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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00683475

Enrollment

138

Registered

2008-05-23

Start date

2008-08-31

Completion date

2011-09-30

Last updated

2014-10-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Prostate Cancer

Keywords

Prostate Cancer

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.

Interventions

BIOLOGICALIMC-A12

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.

DRUGMitoxantrone

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.

DRUGPrednisone

Prednisone (5 mg) is to be self-administered PO BID, each day of the 21-day cycle.

BIOLOGICALIMC-1121B (ramucirumab)

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Composite Progression-free Survival (cPFS)	Randomization to composite progressive disease, up to 23.4 months	Defined as the median time from randomization to the earliest of: 1. Tumor progression by Response Evaluation Criteria in Solid Tumors (RECIST); 2. Evidence of progression by bone scan, performed after completion of the first 3 cycles, demonstrating the appearance of \>=2 new lesions; 3. 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) 4. Symptomatic progression (for participants without measurable disease); 5. Other clinical events attributable to prostate cancer that require major interventions; or 6. 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.

Secondary

Measure	Time frame	Description
Time to Radiographic Evidence of Disease Progression	Randomization to date of radiographic progression, up to 36.3 months	Time between date of randomization and earliest date of radiographic progression defined as either: 1. Tumor progression by RECIST; 2. Evidence of progression by bone scan; 3. 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.
Prostate Specific Antigen (PSA) Response Rate	Baseline up to data cut-off date (up to 36.3 months)	PSA response rate is defined as the percentage of participants with a decrease in PSA \>= 50 percent from baseline.
Composite Progression-free Survival (cPFS) at 6-months	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.
Composite Progression-free Survival (cPFS) at 9-months	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.
Composite Progression-free Survival (cPFS) at 12-months	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.
Overall Survival (OS)	First dose to death due to any cause up to 36.3 months	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.
Objective Response Rate (ORR)	Baseline to date of progressive disease or death up to 36.3 months	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.
Summary Listing of Participants Reporting Treatment-Emergent Adverse Events	Randomization to 36.3 months	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.
Maximum Concentration (Cmax) at Study Day 15	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.
Maximum Concentration (Cmax) at Study Day 16	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.
Maximum Concentration (Cmax) at Study Day 30	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.
Minimum Concentration (Cmin) at Study Day 1	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.
Minimum Concentration (Cmin) at Study Day 15	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.
Minimum Concentration (Cmin) at Study Day 16	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.
Minimum Concentration (Cmin) at Study Day 30	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.
Maximum Concentration (Cmax) at Study Day 1	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
IMC-A12 + Mitoxantrone + Prednisone IMC-A12 intravenous infusion at 6 milligrams/kilogram (mg/kg) on Days 1, 8, and 15 of each 21-day cycle. Mitoxantrone intravenous infusion at 12 milligrams/square meter (mg/m\^2) on Day 1 of each 21-day cycle. Prednisone at 5 milligrams (mg) is to be self-administered orally, each day of the 21-day cycle.	66
IMC-1121B (Ramucirumab) + Mitoxantrone + Prednisone IMC-1121B (ramucirumab) intravenous infusion, 6 milligrams/kilogram (mg/kg) on Days 1, 8, and 15 of each 21-day cycle. Mitoxantrone intravenous infusion at 12 milligrams/square meter (mg/m\^2) on Day 1 of each 21-day cycle. Prednisone at 5 milligrams (mg) is to be self-administered orally, each day of the 21-day cycle.	66
Total	132

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Never Treated: Adverse Event	2	3
Overall Study	Never Treated: Progressive Disease	1	0
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	IMC-A12 + Mitoxantrone + Prednisone	IMC-1121B (Ramucirumab) + Mitoxantrone + Prednisone	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	36 Participants	45 Participants	81 Participants
Age, Categorical Between 18 and 65 years	30 Participants	21 Participants	51 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	3 Participants	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	65 Participants	63 Participants	128 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Black Or African American	4 Participants	6 Participants	10 Participants
Race/Ethnicity, Customized Other	1 Participants	2 Participants	3 Participants
Race/Ethnicity, Customized White	61 Participants	58 Participants	119 Participants
Region of Enrollment United States	66 participants	66 participants	132 participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	66 Participants	66 Participants	132 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	65 / 66	66 / 66
serious Total, serious adverse events	40 / 66	36 / 66

Outcome results

Primary

Composite Progression-free Survival (cPFS)

Defined as the median time from randomization to the earliest of: 1. Tumor progression by Response Evaluation Criteria in Solid Tumors (RECIST); 2. Evidence of progression by bone scan, performed after completion of the first 3 cycles, demonstrating the appearance of \>=2 new lesions; 3. 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) 4. Symptomatic progression (for participants without measurable disease); 5. Other clinical events attributable to prostate cancer that require major interventions; or 6. 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.

Time frame: Randomization to composite progressive disease, up to 23.4 months

Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.~11 participants were censored in the IMC-A12 + Mitoxantrone + Prednisone arm. 15 participants were censored in the IMC-1121B (ramucirumab) + Mitoxantrone + Prednisone arm.

Arm	Measure	Value (MEDIAN)
IMC-A12 + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS)	4.1 months
IMC-1121B (Ramucirumab) + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS)	6.7 months

Secondary

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.

Time frame: 12 months

Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.

Arm	Measure	Value (NUMBER)
IMC-A12 + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS) at 12-months	12.4 percentage of participants
IMC-1121B (Ramucirumab) + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS) at 12-months	20.0 percentage of participants

Secondary

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.

Time frame: 6 months

Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.

Arm	Measure	Value (NUMBER)
IMC-A12 + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS) at 6-months	37.2 percentage of participants
IMC-1121B (Ramucirumab) + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS) at 6-months	59.2 percentage of participants

Secondary

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.

Time frame: 9 months

Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.

Arm	Measure	Value (NUMBER)
IMC-A12 + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS) at 9-months	20.7 percentage of participants
IMC-1121B (Ramucirumab) + Mitoxantrone + Prednisone	Composite Progression-free Survival (cPFS) at 9-months	35.9 percentage of participants

Secondary

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.

Time frame: Day 1