A Study of Olaratumab (IMC-3G3) in Prostate Cancer

Phase 2

Completed

Conditions: Prostate Cancer

Interventions: Biological: Olaratumab
Drug: Prednisone
Drug: Mitoxantrone

Registration Number: NCT01204710

Lead Sponsor: Eli Lilly and Company

Brief Summary: This is a study evaluating the safety and efficacy of the monoclonal antibody olaratumab plus mitoxantrone plus prednisone compared to mitoxantrone plus prednisone in metastatic castration-refractory prostate cancer following disease progression or intolerance on docetaxel-based chemotherapy.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 123

Inclusion Criteria

histologically-confirmed adenocarcinoma of the prostate
radiographic evidence of metastatic prostate cancer (Stage M1 or D2)
has prostate cancer unresponsive or refractory to medical or surgical castration with a serum testosterone level of <50 nanograms per milliliter (ng/mL)
has had disease progression or intolerance on docetaxel-based therapy
prostate-specific antigen (PSA) ≥10 ng/mL
all clinically significant toxic effects of prior surgery, radiotherapy, chemotherapy or hormonal therapy have resolved to ≤Grade 1, based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.02
participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
adequate hematologic function
adequate hepatic function
adequate renal function
urinary protein is ≤1 on dipstick or routine analysis
life expectancy of more than 3 months
fertile man with partners that are women of childbearing potential must use an adequate method of contraception during the study
signed Informed Consent Document

Exclusion Criteria

concurrent active malignancy other than adequately treated nonmelanomatous skin cancer or other noninvasive or in situ neoplasms
The participant has received more than 1 prior cytotoxic chemotherapy regimen for metastatic disease
prior therapy with mitoxantrone for advanced prostate cancer
The participant has a history of symptomatic congestive heart failure or has a pre study echocardiogram or multigated acquisition scan with left ventricular ejection fraction that is ≥10% below the lower limit of normal institutional range
history of prior treatment with other agents that directly inhibit platelet-derived growth factor (PDGF) or platelet-derived growth factor receptors (PDGFR)
known allergy to any of the treatment components: olaratumab, mitoxantrone, and/or prednisone
radiotherapy within 21 days prior to first dose of olaratumab
any investigational therapy within 30 days of randomization
is receiving corticosteroids at a dose >5 mg prednisone PO BID or equivalent
received prior strontium-89, rhenium-186, rhenium-188, or samarium-153 radionucleotide therapy and has either ongoing evidence of bone marrow dysfunction or poorly controlled bone pain
has any ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, psychiatric illness, active bleeding or pathological condition that carries a high risk of bleeding, or any other serious uncontrolled medical disorders
known or suspected brain or leptomeningeal metastases
known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Olaratumab + Mitoxantrone	Olaratumab	1 cycle = 3 weeks (21 days)
Mitoxantrone: Optional Olaratumab Monotherapy	Prednisone	1 cycle = 3 weeks (21 days) Participants who experience progressive disease (PD) have the option to receive olaratumab monotherapy treatment.
Olaratumab + Mitoxantrone	Prednisone	1 cycle = 3 weeks (21 days)
Olaratumab + Mitoxantrone	Mitoxantrone	1 cycle = 3 weeks (21 days)
Mitoxantrone: Optional Olaratumab Monotherapy	Mitoxantrone	1 cycle = 3 weeks (21 days) Participants who experience progressive disease (PD) have the option to receive olaratumab monotherapy treatment.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	Randomization to Measured PD or Death Due to Any Cause Up to 23 Months	PFS is measured from randomization to the earliest date of the following events: PD according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version (v) 1.1, is a ≥20% increase in the sum of diameter of the target lesions taking as reference the smallest sum on study and an absolute increase in the sum diameter of ≥5 millimeter (mm), the appearance of 1 or more new lesions and/or unequivocal progression of existing nontarget lesions, unequivocal evidence of progression by bone scan, clinical progression or death from any cause. For participants who had no documented PD or death or had started new anti-cancer therapy or were lost to follow-up, PFS was censored at their last tumor assessment.

Secondary Outcome Measures

Name	Time	Method
PFS Based on Baseline Circulating Tumor Cells (CTC) Counts	Randomization to Measured PD or Death Due to Any Cause Up to 23 Months	High expression (HE) of CTC was defined as having CTC counts ≥5 cells/7.5 milliliter (mL) and low expression (LE) of CTC was defined as having CTC counts \<5 cells/7.5 mL. PFS is measured from randomization to the earliest date of the following events: PD according to RECIST criteria v. 1.1, is a ≥20% increase in the sum diameter of the target lesions taking as reference the smallest sum on study and an absolute increase in the sum diameter of ≥5 mm, the appearance of 1 or more new lesions and/or unequivocal progression of existing nontarget lesions, unequivocal evidence of progression by bone scan, clinical progression or death from any cause.
OS Based on Baseline CTC Counts	Randomization to Death Due to Any Cause Up to 36 Months	HE of CTC was defined as having CTC counts ≥5 cells/7.5 mL and LE of CTC was defined as having CTC counts \<5 cells/7.5 mL. OS was defined as the time from the date of randomization to the date of death from any cause.
Maximum Concentration (Cmax) of Olaratumab Cycles 1, 2 and 3	Day 1 of Cycles 1, 2 and 3, and Day 8 of Cycles 1 and 3 (21-day cycle)
Percentage of Participants Who Achieved a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]	Randomization to Objective PD or Death Up to 23 Months	Best response is categorized using the RECIST v1.1 guidelines. CR is the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm. PR is a ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the pretreatment sum diameter. Percentage of participants = (number of participants who had CR or PR) / (number of participants treated) \* 100.
Percentage of Participants With a ≥50% Decrease in Prostate Specific Androgen (PSA) From Pretreatment to Any Time	Pretreatment to PD Up to 23 Months	Decrease in PSA ≥50% from pretreatment required confirmation no less than 3 weeks after the initial suggestion of response and occurring prior to documentation of PD. Percentage of participants = (number of participants who had ≥50% decrease in PSA at any time) / (number of participants treated) \* 100.
Overall Survival (OS)	Randomization to Death Due to Any Cause Up to 36 Months	OS was defined as the time from the date of randomization to the date of death from any cause. If the participants were alive at the end of the follow-up period or were lost to follow-up, OS time was censored on the last date the participant was known to be alive.
Percentage of Participants With Anti-Olaratumab Antibody Assessment (Immunogenicity)	From Start of Treatment up to 9 Months	Participants with Treatment Emergent (TE) anti-olaratumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20.
Percentage of Participants With a ≥30% Decrease in PSA From Pretreatment to Week 12	Pretreatment through Week 12	Percentage of participants = (number of participants who had ≥30% decrease in PSA at Week 12) / (number of participants treated) \* 100.
Summary Listing of Participants Reporting Treatment-Emergent Adverse Events (TEAE)	From Start of Treatment Through Study Completion Up to 36 months	Data presented are the number of participants who experienced serious adverse events (SAEs) and other nonserious adverse events (AEs). For participants in mitoxantrone group who had PD and chose optional IMC-3G3 follow-on treatment, the baseline was defined as the last assessment prior to the start of the olaratumab treatment. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events section.
Number of Participants With Negative Platelet-Derived Growth Factor Receptor Alpha (PDGFRα) Protein Expression by Immunohistochemistry (IHC)	Baseline	PDGFRα protein expression (pretreatment) by IHC was assessed in tumor cells, and was provided as a dichotomous variable with "positive" and "negative" expression. "Positive" corresponds to weak intensity membranous staining comprising greater than 30% of the tumor and/or moderate to strong intensity membranous staining comprising greater than 5% of the tumor. "Negative" corresponds to staining that does not meet these requirements.