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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 EITHER BEVACIZUMAB + PLATINUM + PACLITAXEL OR PEMETREXED + PLATINUM AS FIRST-LINE TREATMENT IN PATIENTS WITH STAGE IIIB or IV NON-SQUAMOUS NON-SMALL CELL LUNG CANCER (NSCLC)
- To evaluate the efficacy of onartuzumab compared with placebo in patients with non-squamous NSCLC in the first-line setting, as measured by investigator-assessed PFS in the ITT (unselected) population in each of two combination treatment cohorts: Avastin Treated (Cohort 1): Onartuzumab + bevacizumab + platinum + paclitaxel vs. placebo + bevacizumab + platinum + paclitaxel AND Non–Avastin Treated (Cohort 2): Onartuzumab + platinum + pemetrexed vs. placebo + platinum + pemetrexed
- To evaluate the efficacy of onartuzumab compared with placebo in patients with non-squamous NSCLC in the first-line setting, as measured by investigator-assessed PFS in the subgroup of patients with Met diagnostic–positive tumors (the Met diagnostic–positive population) in each of the two treatment cohorts described above
- To evaluate the efficacy of onartuzumab compared with placebo, as measured by OS, in each of two treatment cohorts described above, for both the ITT and Met diagnostic–positive populations
- To evaluate the efficacy of onartuzumab compared with placebo, as measured by overall response rate (ORR), duration of response (DOR), and disease control rate (DCR), in each of two treatment cohorts described above, for both the ITT and Met diagnostic–positive populations
- To evaluate the safety and tolerability of onartuzumab compared with placebo in patients with non-squamous NSCLC in the first-line setting in each of two treatment cohorts described above, focusing on all AEs, serious AEs, NCI CTCAE Grade ≥ 3 adverse events, and Grade ≥ 3 laboratory toxicities
- To describe the pharmacokinetics (PK) of onartuzumab when given in combination with bevacizumab, platinum, and paclitaxel or pemetrexed
- To evaluate the possible effect of onartuzumab on the PK of bevacizumab, platinum, paclitaxel, and pemetrexed by comparison of the respective onartuzumab and placebo combination treatments
- To evaluate serum levels and incidence of ATAs against onartuzumab
- 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 or Stage IV NSCLC tumors of non-squamous histology. Stage IIIB NSCLC patients are eligible only if they are staged with T4 disease that is not amenable to definitive surgery or radiation therapy.
- For patients who received prior adjuvant chemotherapy or chemoradiotherapy: a treatment-free interval of at least 12 months since the last chemotherapy or chemoradiotherapy cycle
- Adequate tissue for central IHC assay of Met receptor, and EGFR testing if EGFR status is unknown. See Section 18.104.22.168 for tissue requirements.
- 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 if enrolled in Cohort 1)
- 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 if enrolled in Cohort 1)
Hematologic, Biochemical, and Organ Function
- Prior systemic treatment for Stage IIIB or IV non-squamous NSCLC
- Evidence of mixed NSCLC histology with a predominance of the squamouscell type
- 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
- Known central nervous system (CNS) disease, other than stable, treated brain metastasis (no evidence of progression after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and post-treatment brain imaging [computed tomography (CT) scan or magnetic resonance imaging (MRI)] at baseline). Patients should be off corticosteroids for 1 week (7 days) at the time of the post-treatment brain CT/MRI. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery (Gamma Knife linear particle accelerator or equivalent), or a combination, as deemed appropriate by the treating physician, and must have been completed greater than 7 days prior to Day 1 of Cycle 1. During study therapy, patients with stable, treated brain metastasis will be monitored using the same imaging modality (MRI or CT scan) that was used at baseline. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 8 weeks prior to Day 1 of Cycle 1 will be excluded.
- History of another malignancy in the previous 3 years, with a disease-free interval of less than 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.
- Granulocyte count < 1500/mm^3; platelet count < 100,000/mm^3, and hemoglobin < 9.0 g/dL within 7 days of prior 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 Gilberts 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 drug
- Known sensitivity to any component of cisplatin or carboplatin
- 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
Patients who meet any of the following criteria should not be randomized into Cohort 1:Pemetrexed-Related Criteria
- History of Grade ≥ 2 hemoptysis (defined as bright red blood of at least 2.5 mL) in the 3 months prior to enrollment
- Evidence of tumor invading major blood vessels on imaging (e.g., pulmonary artery or superior vena cava)
- Urine dipstick for proteinuria ≥ 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ g of protein in 24 hours.
- Urine protein/creatinine ratio ≥ 1. Patients with urine protein/creatinine ratio ≥ 1 may be enrolled if < 1 g of protein is demonstrated in 24-hour urine collection.
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic > 100 mm Hg on antihypertensive medications).
- History of stroke or transient ischemic attack within 6 months prior to Day 1 of Cycle 1
- History of gastrointestinal fistula, perforation, or abscess; inflammatory bowel disease; or diverticulitis
- Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
- Serious, non-healing wound, active ulcer, or untreated bone fracture.
- Core biopsy or other minor surgical procedure, excluding placement of vascular access device, closed pleurodesis, thoracentesis, and mediastinoscopy, within 7 days prior to Day 1 of Cycle 1
- Inability to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤ 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam)
- Known sensitivity to any component of bevacizumab
Patients who meet any of the following criteria should not be randomized into Cohort 2:
- Known sensitivity to any component of pemetrexed
- Patients unable to discontinue treatment with NSAIDs
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