A Study of Carboplatin and Paclitaxel With or Without MEDI-575 in Untreated, Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the dose, antitumor activity, safety and pharmacology of MEDI-575 in combination with carboplatin/paclitaxel in subjects with previously untreated, advanced non-small cell lung cancer (NSCLC).

Detailed Description
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This is a Phase 1b/2, multicenter, open-label study of MEDI-575 to evaluate the dose, anti-tumor activity, safety, and pharmacology (pharmacokinetics, immunogenicity, and biomarkers) of MEDI-575 in combination with carboplatin/paclitaxel in subjects with previously untreated, advanced non-small cell lung cancer. This study has two phases: dose determination (Phase 1b) and randomization (Phase 2).

Official Title
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A Phase 1b/2 Randomized Study of MEDI-575 in Combination With Carboplatin Plus Paclitaxel Versus Carboplatin Plus Paclitaxel Alone in Adult Subjects With Previously Untreated, Advanced Non-Small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: MEDI-575


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed inoperable Stage IIIB or Stage IV non-small cell lung cancer according to the Seventh Edition of the American Joint Committee on Cancer (AJCC) Tumor Node Metastases (TNM) staging system (only participants with squamous cell carcinoma will be enrolled) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Life expectancy of greater than or equal to (>=) 3 months Prothrombin time elevation less than or equal to (<=) Grade 2 by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) criteria (Version 4.0) is acceptable for participants on anticoagulant therapy Adequate hematologic function Adequate organ function Suitable candidates for therapy with carboplatin/paclitaxel Participants must have at least 1 lesion that is measurable using Response Evaluation Criteria for Solid Tumors Participants must be willing to consent to allow collection of archived NSCLC tumor samples Negative serum beta-human chorionic gonadotropin (beta-hCG) test (women of childbearing potential only) Females of childbearing potential, unless surgically sterile has a sterile male partner, is premenarchal or at least 2 years postmenopausal, or practices abstinence, must use 2 effective methods of avoiding pregnancy (including oral, transdermal, or implanted contraceptives, intrauterine device, female condom with spermicide, diaphragm with spermicide, cervical cap, or use of a condom with spermicide by the sexual partner) from screening, and must agree to continue using such precautions for 90 days after the final dose of treatment; cessation of birth control after this point should be discussed with a responsible physician Males, unless surgically sterile, must use 2 effective methods of birth control with a female partner and must agree to continue using such contraceptive precautions from screening through 90 days after the final dose of treatment Exclusion Criteria: At discretion of the investigator regarding safety of the participants Concurrent enrollment in another clinical study Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for treatment of cancer Previous monoclonal antibody (mAb) treatment specifically directed against platelet-derived growth factor (PDGF) or PDGF receptors History of serious allergy or reaction to any component of the MEDI-575 formulation Receipt of any previous systemic anticancer therapies for advanced or metastatic disease Previous adjuvant/neoadjuvant radiotherapy or chemotherapy for treatment of previous nonmetastatic disease is allowed provided that 6 months have elapsed from the end of such therapies to the time of enrollment New York Heart Association >= Class II congestive heart failure History of myocardial infarction, unstable angina, transient ischemic attack or stroke within the previous 6 months prior to enrollment History of other invasive malignancy within 5 years except for cervical carcinoma in situ (CIS), non-melanomatous carcinoma of the skin or ductal carcinoma in situ (DCIS) of the breast that have been surgically cured Evidence of active infection requiring the use of systemic antimicrobial treatment within 72 hours prior to initial treatment with MEDI-575 Use of immunosuppressive medication (inhaled and topical corticosteroids are permitted) within 7 days prior to enrollment Systemic immunosuppressive steroid therapy Participants may take replacement doses of steroids if on a stable dose for at least 2 weeks prior to enrollment History of active human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Pregnancy or lactation Previous medical history or evidence of an inter-current illness Any physical, social, or psychiatric condition which would prevent effective cooperation or participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Active Comparator: Carboplatin/Paclitaxel<br>Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal. Subjects were enrolled from North America/European Union (EU) and Japan regions. | Drug: Carboplatin<br>* Carboplatin (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min] administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.<br>Drug: Paclitaxel<br>* Paclitaxel 200 milligram per square meter (mg/m^2) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.<br>|
| Experimental: Carboplatin/Paclitaxel + MEDI-575<br>Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal. MEDI-575 alone continued in those participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575. Subjects were enrolled from North America/European Union (EU) and Japan regions. | Drug: Carboplatin<br>* Carboplatin (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min] administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.<br>Drug: Paclitaxel<br>* Paclitaxel 200 milligram per square meter (mg/m^2) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.<br>Drug: MEDI-575<br>* MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal. MEDI-575 alone continued in those participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLT): Phase 1b | A DLT was defined as: Any treatment-related Grade 3 or higher non-hematologic toxicity that occurred during the DLT assessment period with the following exceptions: Grade 3 fever (in the absence of neutropenia) defined as more than (>) 40.0 degree Celcius (> 104.0 degree Fahrenheit) that resolved to normal or baseline within 24 hours of treatment and was not considered a serious adverse event (SAE); or Grade 3 rigors/chills that responded to optimal therapy. Any treatment-related Grade 3 or higher hematologic toxicity. | From Day 1 to Day 21 of first cycle | 
| Progression Free-Survival (PFS) | Progression-free survival defined as the time from randomization (randomization referred to the date of treatment assignment) to disease progression (defined according to Response Evaluation Criteria for Solid Tumors [RECIST] version 1.1 guidelines) or death due to any cause, whichever occurs first. Participants without progression or death at the time of analysis were censored at their last date of tumor evaluation. PFS was assessed only in North America/European Union (EU) participants. Progression-free survival was evaluated using Kaplan-Meier method. | From randomization until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | Best overall response of a participant was defined as the best tumor response [Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)] observed during the trial period assessed according to the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1 criteria. The participant's best overall response assignment depended on the findings of both target and non-target disease and also on the appearance of new lesions. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30 percent (%) in the sum of diameters of target lesion, SD was defined as steady state of disease, and PD was defined as an increase of at least 20% in the sum of diameters of target lesions. | From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) | 
| Objective Response Rate (ORR) | The ORR defined as the percentage of participants with confirmed CR or confirmed PR according to RECIST version 1.1 guidelines. Confirmed responses were those that persist on repeat imaging or assessment greater than or equal to (>=) 4 weeks after the initial documentation of response. The ORR was evaluated using Kaplan-Meier method. | From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) | 
| Time to Response (TTR) | The TTR was measured from initiation of study treatment to the first documentation of objective response (OR). The OR defined as the participants with confirmed CR or confirmed PR according to RECIST version 1.1 guidelines. Confirmed responses were those that persist on repeat imaging or assessment >=4 weeks after the initial documentation of response. The TTR was evaluated using Kaplan-Meier method. | From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) | 
| Duration of Response (DR) | The DR defined as the duration from the first documentation of OR to the first documented disease progression. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. The DR was evaluated using Kaplan-Meier method. | From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) | 
| Time to Progression (TTP) | The TTP was measured from randomization until the documentation of disease progression. Disease progression defined according to RECIST version 1.1 guidelines. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. The TTP was evaluated using Kaplan-Meier method. | From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) | 
| Overall Survival (OS) | Overall survival defined as the time from initiation of study treatment until death due to any cause. Participants who were still alive at the time of analysis were censored at their last date of last contact. The OS was evaluated using Kaplan-Meier method. | From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years) | 
| Number of Participants With Abnormalities in Laboratory Investigations Reported as AEs or SAEs | Laboratory investigations included hematology, coagulation, serum chemistry and urinalysis parameters. Participants with abnormalities in these laboratory investigations recorded as AEs or SAEs were reported. | From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years) | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as AEs | The 12-lead ECG data were performed and obtained in triplicate that is 3 ECGs obtained within a 5 minute time period. Number of participants with ECG abnormalities were reported and recorded as AEs. | From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years) | 
| Maximum Observed Serum Concentration (Cmax) of MEDI-575 After First Dose | The Cmax of MEDI-575 after first dose is reported. | Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15 | 
| Time of Maximal Observed Concentration (Tmax) of MEDI-575 After First Dose | The tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). The Tmax of MEDI-575 after first dose is reported. | Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15 | 
| Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau) of MEDI-575 After First Dose | The AUCtau defined as area under the plasma concentration time profile from time zero to the end of the dosing interval (tau). The AUCtau of MEDI-575 after first dose is reported. | Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15 | 
| Maximum Serum Concentration at Steady State (Cmax,ss) of MEDI-575 | The Cmax,ss of MEDI-575 is reported. | Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion) | 
| Time to Maximum Serum Concentration at Steady State (Tmax,ss) of MEDI-575 | The Tmax,ss of MEDI-575 is reported. | Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion) | 
| Trough Serum Concentration at Steady State (Ctrough,ss) of MEDI-575 | The Ctrough,ss of MEDI-575 is reported. | Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion) | 
| Percentage of Participants With Positive Anti-MEDI-575 Antibodies | Immunogenicity assessment included determination of anti-drug (MEDI-575) antibodies in serum samples. | Day 1 (prior to infusion) of Cycles 1 to 7 (21-day cycle), end of treatment, 30 and 60 days after the last dose (approximately 3 years) | 
| Number of Participants With Platelet-derived Growth Factor Receptor Alpha (PDGFRα) Expression in Tumor Cells of Archived Tumor Samples | The immunohistochemical expression of PDGFRα in tumor cells in archived formalin-fixed paraffin-embedded tissue samples collected at baseline are reported. The transmembrane receptor tyrosine kinase PDGFRα plays an important role in human carcinogenesis, both as a direct target on tumor cells and also as a mediator of stromal support for cancer cell growth. The data of positive-staining tumor cells are reported in 3 categories: intensity (1+ [weak expression, staining in <5 % of tumor cells]; 2+ [moderate expression, staining in >= 5 % of tumor cells]; and 3+ [strong expression, staining in >5 % of the tumor cells]), localization (membranous, cytoplasmic, or nuclear), and frequency (rare, occasional, or frequent). | Baseline (Screening [Days -28 to -1]) | 
| Number of Participants With PDGFRα Expression in Stromal Cells of Archived Tumor Samples | The immunohistochemical expression of PDGFRα in stromal cells in archived formalin-fixed paraffin-embedded tissue samples collected at baseline are reported. The transmembrane receptor tyrosine kinase PDGFRα plays an important role in human carcinogenesis, both as a direct target on tumor cells and also as a mediator of stromal support for cancer cell growth. The data of positive-staining stromal cells are reported in 3 categories: intensity (1+ [weak expression, staining in <5 % of tumor cells]; 2+ [moderate expression, staining in >= 5 % of tumor cells]; and 3+ [strong expression, staining in >5 % of the tumor cells]), localization (membranous, cytoplasmic, or nuclear), and frequency (rare, occasional, or frequent). | Baseline (Screening [Days -28 to -1]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Non-small cell lung cancer, MEDI-575, Platelet-derived growth factor receptor alpha