation 34.7 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 29 (n=30) | 88.17 micrograms per milliliter (µg/mL) | Standard Deviation 27.83 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 36 (n=32) | 67.45 micrograms per milliliter (µg/mL) | Standard Deviation 21.46 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 43 pre-dose (n=26) | 53.09 micrograms per milliliter (µg/mL) | Standard Deviation 19.45 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 43, 15 minutes postdose (n=23) | 176.17 micrograms per milliliter (µg/mL) | Standard Deviation 32.43 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 85 pre-dose (n=5) | 67.36 micrograms per milliliter (µg/mL) | Standard Deviation 23.66 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 85, 15 minutes postdose (n=4) | 199.50 micrograms per milliliter (µg/mL) | Standard Deviation 35.07 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 169 pre-dose (n=3) | 75.97 micrograms per milliliter (µg/mL) | Standard Deviation 49.41 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 169, 15 minutes postdose (n=3) | 207.67 micrograms per milliliter (µg/mL) | Standard Deviation 71.7 |
| Pertuzumab | Serum Concentrations of Pertuzumab | Day 253 pre-dose (n=1) | 40.7 micrograms per milliliter (µg/mL) | — |