A Study of IMC-A12 or Ramucirumab Plus Mitoxantrone and Prednisone in Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether IMC-A12 or IMC-1121B (ramucirumab) with Mitoxantrone and Prednisone is effective in the treatment of metastatic androgen- independent prostate cancer (APIC).

Detailed Description
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Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer-related death in men in the United States. Chemotherapy, either as a single agent or in combination, may lead to clinical response, pain control, and/or improved quality of life. Docetaxel is now the first-line standard therapy for AIPC. Mitoxantrone was approved in 1996 for use in combination with corticosteroids as initial chemotherapy for pain related to advanced Hormone Refractory Prostate Cancer (HRPC). Hormonal manipulations and docetaxel-based chemotherapy are often effective in metastatic prostate cancer; however, disease becomes refractory to these interventions in the majority of men. Although mitoxantrone continues to be a significant agent in the treatment of HRPC, there exists a need for more efficacious therapy in docetaxel-refractory- AIPC. Because of the potential contribution of Insulin Like Growth Factor Receptor (IGF-IR) and VEGFR-2 mediated pathways in prostate cancer pathogenesis, it is hypothesized that each of these biological agents in combination with mitoxantrone and prednisone will result in clinically meaningful activity in AIPC. Therefore, ImClone plans to conduct a randomized Phase 2 trial to assess the safety and efficacy of IMC-A12 or IMC-1121B (ramucirumab) in combination with mitoxantrone and prednisone in participants with AIPC.

Official Title
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A Phase 2, Multicenter, Randomized Study of IMC-A12 or IMC-1121B Plus Mitoxantrone and Prednisone in Metastatic Androgen-Independent Prostate Cancer (AIPC) Following Disease Progression on Docetaxel-Based Chemotherapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Biological: IMC-A12
* Drug: Mitoxantrone
* Drug: Prednisone
* Biological: IMC-1121B (ramucirumab)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has histologically-confirmed adenocarcinoma of the prostate The participant has radiographic evidence of metastatic prostate cancer (stage M1 or D2) The participant has prostate cancer unresponsive or refractory to hormone therapy (androgen-independent) The participant has had disease progression (clinical or radiographic) while receiving docetaxel, or within 120 days of receiving docetaxel-based chemotherapy and in the opinion of the investigator is unlikely to derive significant benefit from additional docetaxel-based therapy, or was intolerant to therapy with this agent The participant must have evidence of progressive disease defined as at least one of the following; Progressive measurable disease: using conventional solid tumor criteria Bone scan progression: at least two new lesions on bone scan Increasing PSA: at least two consecutive rising PSA values over a reference value (PSA #1) taken at least 1 week apart. 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 The participant has a PSA ≥ 2 ng/mL The participant has prior surgical or medical castration with a serum testosterone of <50 ng/mL. If the method of castration is luteinizing hormone releasing level hormone (LHRH) agonists, the participant must be willing to continue the use of LHRH agonists during protocol treatment The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 The participant has adequate hematologic function (absolute neutrophil count [ANC]≥1500/uL, hemoglobin ≥9 g/dL, and platelets ≥100,000/uL) The participant has adequate hepatic function (bilirubin ≤ 1.5 times the upper limit of normal (ULN), Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 3 times the ULN, or ≤ 5 times the ULN if liver metastases are present) The participant has adequate renal function (creatinine ≤ 1.5 x ULN or calculated creatinine clearance > 40 mL/min) The participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA). If urine dipstick or routine analysis indicates ≥ 2+ proteinuria, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study The participant has adequate coagulation function (an international normalized ratio [INR] ≤ 1.5 and a Partial Thromboplastin Time [PTT] ≤ 5 seconds above the ULN [unless on oral anticoagulant therapy]). Participants receiving full-dose anticoagulation therapy are eligible provided they meet all other criteria, are on a stable dose of oral anticoagulant or low molecular weight heparin (and if on warfarin have a therapeutic INR between 2 and 3) The participant has a fasting serum glucose level of < 160 mg/dL, or below the ULN Exclusion Criteria: The participant has received more than one prior cytotoxic chemotherapy regimen for metastatic disease. (Participants who have had a treatment break followed by a second docetaxel-based regimen with subsequent disease progression are eligible.) The participant has received prior therapy with mitoxantrone for advanced prostate cancer (prior adjuvant therapy with mitoxantrone is permitted) The participant has a history of symptomatic congestive heart failure or has a pre-study echocardiogram or multigated acquisition (MUGA) scan with left ventricular ejection fraction (LVEF) that is ≥ 10% below the LLN The participant has received radiotherapy ≤ 21 days prior to first dose of IMC-A12 or Ramucirumab The participant is receiving corticosteroids (dexamethasone, prednisone, or others) at a dose > 5 mg prednisone orally (PO) two times per day (BID) or equivalent. Participants receiving corticosteroids at higher doses may be eligible if their corticosteroid therapy is tapered to study levels (prednisone 5 mg PO BID) prior to first dose of study medication, without concomitant clinical deterioration The participant has known or suspected brain or leptomeningeal metastases The participant has uncontrolled or poorly controlled hypertension The participant has poorly controlled diabetes mellitus. Inclusion Criteria: The participant has histologically-confirmed adenocarcinoma of the prostate The participant has radiographic evidence of metastatic prostate cancer (stage M1 or D2) The participant has prostate cancer unresponsive or refractory to hormone therapy (androgen-independent) The participant has had disease progression (clinical or radiographic) while receiving docetaxel, or within 120 days of receiving docetaxel-based chemotherapy and in the opinion of the investigator is unlikely to derive significant benefit from additional docetaxel-based therapy, or was intolerant to therapy with this agent The participant must have evidence of progressive disease defined as at least one of the following; Progressive measurable disease: using conventional solid tumor criteria Bone scan progression: at least two new lesions on bone scan Increasing PSA: at least two consecutive rising PSA values over a reference value (PSA #1) taken at least 1 week apart. 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 The participant has a PSA ≥ 2 ng/mL The participant has prior surgical or medical castration with a serum testosterone of <50 ng/mL. If the method of castration is luteinizing hormone releasing level hormone (LHRH) agonists, the participant must be willing to continue the use of LHRH agonists during protocol treatment The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 The participant has adequate hematologic function (absolute neutrophil count [ANC]≥1500/uL, hemoglobin ≥9 g/dL, and platelets ≥100,000/uL) The participant has adequate hepatic function (bilirubin ≤ 1.5 times the upper limit of normal (ULN), aspartate transaminase [AST] and alanine transaminase [ALT]≤ 3 times the ULN, or ≤ 5 times the ULN if liver metastases are present) The participant has adequate renal function (creatinine ≤ 1.5 x ULN or calculated creatinine clearance > 40 mL/min) The participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA). If urine dipstick or routine analysis indicates ≥ 2+ proteinuria, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study The participant has adequate coagulation function (an international normalized ratio [INR] ≤ 1.5 and a partial thromboplastin time [PTT] ≤ 5 seconds above the ULN [unless on oral anticoagulant therapy]). Participants receiving full-dose anticoagulation therapy are eligible provided they meet all other criteria, are on a stable dose of oral anticoagulant or low molecular weight heparin (and if on warfarin have a therapeutic INR between 2 and 3) The participant has a fasting serum glucose level of < 160 mg/dL, or below the ULN Exclusion Criteria: The participant has received more than one prior cytotoxic chemotherapy regimen for metastatic disease. (Participants who have had a treatment break followed by a second docetaxel-based regimen with subsequent disease progression are eligible.) The participant has received prior therapy with mitoxantrone for advanced prostate cancer (prior adjuvant therapy with mitoxantrone is permitted) The participant has a history of symptomatic congestive heart failure or has a pre-study echocardiogram or multigated acquisition (MUGA) scan with left ventricular ejection fraction (LVEF) that is ≥ 10% below the LLN The participant has received radiotherapy ≤ 21 days prior to first dose of IMC-A12 or Ramucirumab The participant is receiving corticosteroids (dexamethasone, prednisone, or others) at a dose > 5 mg prednisone orally (PO) two times per day (BID) or equivalent. Participants receiving corticosteroids at higher doses may be eligible if their corticosteroid therapy is tapered to study levels (prednisone 5 mg PO BID) prior to first dose of study medication, without concomitant clinical deterioration The participant has known or suspected brain or leptomeningeal metastases The participant has uncontrolled or poorly controlled hypertension The participant has poorly controlled diabetes mellitus. Participants with a history of diabetes are allowed to participate, provided that their blood glucose is within normal range (fasting < 120 mg/dL or below ULN) and that they are on a stable dietary or therapeutic regimen for this condition The participant has a known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness with a history of diabetes are allowed to participate, provided that their blood glucose is within normal range (fasting < 120 mg/dL or below ULN) and that they are on a stable dietary or therapeutic regimen for this condition The participant has a known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness

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: IMC-1121B (ramucirumab) + Mitoxantrone + Prednisone<br> | Drug: Mitoxantrone<br>* Mitoxantrone is to be administered as an I.V. infusion, at 12 milligrams/square meter (mg/m^2) over 5-15 minutes on Day 1 during a 3-week (21-day) cycle. Mitoxantrone treatment is to be continued for a maximum of 12 cycles (total cumulative dose of mitoxantrone is restricted to ≤ 144 mg/m^2) or until there is evidence of disease progression, death, or intolerable toxicity.<br>Drug: Prednisone<br>* Prednisone (5 mg) is to be self-administered PO BID, each day of the 21-day cycle.<br>Biological: IMC-1121B (ramucirumab)<br>* IMC-1121B (ramucirumab) is to be administered as an intravenous (IV) infusion, 6 milligrams/kilogram (mg/kg) over 1 hour on Days 1, 8, and 15 of each 3-week (21-day) cycle. Ramucirumab treatment is to continue until there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.<br>* Other names: LY3009806;|
| Experimental: IMC-A12 + Mitoxantrone + Prednisone<br> | Biological: IMC-A12<br>* IMC-A12 is to be administered as an I.V. infusion, 6 mg/kg over 1 hour on Days 1, 8, and 15 of each 3-week (21-day) cycle. IMC-A12 treatment is to continue until there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.<br>* Other names: LY3012217;Drug: Mitoxantrone<br>* Mitoxantrone is to be administered as an I.V. infusion, at 12 milligrams/square meter (mg/m^2) over 5-15 minutes on Day 1 during a 3-week (21-day) cycle. Mitoxantrone treatment is to be continued for a maximum of 12 cycles (total cumulative dose of mitoxantrone is restricted to ≤ 144 mg/m^2) or until there is evidence of disease progression, death, or intolerable toxicity.<br>Drug: Prednisone<br>* Prednisone (5 mg) is to be self-administered PO BID, each day of the 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Progression-free Survival (cPFS) | Defined as the median time from randomization to the earliest of: Tumor progression by Response Evaluation Criteria in Solid Tumors (RECIST); Evidence of progression by bone scan, performed after completion of the first 3 cycles, demonstrating the appearance of >=2 new lesions; New skeletal events (New pathologic bone fracture in the region of metastatic disease; New bone lesion requiring radiation or surgery; Spinal cord or nerve root compression) Symptomatic progression (for participants without measurable disease); Other clinical events attributable to prostate cancer that require major interventions; or Death from any cause Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy. | Randomization to composite progressive disease, up to 23.4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary Listing of Participants Reporting Treatment-Emergent Adverse Events | Data presented are the number of participants who experienced A12 or 1121B (ramucirumab) related treatment-emergent adverse events (TEAE), treatment related serious adverse events (SAE), or any Grade 3 or higher TEAE; any TEAE leading to discontinuation of A12 or 1121B (ramucirumab) treatment, and any TEAE leading to dose modification of A12 or 1121B (ramucirumab). A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Event section. | Randomization to 36.3 months | 
| Time to Radiographic Evidence of Disease Progression | Time between date of randomization and earliest date of radiographic progression defined as either: Tumor progression by RECIST; Evidence of progression by bone scan; New skeletal events (New pathologic bone fracture in the region of metastatic disease; New bone lesion requiring radiation or surgery; Spinal cord or nerve root compression). Participants who were ongoing with no radiographic evidence of disease progression, who discontinued treatment for reasons other than progression,or died before progression were censored at date of last tumor or bone radiographic assessment. Participants who started a new anticancer treatment before progression were censored at date of last tumor or bone radiographic assessment before start of new anti-cancer therapy. | Randomization to date of radiographic progression, up to 36.3 months | 
| Prostate Specific Antigen (PSA) Response Rate | PSA response rate is defined as the percentage of participants with a decrease in PSA >= 50 percent from baseline. | Baseline up to data cut-off date (up to 36.3 months) | 
| Composite Progression-free Survival (cPFS) at 6-months | Data presented are the percentage of participants without disease progression at 6 months. Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy. | 6 months | 
| Composite Progression-free Survival (cPFS) at 9-months | Data presented are the percentage of participants without disease progression at 9 months. Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy. | 9 months | 
| Composite Progression-free Survival (cPFS) at 12-months | Data presented are the percentage of participants without disease progression at 12 months. Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy. | 12 months | 
| Overall Survival (OS) | Overall survival is defined as the time from randomization to the date of death due to any cause. Participants who were alive at the time of study completion were censored at the time the participant was last known to be alive. | First dose to death due to any cause up to 36.3 months | 
| Objective Response Rate (ORR) | Objective response is Complete Response (CR) + Partial Response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. CR is a disappearance of all target and non-target lesions; PR is at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. Objective response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with measurable disease, multiplied by 100. | Baseline to date of progressive disease or death up to 36.3 months | 
| Maximum Concentration (Cmax) at Study Day 1 | Maximum Concentration (Cmax) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 1 | 
| Maximum Concentration (Cmax) at Study Day 15 | Maximum concentration (Cmax) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 15 | 
| Maximum Concentration (Cmax) at Study Day 16 | Maximum concentration (Cmax) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 16 | 
| Maximum Concentration (Cmax) at Study Day 30 | Maximum concentration (Cmax) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 30 | 
| Minimum Concentration (Cmin) at Study Day 1 | Minimum concentration (Cmin) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 1 | 
| Minimum Concentration (Cmin) at Study Day 15 | Minimum concentration (Cmin) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 15 | 
| Minimum Concentration (Cmin) at Study Day 16 | Minimum concentration (Cmin) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 16 | 
| Minimum Concentration (Cmin) at Study Day 30 | Minimum concentration (Cmin) of Ramucirumab. All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted. | Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer