Mitoxantrone ± Cetuximab 2nd Line Androgen Independent Prostate Cancer (AIPC)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Phase II Study of Mitoxantrone vs. Mitoxantrone With Cetuximab in Metastatic Androgen Independent Prostate Cancer (AIPC) Previously Treated With Docetaxel-based Chemotherapy

Conditions
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Androgen-independent Prostate Cancer

Intervention / Treatment
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* Drug: cetuximab
* Drug: Mitoxantrone


Participation Criteria
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Eligibility Criteria
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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

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: Arm 1<br>Erbitux (cetuximab) and Novantrone (mitoxantrone) | Drug: cetuximab<br>* Erbitux (cetuximab) IV over 2 hours (loading dose) on Day 1 (Cycle 1 only), followed by Erbitux (cetuximab) IV over 1 hour weekly thereafter<br>* Other names: Erbitux;Drug: Mitoxantrone<br>* 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<br>* Other names: Novantrone;|
| Experimental: Arm 2<br>Novantrone (mitoxantrone) | Drug: Mitoxantrone<br>* 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<br>* Other names: Novantrone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 24 months. | 
| 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. | 24 months | 
| 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. | 24 months | 
| 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 | 24 months | 
| Prostate-specific Antigen (PSA) Doubling Time | PSA doubling time = [log (2)× t] ÷ [log (final PSA) - log (initial PSA)] | 24 months | 
| 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. | 24 months | 
| 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. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Androgen-independent prostate cancer(AIPC)