Efficacy/Safety of Imprime PGG With Cetuximab & Paclitaxel/Carboplatin Therapy in Pts With Untreated Advanced Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
The Phase 2 study described in this protocol will serve to evaluate the antitumor activity, safety and pharmacokinetic profile of Imprime PGG when combined with cetuximab and concomitant paclitaxel and carboplatin therapy in patients with previously untreated advanced NSCLC. Additionally, this study will provide guidance for the design of more definitive efficacy studies of Imprime PGG in NSCLC patients.

Official Title
-----------------
Efficacy and Safety Study of Imprime PGG® Injection in Combination With Cetuximab and Concomitant Paclitaxel and Carboplatin Therapy in Patients With Previously Untreated Advanced (Stage IIIB or IV) Non-Small Cell Lung Cancer

Conditions
-----------------
NSCLC

Intervention / Treatment
-----------------
* Biological: Imprime PGG Injection
* Biological: Cetuximab
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has read, understood and signed the informed consent form (ICF) approved by the Independent Review Board/Ethics Committee (IRB/EC) Is between the ages of 18 and 75 years old, inclusive Has histologically or cytologically confirmed stage IIIB (malignant pericardial or pleural effusion) or stage IV non-small cell lung cancer Has measurable disease, defined as at least one tumor that fulfills the criteria for a target lesion according to RECIST Has an ECOG performance status of 0 or 1 Has a life expectancy of > 3 months Has adequate hematologic function as evidenced by: ANC ≥ 1,500/μL PLT ≥ 100,000/μL HGB ≥ 9 g/dL obtained within 1 week prior to the first dose of study medication; Has adequate renal function as evidenced by: Serum creatinine ≤ 1.5 X the upper limit of normal (ULN) for the reference lab Urine dipstick for proteinuria of < 1+ (i.e., either 0 or trace) within 2 weeks of Day 1 If urine dipstick is ≥ 1+, then urine protein excretion must be ≤ 500 mg over a 24 hour collection obtained within 1 week prior to the first dose of study medication; Has adequate hepatic function as evidenced by: Serum total bilirubin ≤ 1.0 mg/dL AST ≤ 2.5X ULN for the reference lab (≤ 5X ULN for subjects with known hepatic metastases) ALT ≤ 2.5X ULN for the reference lab (≤ 5X ULN for subjects with known hepatic metastases) obtained within 1 week prior to the first dose of study medication; If a woman of childbearing potential or a fertile man (and his partners), must agree to use an effective form of contraception (hormonal contraceptive, double-barrier method or abstinence) during the study. Exclusion Criteria: Has received prior systemic chemotherapy at any time for lung cancer; Has received previous radiation therapy to >30% of active bone marrow or any radiation therapy within 3 weeks of Day 1 Has a known hypersensitivity to baker's yeast, or has an active yeast infection Has had previous exposure to Betafectin® or Imprime PGG Has an active infection Presents with any of the following medical diagnoses/conditions at the time of screening: Central nervous system (CNS) metastases Uncontrolled hypertension (>150/100 mmHg) or hypertension that requires > two agents for adequate control Peripheral neuropathy ≥ grade 2 from any cause Fever of >38.5° C within 3 days prior to screening or Day 1, initial dosing Known HIV/AIDs, Hepatitis B, Hepatitis C, connective tissue or autoimmune disease, or other clinical diagnosis, ongoing or intercurrent illness that in the physician's opinion could interfere with participation Has a history of any of the following medical diagnoses/conditions: Myocardial infarction or an unstable or uncontrolled disease or condition related to or impacting cardiac function (e.g., unstable angina, congestive heart failure) within the previous 6 months Second malignancy within the previous 5 years, other than basal cell carcinoma, cervical intra-epithelial neoplasia or curatively treated prostate cancer with a PSA of <2.0 ng/mL Has a known hypersensitivity to cetuximab, murine proteins, or any component of cetuximab Has a know sensitivity to Cremophor EL Has previously received treatment with cetuximab If female, is pregnant or breast-feeding Is receiving concurrent investigational therapy or has received investigational therapy within a period of 30 days prior to the first scheduled day of dosing (investigational therapy is defined as treatment for which there is currently no regulatory-authority-approved indication) Has previously received an organ or progenitor/stem cell transplant.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imprime PGG<br>Imprime PGG Injection + Cetuximab + Paclitaxel/Carboplatin | Biological: Imprime PGG Injection<br>* 4 mg/kg i.v. over 2 hrs, weekly, in three week cycles<br>Biological: Cetuximab<br>* initial loading dose of 400 mg/m^2 over 120 min and subsequent doses at 250 mg/m^2 over 60 min, weekly on Days 1, 8 and 15 of each 3-week treatment cycle<br>* Other names: Erbitux;Drug: Paclitaxel<br>* 200 mg/m^2 i.v. over 3 hr on Day 2 of each 3-week treatment cycle for the first 4 to 6 treatment cycles<br>* Other names: Nov-Onxol;Drug: Carboplatin<br>* dose equal to an AUC of 6 mg/mL · min based on the Calvert formula; i.v. over 30 min on Day 2 of each 3-week treatment cycle for the first 4 to 6 treatment cycles<br>* Other names: Paraplatin;|
| Active Comparator: Control<br>Cetuximab + Paclitaxel/Carboplatin | Biological: Cetuximab<br>* initial loading dose of 400 mg/m^2 over 120 min and subsequent doses at 250 mg/m^2 over 60 min, weekly on Days 1, 8 and 15 of each 3-week treatment cycle<br>* Other names: Erbitux;Drug: Paclitaxel<br>* 200 mg/m^2 i.v. over 3 hr on Day 2 of each 3-week treatment cycle for the first 4 to 6 treatment cycles<br>* Other names: Nov-Onxol;Drug: Carboplatin<br>* dose equal to an AUC of 6 mg/mL · min based on the Calvert formula; i.v. over 30 min on Day 2 of each 3-week treatment cycle for the first 4 to 6 treatment cycles<br>* Other names: Paraplatin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) in Each Study Arm Based on Independent Central Radiology Review | Overall objective response rate was defined as the number of participants experiencing a best overall response of either complete response (CR) or partial response (PR) based on the modified RECIST v1.0 criteria. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. | From first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Each Study Arm Based on the Safety Population | Overall survival (OS) was defined as the time from the date of randomization until the date of documented death of the subject due to any cause, including death due to relapses that were successfully retreated. Subjects who were lost to follow-up or who were still alive at the time of analysis were censored at the last contact dates. | From the time of randomization to death, subject being lost to follow-up or study completion | 
| Disease Control Rate (DCR) in Each Study Arm Based on Independent Central Radiology Review | The disease control rate (DCR) was defined as the number of participants experiencing a best overall tumor response of either CR, PR or SD. For stable disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. | From first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | 
| Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | The best observed overall response rates were defined as the number of participants experiencing a best overall response of either complete response (CR), partial response (PR) or stable disease (SD) based on the modified RECIST v1.0 criteria. For stable disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. | From the first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | 
| Duration of Objective Tumor Response in Each Study Arm Based on Independent Central Radiology Review | The duration of objective tumor response was measured from the time at which criteria are met for CR or PR (whichever status is recorded first) until the first date on which recurrence or progressive disease is objectively documented per modified RECIST v1.0. Subjects who did not progress as of the data cutoff date were censored at their last tumor assessment date. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. | From the first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | 
| Duration of Time to Progression (TTP) in Each Study Arm Based on Independent Central Radiology Review | Time-to-progression (TTP) was defined as the time from the date of randomization to the first date of documented progressive disease. Progressive disease was identified by radiologic progressive disease according to modified RECIST v1.0, or in the case of the Investigator Radiologic Review, it may also be defined by clinical progression as determined by the investigator. If a subject received any further anti-cancer therapy without prior documentation of disease progression, the subject was censored at the date of last tumor assessment before starting anti-cancer treatment. Subjects who died on study from other causes (not related to study disease) and subjects who were lost to follow-up or who were alive without documented progressive disease as of the data cut-off date for analysis were censored at the last tumor assessment date. | From time of randomization to first date of documented progression, or last tumor assessment date, up to 15 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Imprime PGG, NSCLC, Cetuximab