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Report for Clinical Trial NCT01193881

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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

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.

NCT01193881 Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4 Interventions

Name: Erlotinib Hydrochloride

Description: Given PO
Type: Drug
Group Labels: 1

Treatment (erlotinib, RO4929097)

Name: Gamma-Secretase Inhibitor RO4929097

Description: Given PO
Type: Drug
Group Labels: 1

Treatment (erlotinib, RO4929097)

Name: Laboratory Biomarker Analysis

Description: Correlative studies
Type: Other
Group Labels: 1

Treatment (erlotinib, RO4929097)

Name: Pharmacological Study

Description: Correlative studies
Type: Other
Group Labels: 1

Treatment (erlotinib, RO4929097)


Primary Outcomes

Measure: Incidence of adverse events assessed using NCI CTCAE version 4.0 (Dose escalation phase)

Time: Within 30 days of last drug dose

Measure: Maximum-tolerated dose of RO4929097 and erlotinib hydrochloride defined as the highest dose tested causing dose limiting toxicity in < 2/6 patients assessed using National Cancer Institute (NCI) CTCAE version 4.0 (Dose escalation phase)

Time: At least 3 weeks after day 1 of course 1

Description: The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

Measure: Percentage of change in expression of Notch and other tumor and blood biomarkers (Expansion cohort)

Time: Baseline to 6 weeks

Description: Will be correlated with response and baseline expression of biomarkers. The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

Measure: Percentage of tumor shrinkage (Expansion cohort)

Time: Up to 6 weeks

Measure: Response rate by RECIST 1.1 (Expansion cohort)

Time: Up to 12 weeks

Description: Will be correlated with baseline expression or biomarkers.

Measure: Time to progression (Expansion cohort)

Time: Up to 12 weeks

Other Outcomes

Measure: Efficacy of this combination in unselected patients and in patients with intrinsic or acquired erlotinib resistance (Dose escalation phase)

Time: Up to 12 weeks

Description: Correlations between Notch pathway gene polymorphisms and tumor and blood biomarkers will be assessed. Correlations between Notch pathway gene polymorphisms and tumor shrinkage/response on therapy will also be assessed.

Measure: Host Notch pathway gene polymorphisms

Time: Up to 6 weeks

Description: Exploratory assessments of correlations of tumor shrinkage and response on the combination with pre-therapy tumor expression of Notch and other tumor and blood biomarkers will be conducted.

Measure: Pre-therapy tumor expression of Notch and other tumor and blood biomarkers (Dose escalation phase)

Time: Baseline

Description: Correlations between Notch pathway markers and stem cell markers will be assessed.

Measure: Stem cell markers

Time: Up to 6 weeks

Purpose: Treatment

Allocation: N/A

Single Group Assignment


There is one SNP

SNPs


1 T790M

(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. --- T790M ---

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). --- T790M ---

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. --- T790M ---



HPO Nodes


HPO: