RO4929097 and Erlotinib Hydrochloride in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer

Stage IV Non-Small Cell Lung Cancer Clinical Trial

Official title: Addition of the Gamma-Secretase Inhibitor RO4929097 to Erlotinib in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

Status Terminated

Clinical Trial Summary

This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) and erlotinib hydrochloride when given together in treating patients with non-small cell lung cancer that is stage IV or has come back. RO4929097 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. To define the maximum-tolerated dose (MTD) and toxicity of RO4929097 combined with erlotinib (erlotinib hydrochloride) in patients with advanced non-small cell lung cancer (NSCLC). (Dose escalation portion) II. To assess whether the probability of detectable tumor shrinkage or response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria correlates with pre-therapy immunohistochemistry (IHC) and reverse phase protein array (RPPA) expression of Notch 1, 2, 3, and 4. (Dose escalation portion) III. A preliminary, exploratory assessment will be performed with respect to percent tumor shrinkage and the probability of response over the first 2 cycles of therapy. (Expansion cohort) IV. A preliminary, exploratory assessment will be performed with respect to change in tumor immunohistochemistry (IHC) scores and reverse phase protein array (RPPA) expression for Notch 1, 2, 3, and 4 over the first 2 cycles of erlotinib. (Expansion cohort)

SECONDARY OBJECTIVES:

I. To perform a preliminary exploratory assessment of whether probability of detectable tumor shrinkage/response correlates with pre RO4929097 presence in tumor of an activating epidermal growth factor receptor (EGFR) mutation, the T790M EGFR mutation, met proto-oncogene (c-MET) gene amplification or insulin-like growth factor 1 receptor (IGF-1R) expression or activation or various Notch pathway markers. (Dose escalation portion) II. To perform a preliminary exploratory assessment of whether addition of RO4929097 to erlotinib leads to tumor shrinkage/response in any tumor deposits that had previously exhibited growth on erlotinib alone. (Dose escalation portion) III. Conduct a preliminary exploratory assessment on the expansion cohort with respect to tumor shrinkage/response of the following over the first 2 cycles of erlotinib and RO4929097 treatment with and without the presence of mutation, amplification, and activation of markers: tumor IHC scores and RPPA expression of the Notch ligand jagged 1 (Jag1), and the Notch targets hairy and enhancer of split 1 (HES1), hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1); tumor IHC scores and RPPA expression of putative stem cell markers cluster of differentiation (CD)24 (decreased in stem cells), CD44, CD133, dehydrogenase and of the epithelial to mesenchymal transition (EMT) markers E-cadherin and vimentin; detectability in tumor of EGFR T790M mutations, MET amplification, and IGF-1R expression and activation; and soluble markers of angiogenesis, including stromal cell-derived factor 1 alpha (SDF-1alpha), basic fibroblastic growth factor (bFGF), cryptic epitope of collagen IV, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF). (Expansion cohort) IV. Conduct a preliminary exploratory assessment of whether percent tumor shrinkage/response or time to progression correlates with pre-therapy IHC and RPPA expression of Notch 1, 2, 3 and 4, the above Notch pathway and stem cell markers, with baseline detectability of T790M mutations and MET amplification, and with baseline IGF-1R expression and activation, and with change in these markers from the initial biopsy to the subsequent biopsy. (Expansion cohort) V. In tumor samples collected both during the dose escalation phase and in the expansion cohort, assess if IHC and RPPA expression of Notch, Notch ligand and Notch targets correlates with expression of stem cell markers.

VI. Assess if percent tumor shrinkage/response, time to progression and baseline and change in IHC and RPPA expression of Notch, Notch ligand, Notch targets and stem cell markers varies with: tumor Notch gene amplification as assessed by fluorescent in situ hybridization (FISH); tumor IHC and RPPA expression of selected members of the Wnt and Hedgehog pathways (since these could lead to stem cell properties in cells that do not express Notch); host (peripheral blood mononuclear cell) polymorphisms for relevant genes in the Notch pathway; tumor micro ribonucleic acid (RNA) levels.

VII. Trough levels of erlotinib and RO4929097 will be measured in plasma samples of all patients on the dose-escalation portion of the study approximately 24 hours after the cycle 1, day 1 dose and again approximately 24 hours after the cycle 2, day 1 dose. These measurements are being done to permit a preliminary exploratory assessment of whether there is induction of metabolism of one or both drugs that will lead to decreased drug plasma concentrations.

VIII. In the Expansion Cohort, plasma levels of erlotinib and RO4929097 will be measured approximately 24 hours after the cycle 2, day 21 erlotinib dose (just prior to initiation of cycle 3), and plasma levels of both agents will be measured in plasma approximately 24 hours after the cycle 3, day 1 doses of both agents. These measurements are done to permit a preliminary exploratory assessment of whether: plasma drug levels correlate with % tumor shrinkage/response or with change in tumor biomarkers over the first 6 weeks of therapy; erlotinib plasma concentrations are affected by RO4929097 administration.

OUTLINE: This is a dose-escalation study.

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks. ;

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Recurrent Non-Small Cell Lung Carcinoma
• Stage IV Non-Small Cell Lung Cancer

• NCT number: NCT01193881
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Terminated
• Phase: Phase 1
• Start date: August 2010
• Completion date: August 2015