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Phase 2 Study Assessing Efficacy and Safety of Crizotinib in Patients Harboring an Alteration on ALK, MET or ROS1

ABSTRACT: This is a biology driven, trans-tumoral, multicentric phase II trial assessing the efficacy and the safety of the targeted agent crizotinib as a monotherapy in 23 cohorts of patients with identified activating molecular alterations in the crizotinib target genes. A cohort is defined by a pathology and a crizotinib-target alteration (eg gastric cancer with MET amplification). For each cohort a two-stage design will be implemented. In the situation where expected accrual allows for a sufficient number of patients to be accrued, the alpha and beta errors will be fixed at 10%. However, in very rare diseases, such as inflammatory myofibroblastic tumor (IMT), neuroblastoma, glioblastoma, and rhabdomyosarcoma (RMS), it is anticipated that the target number may not be achievable in a reasonable timeframe; for these cohorts, the alpha and beta errors will be fixed at 15%. Consequently three different statistical designs will be a priori considered according to the expected response rate and incidence.

DISEASE(S): Patients With Metastatic Or Unresectable Locally Advanced Malignancies Harboring Specific Genomic Alterations Regarding The Biological Crizotinib Targets, And Who Are No More Amenable To Curative Treatment,Hematologic Neoplasms,Rhabdomyosarcoma,Glioblastoma,Colorectal Cancer,Inflammatory Myofibroblastic Tumour,Neuroblastoma,Breast Cancer,Ovarian Cancer,Thyroid Cancer,Gastric Cancer,Non-small Cell Lung Cancer,Renal Cell Carcinoma,Metastatic Cancer,Liver Carcinoma,Anaplastic Large Cell Lymphoma T- And-cell Types,Solid Tumors,Cholangiocarcinoma,Hematologic Cancers

PROVIDER: 2158683 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively). For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively).

Project description:Background & Aims: Patients with beta-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) have demonstrated limited clinical benefit to first-line immunotherapy (IO). Animal models of HCC expressing mutant-beta-catenin and additional aberrations via hydrodynamic tail vein injection with sleeping beauty transposon/transposase (SB-HDTVI) represent clinically relevant human HCC subsets. Here, we perform transcriptomic analysis on multiple beta-catenin-mutated and non-mutated HCC animal models to identify Mutated beta-catenin Gene Signature (MBGS) for HCC patient stratification for CTNNB1-mutations and IO response. Methods: We co-expressed in mice mutant-NFE2L2 and hMET +- mutant-CTNNB1 via SB-HDTVI and monitored for HCC development. Bulk RNA-sequencing was assessed for transcriptional differences between various beta-catenin-mutated and non-mutated models. MBGS was generated for predictive ability of CTNNB1 mutations and IO resistance in multiple HCC patient cohorts. Results: Co-expression of S45Y-beta-catenin + G31A-NFE2L2 + hMet (beta-N-M) resulted in HCC development by 4.5 weeks while co-expression of G31A-NFE2L2 + hMet (N-M) led to HCC by 14 weeks with tumors being positive for expected targets by immunohistochemistry (IHC). Bulk RNA-sequencing comparing beta-catenin-driven versus non-beta-catenin driven models yielded 95 common upregulated genes. Differential gene expression analysis of the common genes comparing CTNNB1-mutated vs non-mutated TCGA patients narrowed the gene panel to 13-(or 10-) genes. This MBGS predicted CTNNB1-mutation status in TCGA (n=374) and French (n=398) patient cohorts (with ROC AUC of 0.90 and 0.94). High MBGS expression was also associated with no overall and progression-free survival benefit when comparing atezolizumab + bevacizumab versus sorafenib arms in IMbrave150 cohort implying fewer treatment effects. Conclusions: In an era of patient molecular stratification for HCC, MBGS may aid in optimally selecting patients for IO through diagnosis of a molecular subset which lacks optimal response.

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Phase 2 Study Assessing Efficacy and Safety of Crizotinib in Patients Harboring an Alteration on ALK, MET or ROS1

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