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A randomized, phase II, multicenter, double-blind, placebo-controlled study evaluating the efficacy and safety of onartuzumab (MetMAb) in combination with paclitaxel + cisplatin or carboplatin as first-line treatment for patients with stage IIIB (T4 disease) or IV squamous non-small cell lung cancer (nsclc).
- Primary Objectives
- To evaluate the efficacy of onartuzumab + paclitaxel + platinum (cisplatin or carboplatin) relative to placebo + paclitaxel + platinum as measured by investigator-assessed progression-free survival (PFS)
- To evaluate the efficacy of onartuzumab + paclitaxel + platinum relative to placebo + paclitaxel + platinum as measured by investigator-assessed progression-free survival (PFS) in the subgroup of patients with Met diagnostic-positive squamous NSCLC
- Secondary Objectives
- To evaluate the efficacy of onartuzumab + paclitaxel + platinum relative to placebo + paclitaxel + platinum as measured by overall survival (OS) in all patients and in those with Met diagnostic-positive squamous NSCLC
- To evaluate the efficacy of onartuzumab + paclitaxel + platinum relative to placebo + paclitaxel + platinum as measured by overall response rate (ORR), duration of response (DOR), and disease control rate (DCR) in all patients and in those with Met diagnostic-positive squamous NSCLC
- To evaluate the safety and tolerability of onartuzumab + paclitaxel + platinum in all patients and those with Met diagnostic-positive squamous NSCLC
- To describe the pharmacokinetics (PK) of onartuzumab when given with paclitaxel and platinum
- To evaluate the possible effect of onartuzumab on the PK of paclitaxel and platinum by comparison of the respective onartuzumab and placebo combination treatments
- To evaluate the serum levels and incidence of ATAs against onartuzumab
- Exploratory Objectives
- To explore potential relationships between immunogenicity response and pharmacokinetics, safety, and activity
- To evaluate the potential association of exploratory tissue, serum and plasma biomarkers and circulating tumor cells in blood with study drug response, including efficacy and/or adverse events, and to increase knowledge and understanding of NSCLC biology
- Ability and willingness to provide written informed consent and to comply with the study protocol
- Male or female, 18 years of age or older
- ECOG performance status of 0 or 1
- Histologically or cytologically confirmed Stage IIIB (T4 N2M0 or T4N3M0) or Stage IV NSCLC tumors of squamous histology
- Stage IIIB NSCLC patients are eligible only if their disease is not amenable to definitive surgery or radiation therapy.
- Patients with stable, treated brain metastases are eligible as long as there is no evidence of progression after treatment and no ongoing requirement for dexamethasone or other corticosteroid treatment.
- No prior chemotherapy for squamous NSCLC
- Adequate tissue for central IHC assay of Met receptor, and EGFR testing if EGFR status is unknown
- Radiographic evidence of disease (measurable disease is strongly preferred but not mandatory)
- To be considered evaluable for complete response (CR) or partial response (PR) assessment, patients must have at least one lesion measurable according to RECIST v1.1.
- If the lesion is the only site of disease, it must be outside a previous radiotherapy field, unless disease progression has been documented at that site since radiation.
- Patients may have received prior radiation therapy provided they have recovered from any toxic effects thereof and that at least 7 days have elapsed between the last fraction and randomization.
- For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use an adequate method of contraception, during the treatment period and for at least 90 days after the last dose of onartuzumab/placebo and 6 months after the last dose of paclitaxel
- For male patients who are partners of premenopausal women: agreement to use a barrier method of contraception during the treatment period and for at least 90 days after the last dose of onartuzumab/placebo and 6 months after the last dose of paclitaxel
- Cancer-Related Criteria
- Prior systemic treatment for Stage IIIB or IV squamous NSCLC
- NSCLC with histology classified as adenocarcinoma, large cell, mixed adenosquamous, or NSCLC not otherwise specified (NOS)
- Prior exposure to experimental treatment targeting either the HGF or Met pathway
- Patients with tumors confirmed to have EGFR-activating mutations who are suitable for anti-EGFR therapy (e.g., gefitinib or erlotinib), as determined by the investigator, unless that treatment is unavailable or refused by the patient
- Uncontrolled brain metastases and treatment by neurosurgical resection or brain biopsy within 4 weeks prior to Day 1 of Cycle 1
- History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years
- Patients with prior history of in situ cancer that was treated surgically with curative intent, localized prostate cancer that has been treated surgically with curative intent, or basal or squamous cell skin cancer are eligible.
- Hematologic, Biochemical, and Organ Function
- Granulocyte count < 1500/mm3; platelet count < 100,000/mm3, and hemoglobin < 9.0 g/dL within 7 days prior to enrollment
- Partial thromboplastin time (PTT), international normalized ratio (INR), or prothrombin time (PT) > 1.5 x the upper limit of normal (ULN) (except for patients receiving anticoagulation therapy)
- AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP) ≥ 2.5 x ULN; [≥ 5 x ULN with liver metastases]
- Total bilirubin ≥ 1.5 x ULN (except in patients diagnosed with Gilbert's disease).
- Serum calcium > ULN corrected for low serum albumin concentrations
- Corrected calcium (mg/dL) = serum Ca + [(4.0 - measured serum albumin) x 0.8]
- Corrected calcium (mmol/L) = serum calcium + 0.02 x (40 - serum albumin)
- Serum creatinine > 1.5 x ULN or calculated creatinine clearance (CrCl) < 60 mL/min (Cockcroft and Gault)
- Uncontrolled diabetes as evidenced by fasting serum glucose level > 200 mg/dL
- Pregnancy or lactation (or positive pregnancy test within 48 hours before starting any component of study medication)
- Significant history of cardiovascular disease (i.e., unstable angina, uncontrolled hypertension, congestive heart failure, as defined by the New York Heart Association [NYHA] as Class II, III, or IV [The Criteria Committee of the NYHA 1994]) within 6 months prior to Day 1 of Cycle 1, myocardial infarction within the previous year, or current cardiac ventricular arrhythmias requiring medication
- Serious (≥ Grade 3) active infection at the time of randomization, or other serious underlying medical conditions that would impair the ability of the patient to receive protocol treatment
- Patients known to be HIV positive
- Any condition (e.g., psychological, geographical, etc.) that does not permit compliance with study and follow-up procedures
- Life expectancy of < 12 weeks
- Receipt of an investigational drug within 28 days prior to initiation of study treatment
- Known sensitivity to any component of cisplatin, carboplatin, or paclitaxel
- Any major surgery, major surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1, or an anticipated need for major surgery during the study
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