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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Phase 2 Study of Human Anti-PDGFRα Monoclonal Antibody IMC-3G3 Plus Mitoxantrone Plus Prednisone or Mitoxantrone Plus Prednisone in Metastatic Castration-Refractory Prostate Cancer Following Disease Progression or Intolerance on Docetaxel-based Chemotherapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Biological: Olaratumab
* Drug: Mitoxantrone
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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

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: Olaratumab + Mitoxantrone<br>1 cycle = 3 weeks (21 days) | Biological: Olaratumab<br>* 15 milligrams per kilogram (mg/kg) intravenous (IV) Days 1 and 8<br>* Other names: LY3012207;Drug: Mitoxantrone<br>* Mitoxantrone 12 milligrams per square meter (mg/m²) IV Day 1 Mitoxantrone is to be administered for up to 12 cycles (total cumulative dose of mitoxantrone is restricted to ≤144 mg/m²)<br>Drug: Prednisone<br>* 5 mg orally (PO) twice daily (BID) on each day<br>|
| Active Comparator: Mitoxantrone: Optional Olaratumab Monotherapy<br>1 cycle = 3 weeks (21 days) Participants who experience progressive disease (PD) have the option to receive olaratumab monotherapy treatment. | Drug: Mitoxantrone<br>* Mitoxantrone 12 milligrams per square meter (mg/m²) IV Day 1 Mitoxantrone is to be administered for up to 12 cycles (total cumulative dose of mitoxantrone is restricted to ≤144 mg/m²)<br>Drug: Prednisone<br>* 5 mg orally (PO) twice daily (BID) on each day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | 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. | Randomization to Measured PD or Death Due to Any Cause Up to 23 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | Randomization to Death Due to Any Cause Up to 36 Months | 
| Percentage of Participants Who Achieved a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 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. | Randomization to Objective PD or Death Up to 23 Months | 
| Percentage of Participants With a ≥50% Decrease in Prostate Specific Androgen (PSA) From Pretreatment to Any Time | 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. | Pretreatment to PD Up to 23 Months | 
| Percentage of Participants With a ≥30% Decrease in PSA From Pretreatment to Week 12 | Percentage of participants = (number of participants who had ≥30% decrease in PSA at Week 12) / (number of participants treated) * 100. | Pretreatment through Week 12 | 
| Summary Listing of Participants Reporting Treatment-Emergent Adverse Events (TEAE) | 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. | From Start of Treatment Through Study Completion Up to 36 months | 
| PFS Based on Baseline Circulating Tumor Cells (CTC) Counts | 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. | Randomization to Measured PD or Death Due to Any Cause Up to 23 Months | 
| OS Based on Baseline CTC Counts | 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. | Randomization to Death Due to Any Cause Up to 36 Months | 
| Number of Participants With Negative Platelet-Derived Growth Factor Receptor Alpha (PDGFRα) Protein Expression by Immunohistochemistry (IHC) | 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. | Baseline | 
| Percentage of Participants With Anti-Olaratumab Antibody Assessment (Immunogenicity) | 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. | From Start of Treatment up to 9 Months | 
| 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) | 

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