Clinical trial NCT00913835: A Study of Liposomal Doxorubicin With or Without Olaratumab (IMC-3G3) in Platinum-Refractory or Resistant Advanced Ovarian Cancer
Official title: Randomized Phase 2 Trial Investigating Liposomal Doxorubicin With or Without Anti-Platelet Derived Growth Factor Receptor-Alpha (PDGFRα) Monoclonal Antibody IMC-3G3 in Patients With Platinum-Refractory or Platinum-Resistant Advanced Ovarian Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Neoplasms
Keywords: Liposomal Doxorubicin
IMC-3G3
3G3
Platinum resistant
Platinum refractory
Ovary
Neoplasm
PDGFr
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2009-06-04
Enrollment: 125
Sex: FEMALE
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 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.

Eligibility criteria: 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

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

Primary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Randomization to Progressive Disease (PD) or Date of Death (Up to 35 Months)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: First Day of Therapy to Date of Death (Up to 35 Months)
measure: Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
timeFrame: Randomization to PD (Up to 35 Months)
measure: Median Duration of Response
timeFrame: Date of Initial CR or PR to PD (Up to 35 Months)
measure: Number of Participants With Adverse Events (AEs) and Who Died
timeFrame: Baseline Up to End of Treatment and 30-day Post-dose Follow-up (Up to 35 Months)
measure: Percentage of Participants With Anti-Olaratumab Antibodies
timeFrame: Baseline Up to 30-Day Postdose Follow-Up (Up To 35 Months)
measure: 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)
timeFrame: From Start of Olaratumab Monotherapy to PD or Date of Death (Up to 20 Weeks)
measure: Area Under the Curve (AUC) of Olaratumab
timeFrame: 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)
measure: Maximum Concentration (Cmax) of Olaratumab
timeFrame: 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)
measure: Half-life (t1/2) of Olaratumab
timeFrame: 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)
measure: Clearance (CL) of Olaratumab
timeFrame: 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)
measure: Apparent Volume of Distribution (Vss) of Olaratumab
timeFrame: 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)
measure: 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)
timeFrame: Randomization to PD or Date of Death (Up to 130 Weeks)
Other outcomes:
Locations:
city: Joliet
country: United States
facility: ImClone Investigational Site
state: Illinois
city: Indianapolis
country: United States
facility: ImClone Investigational Site
state: Indiana
city: Baltimore
country: United States
facility: ImClone Investigational Site
state: Maryland
city: Boston
country: United States
facility: ImClone Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: ImClone Investigational Site
state: Michigan
city: Charlotte
country: United States
facility: ImClone Investigational Site
state: North Carolina
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: McGuire WP, Penson RT, Gore M, Herraez AC, Peterson P, Shahir A, Ilaria R Jr. Randomized phase II study of the PDGFRalpha antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer. BMC Cancer. 2018 Dec 27;18(1):1292. doi: 10.1186/s12885-018-5198-4.