A Study of Liposomal Doxorubicin With or Without Olaratumab (IMC-3G3) in Platinum-Refractory or Resistant Advanced Ovarian Cancer

Phase 2

Completed

• Conditions: Ovarian Neoplasms
• Interventions: Biological: Olaratumab; Drug: liposomal doxorubicin

• Registration Number: NCT00913835
• Lead Sponsor: Eli Lilly and Company

Brief Summary

The purpose of this study is to determine if participants with platinum-refractory or platinum-resistant advanced ovarian cancer have a better outcome when treated with Olaratumab (IMC-3G3) in combination with Liposomal Doxorubicin than when treated with Liposomal Doxorubicin alone.

Detailed Description

The primary objective of this study is to evaluate the progression-free survival (PFS) in participants with platinum-refractory or platinum-resistant advanced ovarian cancer when treated with the monoclonal antibody Olaratumab in combination with liposomal doxorubicin versus liposomal doxorubicin alone.

Study Timeline

• Study Start: 2009-06
• Study First Submitted: 2009-06-02
• Study First Submitted QC: 2009-06-03
• Study First Posted: 2009-06-04
• Disposition First Submitted: 2011-09-19
• Disposition First Submitted QC: 2011-09-19
• Disposition First Posted: 2011-09-26
• Primary Completion: 2011-10
• Study Completion: 2014-02
• Results First Submitted: 2016-11-18
• Results First Submitted QC: 2017-03-03
• Results First Posted: 2017-04-14
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-10
• Last Update Posted: 2019-09-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 125

Inclusion Criteria

• The participant has histologically or cytologically confirmed epithelial ovarian cancer, primary peritoneal carcinoma, fallopian tube cancer, or ovarian clear cell carcinoma
• The participant must have at least one of the following: a platinum-free interval of ≤12 months after the final dose of primary or subsequent platinum-based therapy (platinum-resistant), progression during primary or subsequent platinum-based therapy (platinum-refractory), or persistent radiographic disease after primary or subsequent platinum-based therapy (platinum-refractory)
• The participant has a pre-study echocardiogram or multigated acquisition (MUGA) scan with an actual left ventricular ejection fraction (LVEF) ≥50%, within 21 days prior to randomization
• The participant has at least one unidimensionally measurable target lesion [≥20 millimeters (mm) with conventional techniques, or ≥10 mm by spiral computed tomography (CT) or magnetic resonance imaging (MRI)], as defined by Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST v1.0) guidelines. Tumors within a previously irradiated field will be designated as "nontarget" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
• The participant has recovered to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v3.0) from the effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other targeted therapies for ovarian cancer, with the exception of alopecia or peripheral neuropathy (which must have resolved to ≤Grade 2). The exceptions for such effects are allowed lab values of ≤Grade 2 specified elsewhere in these inclusion criteria
• The participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤1 at study entry
• The participant has the ability to understand and the willingness to sign a written informed consent
• The participant has adequate hematological functions [absolute neutrophil count (ANC) ≥1200 cells/microliter (cells/μL), hemoglobin ≥9 grams/deciliter (g/dL), and platelets ≥100,000 cells/μL]
• The participant has adequate hepatic function as defined by total bilirubin ≤1.5 × the upper limit of normal (ULN), and aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 × the ULN (or ≤5 × the ULN in the presence of known liver metastases)
• The participant has adequate renal function as defined by serum creatinine ≤1.5 × the institutional ULN. If creatinine is above the ULN, the participant's creatinine clearance is ≥60 milliliters/minute (mL/min)
• The participant has urinary protein ≤1+ on dipstick or routine urinalysis; if urine dipstick or routine analysis is ≥2+, a 24-hour urine for protein must demonstrate <1000 milligrams (mg) of protein to allow participation
• The participant must have adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) ≤5seconds above ULN. Participants on anticoagulation must be on a stable dose of anticoagulant with a therapeutic INR and no active bleeding within 14 days prior to randomization, or on low molecular weight heparin AND have no pathological condition carrying a high risk of bleeding. Mild elevations of PTT of up to 1.5 × the ULN are acceptable, provided that, in the opinion of the investigator, they are related to ongoing use of coumarins [for example (e.g.), warfarin]
• The participant has a pre-study echocardiogram or MUGA scan with an actual LVEF ≥50%, within 21 days prior to randomization
• Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to randomization and for the duration of study participation

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Exclusion Criteria

• The participant has brain metastases or leptomeningeal disease
• The participant received more than one biologic and/or more than one hormonal therapy, administered either concomitantly with platinum-based therapy or separately
• The participant has a history of treatment with other agents targeting platelet derived growth factor (PDGF) or PDGF receptor (PDGFR)
• The participant has an increased level of cancer antigen-125 (CA-125) in the absence of concomitant clinical or radiographic progression
• The participant has received radiotherapy, chemotherapy, or biologic therapy directed at the malignant tumor within 3 weeks prior to randomization, or hormonal therapy directed at the malignant tumor within 1 week prior to randomization. Continuation of hormone replacement therapy is permitted
• The participant has a suspected impending bowel obstruction (including partial obstruction), based on clinical or radiographic data
• The participant has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to that of IMC-3G3
• The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure,uncontrolled hypertension, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• The participant has a history of another primary cancer, with the exception of: a) curatively resected nonmelanomatous skin cancer; b) curatively treated cervical carcinoma in-situ; or c) other primary solid tumor treated with curative intent and no known active disease present and no treatment administered during the last 3 years prior to randomization
• The participant is pregnant or lactating
• The participant has ongoing side effects ≥Grade 2 due to agents administered more than 28 days prior to randomization. The exceptions for such effects are allowed lab values and toxicities of ≤Grade 2, specified in the inclusion criteria
• The participant has unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction 6 months prior to randomization
• The participant has participated in clinical trials of experimental agents within 28 days prior to randomization
• The participant has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders
• The participant has a serious or nonhealing active wound, ulcer, or bone fracture
• The participant has known human immunodeficiency virus positivity
• The participant had a major surgical procedure, an open biopsy, or significant traumatic injury within 28 days prior to randomization
• The participant has received an anthracycline for any indication in the past

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Olaratumab and Liposomal Doxorubicin	liposomal doxorubicin	Olaratumab and Liposomal Doxorubicin
Liposomal Doxorubicin: Optional Olaratumab Monotherapy	liposomal doxorubicin	Liposomal Doxorubicin Monotherapy until disease progression. Upon disease progression the participant had the option to receive Olaratumab monotherapy.
Olaratumab and Liposomal Doxorubicin	Olaratumab	Olaratumab and Liposomal Doxorubicin
Liposomal Doxorubicin: Optional Olaratumab Monotherapy	Olaratumab	Liposomal Doxorubicin Monotherapy until disease progression. Upon disease progression the participant had the option to receive Olaratumab monotherapy.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	Randomization to Progressive Disease (PD) or Date of Death (Up to 35 Months)	PFS is defined as the time from the day of randomization to the first evidence of progression as defined by Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) criteria or death from any cause. Progressive Disease (PD) is a 20% increase over the smallest sum of target lesions or new lesions. Participants who died without a reported prior disease progression were considered to have progressed on the day of their death. Participants who did not progress and were subsequently lost to follow-up had their data censored at the day of last tumor assessment.

Secondary Outcome Measures

Name	Time	Method
Apparent Volume of Distribution (Vss) of Olaratumab	Prior to and 1 h after Olaratumab Infusion in Cycles 1, 2, and 4 and 48 h or 72 h, 144 h, 240 h or 264 h and 336 h Post-dose in Cycles 1 and 4 (28-day Cycles)	Vss is an estimate of drug distribution independent of the elimination process and is proportional to the amount of drug in the body versus the drug plasma concentration at steady-state.
PFS for Participants Who Had Tissue Samples for Platelet Derived Growth Factor Receptor Alpha (PDGFRα) Expression Determined by Immunohistochemistry (IHC) (Association Between PDGFRα Tumor Expression and PFS)	Randomization to PD or Date of Death (Up to 130 Weeks)	PFS is defined as the time from the day of randomization to the first evidence of progression as defined by RECIST v1.0 criteria or death from any cause. PD is a 20% increase over the smallest sum of target lesions or new lesions. Participants who died without a prior disease progression were considered to have progressed on the day of their death. Participants who did not progress and were subsequently lost to follow-up had their data censored at the day of last tumor assessment. PDGFRα protein expression at baseline in tumor cells is determined by IHC using H-Scores and a cut point of 0. Participants were considered to have a high relative expression when H-Score is \>0 and a low relative expression when H-Score=0. H-Score was calculated by summing the percentage of cell staining at each intensity multiplied by the weighted intensity of staining. Staining intensity: 0 (no staining), 1+ (weak staining), 2+ (medium staining), 3+ (strongest staining). H-Scores could range from 0-300.
Overall Survival (OS)	First Day of Therapy to Date of Death (Up to 35 Months)	OS is defined as the time from first day of therapy to the date of death from any cause. Participants who were alive at the end of the follow-up period or were lost to follow-up, OS was censored on the last date the participant was known to be alive.
Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]	Randomization to PD (Up to 35 Months)	The percentage of participants with a best overall response of confirmed CR or PR defined using RECIST v1.0 criteria. CR is the disappearance of all target and non-target lesions and normalization of cancer antigen-125 (CA-125) levels. PR is defined as having a ≥30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. The percentage of participants with objective response was calculated as: (number of participants whose best overall response of CR or PR/number of participants treated) \* 100.
Median Duration of Response	Date of Initial CR or PR to PD (Up to 35 Months)	Duration of response is the interval from the date of initial CR or PR until the first date criteria for PD is met using RECIST v1.0 criteria, or initiation of other (or additional) antitumor therapy is first reported, or death due to any cause. CR is the disappearance of all target and non-target lesions and the normalization of tumor marker levels. PR is a ≥30% decrease in the sum of the LD of target lesions without new lesions and progression of non-target lesions. PD is a ≥20% increase in the sum of the LD of target lesions and/or unequivocal progression of existing non-target lesions and/or detection of 1 or more new lesions. Participants who did not relapse were censored on the day of their last tumor assessment.
Number of Participants With Adverse Events (AEs) and Who Died	Baseline Up to End of Treatment and 30-day Post-dose Follow-up (Up to 35 Months)	Reported are the number of participants with clinically significant events, defined as serious AEs (SAEs) and other non-serious AEs regardless of causality and those who died during treatment and during the 30-day post-dose follow-up. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module of this report.
Percentage of Participants With Anti-Olaratumab Antibodies	Baseline Up to 30-Day Postdose Follow-Up (Up To 35 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.
PFS of Participants Who Received Olaratumab After Liposomal Doxorubicin Monotherapy (Descriptive Statistics for Safety and Efficacy for Participants Who Continue on Olaratumab Monotherapy Following Disease Progression on Liposomal Doxorubicin Monotherapy)	From Start of Olaratumab Monotherapy to PD or Date of Death (Up to 20 Weeks)	PFS is defined as the time from start of Olaratumab monotherapy to the first evidence of progression as defined by RECIST v1.0 criteria or death from any cause. PD is a 20% increase over the smallest sum of target lesions or new lesions. Participants who died without a reported prior disease progression were considered to have progressed on the day of their death. Participants who did not progress and were subsequently lost to follow-up had their data censored at the day of last tumor assessment.
Area Under the Curve (AUC) of Olaratumab	Prior to and 1 Hour (h) After Olaratumab Infusion in Cycles 1, 2, and 4 and 48 h or 72 h, 144 h, 240 h or 264 h and 336 h Post-dose in Cycles 1 and 4 (28-day Cycles)
Maximum Concentration (Cmax) of Olaratumab	Prior to and 1 h after Olaratumab Infusion in Cycles 1, 2, and 4 and 48 h or 72 h, 144 h, 240 h or 264 h and 336 h Post-dose in Cycles 1 and 4 (28-day Cycles)
Half-life (t1/2) of Olaratumab	Prior to and 1 h after Olaratumab Infusion in Cycles 1, 2, and 4 and 48 h or 72 h, 144 h, 240 h or 264 h and 336 h Post-dose in Cycles 1 and 4 (28-day Cycles)	The time it takes to reduce the concentration of Olaratumab in the plasma by 50%.
Clearance (CL) of Olaratumab	Prior to and 1 h after Olaratumab Infusion in Cycles 1, 2, and 4 and 48 h or 72 h, 144 h, 240 h or 264 h and 336 h Post-dose in Cycles 1 and 4 (28-day Cycles)	CL is the volume of serum cleared of Olaratumab per unit of time after a single dose of Olaratumab

Trial Locations

Locations (1)

ImClone Investigational Site; 🇺🇸 Charlotte, North Carolina, United States