Combination Chemotherapy With CS-1008 to Treat Ovarian Cancer

Study Overview
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Brief Summary
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This trial assessed the effect of treatment with CS-1008 in combination with paclitaxel/carboplatin on response in patients with locally advanced or metastatic ovarian cancer.

Detailed Description
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This trial assessed CS-1008 administered in combination with paclitaxel/carboplatin to patients with Stage IIIC or IV ovarian cancer who had suboptimal debulking surgery with residual measurable/evaluable disease and who had not received prior therapy for their disease. The effect of this first-line treatment in patients was assessed by complete response rate.

Official Title
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Phase 2 Study of CS-1008 in Combination With Chemotherapy (Paclitaxel/Carboplatin) in Locally Advanced or Metastatic Ovarian Cancer

Conditions
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Ovarian Cancer Stage IIIC, Ovarian Cancer Stage IV

Intervention / Treatment
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* Drug: CS-1008
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, epithelial carcinoma of the ovary or primary peritoneal carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage IIIC or IV). (Participants with the following histologic epithelial cell types are eligible for the study: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma not otherwise specified.) Enrollment within 6 weeks after surgical resection (debulking). Residual tumor masses > 1 cm and objectively measurable/evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. No prior therapy for ovarian cancer (ie, chemotherapy or radiotherapy [RT] to the abdomen or pelvis) other than surgical debulking of disease. At least 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Adequate organ and bone marrow function as evidenced by: Absolute neutrophil count ≥ 1,500/µL (equivalent to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 grade 1) Platelet count ≥ 100,000/µL (CTCAE grade 0 to 1) Hemoglobin ≥ 9 g/dL Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) (CTCAE grade 1) Bilirubin ≤ 1.5 x ULN (CTCAE grade 1) Aspartate aminotransferase (AST) and alkaline phosphatase ≤ 2.5 x ULN (CTCAE grade 1) Adequate neurologic function (ie, sensory and motor neuropathy ≤ CTCAE grade 1). Women of childbearing potential must be willing to consent to using effective contraception while on treatment and for 3 months thereafter. All subjects of childbearing potential must have a negative pregnancy test (serum or urine) result ≤ 72 hours before initiating study treatment. Participants must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an institutional review board-approved informed consent form (ICF) before performance of any study-specific procedures or tests. Exclusion Criteria: Prior invasive malignant disease within 5 years except for squamous cell or basal cell carcinoma. Current diagnosis of borderline epithelial ovarian tumor (formerly tumors of low malignant potential) or recurrent ovarian epithelial cancer. Positive human immunodeficiency virus (HIV) or hepatitis B surface antigen (HBsAg) because of the potential for additional toxicity from the treatment regimen. Anticipation of need for a major surgical procedure or radiotherapy (RT) during the study. History of any of the following conditions within 6 months before study enrollment: myocardial infarction; severe/unstable angina pectoris; coronary/peripheral artery bypass graft; New York Heart Association (NYHA) class III or IV congestive heart failure; cerebrovascular accident or transient ischemic attack, pulmonary embolism, or other clinically significant thromboembolic event; clinically significant pulmonary disease (eg, severe chronic obstructive pulmonary disease or asthma). Clinically active brain metastasis (ie, untreated, still requiring therapy with steroids or RT, or with progression within 4 weeks after completion of RT); an uncontrolled seizure disorder; spinal cord compression; or carcinomatous meningitis. Pregnant or lactating. Prior treatment with CS-1008, other agonistic DR5 antibodies, or tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Known history of hypersensitivity reactions to any of the components of CS-1008, paclitaxel (or docetaxel), or carboplatin formulations. Serious intercurrent medical or psychiatric illnesses or any other conditions that in the opinion of the Investigator would impair the ability to give informed consent or unacceptably reduce protocol compliance or safety of the study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CS-1008 with paclitaxel and carboplatin<br>CS-1008 will be administered with paclitaxel and carboplatin. | Drug: CS-1008<br>* CS-1008 intravenous (IV) infusion 10 mg/kg on Day 1 of Cycle 1 and 8 mg/kg once every 3 weeks (1 cycle) for Cycle 2-6<br>Drug: Paclitaxel<br>* Paclitaxel 175 mg/m^2 IV infusion once every 3 weeks (1 cycle) for 6 cycles<br>* Other names: Taxol;Drug: Carboplatin<br>* Carboplatin (target area under the concentration versus time curve of 6.0 mg/mL/min using the Calvert Formula) IV infusion once every 3 weeks (1 cycle) for 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response and Objective Response Rate Following Treatment With CS-1008 in Combination With Chemotherapy (Paclitaxel/Carboplatin) in Locally Advanced or Metastatic Ovarian Cancer | The best overall response is the best response (in the order of confirmed complete response [CR], confirmed partial response [PR], unconfirmed CR, unconfirmed PR, stable disease [SD], and progressive disease [PD]) among all overall responses recorded from the start of treatment until the participant withdraws from the study. If there is no tumor assessment after the first dose of study drug, the best overall response is classified as Inevaluable. CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD defined as at least a 20% increase in the sum of diameters of target lesions. Objective response rate was defined as confirmed CR and confirmed PR. | Baseline up to first documented objective response, disease progression, or study withdrawal, up to 1 year 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Sum of Longest Diameters of Target Lesions Following Treatment With CS-1008 in Combination With Chemotherapy (Paclitaxel/Carboplatin) in Locally Advanced or Metastatic Ovarian Cancer | A sum of the diameters for all target lesions will be calculated and reported as the baseline sum of diameters, defined as the last non-missing value before initial administration of study treatment. The baseline sum of diameters will be used as reference for characterization of the objective tumor response. The change from baseline in the sum of longest diameters of target lesions is being reported. Negative values indicate an improvement in tumor reduction. | Baseline to Cycle 3, Week 3 Day 1; Cycle 6, Week 3 Day 1 (each cycle 21 days) up to end of study, approximately 1 year 10 months postdose | 
| Participants With Treatment-Emergent Adverse Events Grade 3 or Higher by System Organ Class and Preferred Term Following Treatment With CS-1008 in Combination With Chemotherapy (Paclitaxel/Carboplatin) in Locally Advanced or Metastatic Ovarian Cancer | Treatment-emergent adverse events (TEAEs) were defined as those events that occur, having been absent before the study, or worsen in severity after the initiation of CS-1008 and/or paclitaxel/docetaxel/carboplatin administration. All adverse events (AEs) were graded (1 to 5) according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0, where Grade 1 was mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening or disabling, and Grade 5 death related to AE. | Baseline up to 30 days after last dose, up to 1 year 10 months postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian Cancer Stage IIIC, Ovarian Cancer Stage IV, CS-1008, Paclitaxel, Carboplatin