Clinical trial NCT00683475: A Study of IMC-A12 or Ramucirumab Plus Mitoxantrone and Prednisone in Prostate Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: Prostate Cancer
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2008-05-23
Enrollment: 138
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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;

  1. Progressive measurable disease: using conventional solid tumor criteria
  2. Bone scan progression: at least two new lesions on bone scan
  3. 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;

  1. Progressive measurable disease: using conventional solid tumor criteria
  2. Bone scan progression: at least two new lesions on bone scan
  3. 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

Primary outcomes:
measure: Composite Progression-free Survival (cPFS)
timeFrame: Randomization to composite progressive disease, up to 23.4 months
Secondary outcomes:
measure: Summary Listing of Participants Reporting Treatment-Emergent Adverse Events
timeFrame: Randomization to 36.3 months
measure: Time to Radiographic Evidence of Disease Progression
timeFrame: Randomization to date of radiographic progression, up to 36.3 months
measure: Prostate Specific Antigen (PSA) Response Rate
timeFrame: Baseline up to data cut-off date (up to 36.3 months)
measure: Composite Progression-free Survival (cPFS) at 6-months
timeFrame: 6 months
measure: Composite Progression-free Survival (cPFS) at 9-months
timeFrame: 9 months
measure: Composite Progression-free Survival (cPFS) at 12-months
timeFrame: 12 months
measure: Overall Survival (OS)
timeFrame: First dose to death due to any cause up to 36.3 months
measure: Objective Response Rate (ORR)
timeFrame: Baseline to date of progressive disease or death up to 36.3 months
measure: Maximum Concentration (Cmax) at Study Day 1
timeFrame: Day 1
measure: Maximum Concentration (Cmax) at Study Day 15
timeFrame: Day 15
measure: Maximum Concentration (Cmax) at Study Day 16
timeFrame: Day 16
measure: Maximum Concentration (Cmax) at Study Day 30
timeFrame: Day 30
measure: Minimum Concentration (Cmin) at Study Day 1
timeFrame: Day 1
measure: Minimum Concentration (Cmin) at Study Day 15
timeFrame: Day 15
measure: Minimum Concentration (Cmin) at Study Day 16
timeFrame: Day 16
measure: Minimum Concentration (Cmin) at Study Day 30
timeFrame: Day 30
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: ImClone Investigational Site
state: California
city: New Haven
country: United States
facility: ImClone Investigational Site
state: Connecticut
city: Boca Raton
country: United States
facility: ImClone Investigational Site
state: Florida
city: Port St. Lucie
country: United States
facility: ImClone Investigational Site
state: Florida
city: Atlanta
country: United States
facility: ImClone Investigational Site
state: Georgia
city: Chicago
country: United States
facility: ImClone Investigational Site
state: Illinois
city: Chlcago
country: United States
facility: ImClone Investigational Site
state: Illinois
city: Evanston
country: United States
facility: ImClone Investigational Site
state: Illinois
city: Maryville
country: United States
facility: ImClone Investigational Site
state: Illinois
city: Cedar Rapids
country: United States
facility: ImClone Investigational Site
state: Iowa
city: Metairie
country: United States
facility: ImClone Investigational Site
state: Louisiana
city: Ann Arbor
country: United States
facility: ImClone Investigational Site
state: Michigan
city: Rochester
country: United States
facility: ImClone Investigational Site
state: Minnesota
city: St Louis
country: United States
facility: ImClone Investigational Site
state: Missouri
city: Billings
country: United States
facility: ImClone Investigational Site
state: Montana
city: Roseland
country: United States
facility: ImClone Investigational Site
state: New Jersey
city: Buffalo
country: United States
facility: ImClone Investigational Site
state: New York
city: East Setauket
country: United States
facility: ImClone Investigational Site
state: New York
city: New York
country: United States
facility: ImClone Investigational Site
state: New York
city: New York
country: United States
facility: ImClone Investigational Site
state: New York
city: New York
country: United States
facility: ImClone Investigational Site
state: New York
city: New York
country: United States
facility: ImClone Investigational Site
state: New York
city: Durham
country: United States
facility: ImClone Investigational Site
state: North Carolina
city: Cleveland
country: United States
facility: ImClone Investigational Site
state: Ohio
city: Philadelphia
country: United States
facility: ImClone Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: ImClone Investigational Site
state: Pennsylvania
city: Greenville
country: United States
facility: ImClone Investigational Site
state: South Carolina
city: Knoxville
country: United States
facility: ImClone Investigational Site
state: Tennessee
city: Nashville
country: United States
facility: ImClone Investigational Site
state: Tennessee
city: Abilene
country: United States
facility: ImClone Investigational Site
state: Texas
city: Dallas
country: United States
facility: ImClone Investigational Site
state: Texas
city: Houston
country: United States
facility: ImClone Investigational Site
state: Texas
city: Houston
country: United States
facility: ImClone Investigational Site
state: Texas
city: Seattle
country: United States
facility: ImClone Investigational Site
state: Washington
city: Seattle
country: United States
facility: ImClone Investigational Site
state: Washington
city: Madison
country: United States
facility: ImClone Investigational Site
state: Wisconsin
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References:
citation: Hussain M, Rathkopf D, Liu G, Armstrong A, Kelly WK, Ferrari A, Hainsworth J, Joshi A, Hozak RR, Yang L, Schwartz JD, Higano CS. A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer. Eur J Cancer. 2015 Sep;51(13):1714-24. doi: 10.1016/j.ejca.2015.05.019. Epub 2015 Jun 13.