Androgen-independent Prostate Cancer
Conditions
Keywords
Androgen-independent prostate cancer(AIPC)
Brief summary
To determine the time to progression produced by the combination of Novantrone (mitoxantrone) and Erbitux (cetuximab) versus Novantrone alone in metastatic AIPC patients previously treated with docetaxel-based chemotherapy. TTP is defined as time from the start of treatment date to the date the patient is first recorded as having disease progression, even in patients who discontinue study treatment early due to toxicity.
Detailed description
This is a nonblinded, randomized phase II study to determine the activity of Novantrone (mitoxantrone) with or without Erbitux (cetuximab) in patients with androgen independent prostate cancer (AIPC) who have been treated previously with docetaxel chemotherapy. The Novantrone (mitoxantrone)-only treatment arm will serve as a concurrent control arm to aid in the determination of the benefit of the Novantrone (mitoxantrone)-Erbitux (cetuximab) combination in this setting. Patients will be randomly assigned 2:1 to 1 of 2 treatment arms; 93 patients in Arm 1 and 47 patients in Arm 2. A balanced randomization procedure will be performed utilizing a code list that will be developed prior to the study opening. Because the patients will be stratified by performance status (ECOG 0 and 1 vs. ECOG 2), the list will be developed to ensure a balance between the 2 treatment arms.
Interventions
DRUGcetuximab
Erbitux (cetuximab) IV over 2 hours (loading dose) on Day 1 (Cycle 1 only), followed by Erbitux (cetuximab) IV over 1 hour weekly thereafter
DRUGMitoxantrone
Novantrone (mitoxantrone) IV Day 1 + Prednisone QD for ten (10) 21-day cycles Standard androgen deprivation therapy (ADT) will be continued in all patients who enter study on LHRH agonists
Sponsors
Eli Lilly and Company
Oregon Health and Science University
US Oncology Research
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 confirmed adenocarcinoma of the prostate. Note: Patients may have either measurable or non-measurable disease. * Radiographic evidence of regional or distant metastases * Current evidence of progression (by PSA and/or imaging studies) despite standard hormonal therapy. * Progression by PSA will be defined as: A rising PSA defined as: at least 2 rises in PSA over a reference value (PSA #1). The first rising PSA (PSA #2) must be taken at least 1 week after PSA #1. A third PSA (PSA #3) is required to be greater than PSA #2; if not, a fourth PSA (PSA #4) is required to be greater than PSA #2. Progression for nonmeasurable disease will be defined as 2 or more new bone lesions; for measurable disease, progression will be defined by standard RECIST criteria. * For patients who have been on antiandrogen therapy (ie, bicalutamide, flutamide, etc.), patients must have discontinued anti-androgen therapy for at least 6 weeks (4 weeks for flutamide) without evidence of an antiandrogen withdrawal response. A washout period will not be required for patients who did not respond to an antiandrogen prescribed as second line hormonal therapy. For patients whose progression is documented by PSA, the last required PSA must be after the required anti-androgen washout period (4-6 weeks as appropriate). * One prior docetaxel-containing regimen. Patients must have received at least 2 doses in an every 3-week schedule or 6 doses on a weekly schedule of docetaxel. Patients may have discontinued therapy due to progression, intolerance, completion of planned therapy, or other reasons. Chemotherapy treatment with any second-line regimen will not be permitted. Patients who have been previously treated with a first-line docetaxel-based doublet regimen will be eligible for this study, (eg, patients treated on a prior first-line trial containing a docetaxel/carboplatin or other docetaxel-based doublet). * Serum testosterone levels (See protocol for specific details) (unless surgically castrate). Patients must continue androgen deprivation with an LHRH agonist if they have not undergone orchiectomy * ECOG performance status * Laboratory criteria for entry: * absolute neutrophil count * platelets * bilirubin * AST or ALT * Life expectancy greater than 3 months * Age greater than or equal to 18 years * Agree to use contraceptives while on study if sexually active, and for 2 months after the last dose of study drug. * Has signed a Patient Informed Consent Form * Has signed a Patient Authorization Form
Exclusion criteria
* More than 1 prior chemotherapy regimen for metastatic disease * Prior history of uncontrolled congestive heart failure or left ventricular ejection fraction (LVEF) that is less than the institution's lower limit of normal on MUGA or echocardiogram * A second active malignancy (diagnosed within 5 years) except adequately treated non-melanoma skin cancer or other non-invasive or in-situ neoplasm * Significant active concurrent medical illness or infection * Treatment with chemotherapy for AIPC within the past 21 days * Prior treatment with Novantrone (mitoxantrone) * Prior therapy which specifically and directly targets the EGFR pathway * Prior severe infusion reaction to a monoclonal antibody * Recent myocardial infarction (within prior 6 months) * Prior treatment with radionuclides, with the exception of prior treatment with samarium, which will be allowed provided at least 8 weeks have passed since administration. * Is receiving concurrent immunotherapy, hormonal therapy, radiation therapy, or any other non-protocol therapy (excluding LHRH antagonist) * Is receiving concurrent investigational therapy or has received such therapy within the past 30 days * Has evidence of CNS involvement * Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection. * Is unable to comply with requirements of study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Progression (TTP) | 24 months | TTP will be measured from the start of treatment date to the date the patient is first recorded as having disease progression (even in patients who discontinue study treatment early due to toxicity or death due to disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 24 months | ORR = CR + PR Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. |
| Median Time to Prostate-specific Antigen (PSA) Progression | 24 months | Defined as the time from initiation of therapy until the first 25% increase from baseline in non-responders or 50% increase from nadir in responders as defined above. A minimum increase in the PSA of 5 ng/mL will be required for progression. |
| Prostate-specific Antigen (PSA) Response Rate | 24 months | Defined as the fraction of patients with a ≥50% reduction in serum PSA confirmed by a second serum PSA at least 3 weeks later |
| 2-year Radiographically Evident Progression-free Survival (REPFS). | 24 months. | Radiographic progression: 1\) For bone scan, 2 unequivocal new lesions confirmed by a subsequent bone scan with at least 1 more new lesion; 2) Skeletal related event (eg, fracture, need for radiation to bone for pain, spinal cord compression, need for surgery to bone to prevent or treat a pathologic fracture). |
| Median Progression-free Survival (PFS) | 24 months | PFS is measured from the date of randomization to the date of first documented disease progression or date of death, whichever comes first. If a patient neither progresses nor dies, this patient will be censored at last contact date. |
| Median Overall Survival (OS) | 30 months | OS is measured from the date of randomization to the date of death for a dead patient. If a patient is still alive or is lost to follow up, the patient will be censored at the last contact date. |
| Prostate-specific Antigen (PSA) Doubling Time | 24 months | PSA doubling time = \[log (2)× t\] ÷ \[log (final PSA) - log (initial PSA)\] |
Countries
United States
Participant flow
Recruitment details
Between May 2008 and March 2009, 115 eligible patients were enrolled, 75 in the CMP arm and 40 in the MP arm.
Pre-assignment details
5 patients with Withdrew Consent and 23 patients with Failed Entry.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 Novantrone+Erbitux | 75 |
| Arm 2 Novantrone | 40 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 16 | 13 |
| Overall Study | Disease Progression | 44 | 14 |
| Overall Study | Investigator Request | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Patient Request | 6 | 1 |
Baseline characteristics
| Characteristic | Arm 1 | Arm 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 58 Participants | 32 Participants | 90 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 8 Participants | 25 Participants |
| Age, Continuous | 71.5 years STANDARD_DEVIATION 8.7 | 70.7 years STANDARD_DEVIATION 8.1 | 71.2 years STANDARD_DEVIATION 8.5 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 5 participants | 5 participants | 10 participants |
| Race/Ethnicity, Customized Caucasian | 65 participants | 32 participants | 97 participants |
| Race/Ethnicity, Customized Hispanic | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 75 participants | 40 participants | 115 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 75 Participants | 40 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 74 / 75 | 39 / 39 |
| serious Total, serious adverse events | 39 / 75 | 12 / 39 |
Outcome results
Primary
Median Time to Progression (TTP)
TTP will be measured from the start of treatment date to the date the patient is first recorded as having disease progression (even in patients who discontinue study treatment early due to toxicity or death due to disease progression.
Time frame: 24 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Median Time to Progression (TTP) | 4.9 Months |
| Arm 2 | Median Time to Progression (TTP) | 6.6 Months |
Secondary
2-year Radiographically Evident Progression-free Survival (REPFS).
Radiographic progression: 1\) For bone scan, 2 unequivocal new lesions confirmed by a subsequent bone scan with at least 1 more new lesion; 2) Skeletal related event (eg, fracture, need for radiation to bone for pain, spinal cord compression, need for surgery to bone to prevent or treat a pathologic fracture).
Time frame: 24 months.
Population: Patients who received bone scans or had bone progression only (bone pain/pathologic fracture/palliative radiation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | 2-year Radiographically Evident Progression-free Survival (REPFS). | 0.73 Probability of REPFS at 2-year |
| Arm 2 | 2-year Radiographically Evident Progression-free Survival (REPFS). | 0.80 Probability of REPFS at 2-year |
Secondary
Median Overall Survival (OS)
OS is measured from the date of randomization to the date of death for a dead patient. If a patient is still alive or is lost to follow up, the patient will be censored at the last contact date.
Time frame: 30 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Median Overall Survival (OS) | 11.9 months |
| Arm 2 | Median Overall Survival (OS) | 15.7 months |
Secondary
Median Progression-free Survival (PFS)
PFS is measured from the date of randomization to the date of first documented disease progression or date of death, whichever comes first. If a patient neither progresses nor dies, this patient will be censored at last contact date.
Time frame: 24 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Median Progression-free Survival (PFS) | 4.2 months |
| Arm 2 | Median Progression-free Survival (PFS) | 5.5 months |
Secondary
Median Time to Prostate-specific Antigen (PSA) Progression
Defined as the time from initiation of therapy until the first 25% increase from baseline in non-responders or 50% increase from nadir in responders as defined above. A minimum increase in the PSA of 5 ng/mL will be required for progression.
Time frame: 24 months
Population: Patients with Prostate-specific antigen (PSA) Information
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Median Time to Prostate-specific Antigen (PSA) Progression | 2.7 Months |
| Arm 2 | Median Time to Prostate-specific Antigen (PSA) Progression | 2.7 Months |
Secondary
Objective Response Rate (ORR)
ORR = CR + PR Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD.
Time frame: 24 months
Population: Patients with solid tumors
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | Objective Response Rate (ORR) | 2.2 percentage of participants |
| Arm 2 | Objective Response Rate (ORR) | 3.8 percentage of participants |
Secondary
Prostate-specific Antigen (PSA) Doubling Time
PSA doubling time = \[log (2)× t\] ÷ \[log (final PSA) - log (initial PSA)\]
Time frame: 24 months
Population: Evaluable Population with Prostate-specific antigen (PSA) Information
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Prostate-specific Antigen (PSA) Doubling Time | 2.3 months |
| Arm 2 | Prostate-specific Antigen (PSA) Doubling Time | 1.5 months |
Secondary
Prostate-specific Antigen (PSA) Response Rate
Defined as the fraction of patients with a ≥50% reduction in serum PSA confirmed by a second serum PSA at least 3 weeks later
Time frame: 24 months
Population: Evaluable Population with Prostate-specific antigen (PSA) Information
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | Prostate-specific Antigen (PSA) Response Rate | 7.7 percentage of participants |
| Arm 2 | Prostate-specific Antigen (PSA) Response Rate | 17.6 percentage of participants |