Study of Everolimus, Pemetrexed, Carboplatin, and Bevacizumab to Treat Stage IV Lung Cancer
The purpose of this study is to identify a well-tolerated dose of everolimus in combination with chemotherapy treatment for patients with advanced lung cancer.
Non Small Cell Lung Cancer
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Dose Escalation Study of Everolimus, Pemetrexed, Carboplatin, and Bevacizumab in Stage IV Non-Squamous Non-Small Cell Lung Cancer|
- Maximum Tolerated Dose (MTD) and Recommended Phase Two Dose (RPTD) of the combination of everolimus with pemetrexed, carboplatin, and bevacizumab in patients with Stage IV non-squamous NSCLC. [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]Measured by adverse event profile at the end of Cycle 1. MTD is the highest dose level where less than one third of 12 evaluable patients experience a dose limiting toxicity as defined by the protocol.
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]
Dose Limiting Toxicity (DLT) adverse events related to everolimus/pemetrexed/carboplatin/bevacizumab administration in patients with Stage IV non-squamous NSCLC. DLTs will be defined during cycle 1 only. Grading of adverse events will be according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Hematologic Adverse Events are defined as:
Grade 4 neutropenia lasting greater than 5 days; Grade 3 or 4 febrile neutropenia; and/or Grade 4 thrombocytopenia
Non-hematologic Adverse Events are defined as:
Grade 3 or greater non-hematologic excluding the following:
Hypersensitivity reaction grade 3 or 4 occurring on day 1 or day 15; Nausea/vomiting grade 3 or 4 in the absence of optimal antiemetics; Diarrhea grade 3 or 4 in the absence of optimal anti-diarrheal therapy; Asthenia grade 3 or 4 of less than 2 weeks duration; and/or Hyperglycemia grade 3 or 4 temporally related to corticosteroid pre-or post-medication
- Antitumor efficacy associated with administration of everolimus/pemetrexed/carboplatin/bevacizumab administration in patients with Stage IV non-squamous NSCLC. [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]number of patients with a response according to the Response Evaluation Criteria in Solid Tumors (RECIST)
- Progression-free survival (PFS) [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]time from start of treatment to time of progression or death (overall PFS)
- Overall Survival (OS) [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]measured from the start of treatment to time of death.
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||March 2014|
|Estimated Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
Experimental: Experimental Phase I Dose Escalation
Pemetrexed: intravenous; 500 mg/m² for Dose Levels 1, 2 and 3
Carboplatin: intravenous; 5 AUC for Dose Level 1; 6 AUC for Dose Levels 2 and 3
Bevacizumab: intravenous; 15 mg/kg for Dose Levels 1, 2, and 3
Everolimus: oral, 2.5 mg/day for Dose Levels 1 and 2; 5.0 mg/day for Dose Level 3
Other Names:Drug: Pemetrexed
Other Name: AlimtaDrug: Carboplatin
Other Names:Drug: Bevacizumab
Other Name: Avastin
The AKT/mTOR pathway is a relevant target in NSCLC based on preclinical data showing aberrant pathway activation in human NSCLC tumors. Everolimus as a single agent has produced some responses as well as prolonged stable disease in both chemonaive and pre-treated NSCLC (Gridelli et al, 2008). There is interest in augmenting tumor responses to chemotherapy by the addition of mTOR inhibition. Additionally, preclinically, everolimus has shown antiangiogenic activity that appears to have different targets than direct VEGF inhibiting strategies and therefore may augment the activity of targeted VEGF inhibitors (Lane et al, 2009). Therefore, we propose to study in a Phase 1 dose escalation design the addition of everolimus in escalating doses in combination with Pem/Carbo/Bev in non-squamous histology NSCLC.
Patients will be entered onto dosing cohorts of 3 patients according to the following dose escalation scheme. The first cohort will begin at dose level 1. At least three patients on each dose level must have completed cycle one before the study leadership (principal investigators, study statisticians) will allow patients to be enrolled onto the successive dose level.
Dose Level (K): 1, 2, 3
Pemetrexed (mg/m²): 500, 500, 500
Carboplatin (AUC): 5, 6, 6
Bevacizumab (mg/kg): 15, 15, 15
Everolimus (mg/day): 2.5, 2.5, 5.0
Dose-limiting toxicities (DLTs) will be defined according to the National Cancer Institute's CTCAE v.4.0 toxicity scale (see Section 3.3 below). The traditional "3+3" dosing scheme will be used for dose escalation.
When the potential MTD has been identified, it will be expanded to a total of 12 patients.
|Contact: Jennifer Newman, CTC Operations||(206) firstname.lastname@example.org|
|United States, Arizona|
|University of Arizona Cancer Center||Recruiting|
|Tuscon, Arizona, United States, 85724|
|Contact: Linda L. Garland, MD 520-626-3434 email@example.com|
|Contact: Jeanette Cardenas 520-694-9082 firstname.lastname@example.org|
|Principal Investigator: Linda L. Garland, MD|
|United States, Kentucky|
|University of Kentucky Markey Cancer Center||Not yet recruiting|
|Lexington, Kentucky, United States, 40536|
|Contact: Dennie V. Jones, MD 859-257-2014 email@example.com|
|Principal Investigator: Dennie V. Jones, MD|
|United States, Oregon|
|Providence Cancer Center||Recruiting|
|Portland, Oregon, United States, 97213|
|Contact: Rachel Sanborn, MD 503-215-5396 Rachel.Sanborn@providence.org|
|Contact: Brenda Fisher, RN (503) 215-2613 Brenda.Fisher@providence.org|
|Principal Investigator: Rachel Sanborn, MD|
|United States, Washington|
|Cancer Research And Biostatistics Clinical Trials Consortium||Recruiting|
|Seattle, Washington, United States, 98101|
|Contact: CTC Operations Office 206-839-1738 firstname.lastname@example.org|
|Principal Investigator:||Linda L. Garland, MD||University of Arizona|
|Study Chair:||John Crowley, PhD||Cancer Research And Bioststistics|