Clinical Trial: Circulating Tumor DNA (ctDNA) as a Prognostic Tool in Patients With Advanced Lung Adenocarcinoma

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational [Patient Registry]

Official Title: Circulating Tumor DNA (ctDNA) as a Prognostic Tool in Patients With Advanced Lung Adenocarcinoma

Brief Summary:

Lung cancer is the leading cause of cancer death in the U.S. and throughout the world. Lung cancers are broadly divided histologically into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). About 25% of patients with NSCLC have stage I or II disease. The primary treatment modality is surgical resection,2 and 5-year survival rates are 65% for stage I and 41% for stage II disease. However, more than 70% of patients with NSCLC present with stage III or IV disease. Patients with stage III disease are most commonly treated with chemoradiation, and 5-year survival rate is 26%. Chemotherapy and targeted therapy are often used for stage IV disease, which has a 5-year survival rate of 4%.

Tyrosine kinase inhibitor (TKI) is a targeted therapy against specific molecules in critical cell-signaling pathways involved in lung carcinogenesis. The currently available FDA approved TKIs for advanced NSCLC include afatinib, gefitinib, and erlotinib that inhibit epidermal growth factor receptor (EGFR) signaling 6 and crizotinib that inhibits anaplastic lymphoma kinase (ALK) signaling. However, only tumors that carry the corresponding oncogenic mutations (e.g., sensitizing EGFR mutations) would respond well to these TKIs. Meta-analyses of clinical trials evaluating the efficacy of gefitinib and erlotinib have demonstrated that NSCLC patients who are EGFR mutation-positive have a lower risk of disease progression when treated with an EGFR-TKI as compared to those treated with chemotherapy (HR = 0.43, 95% confidence interval, CI=0.38-0.49). EGFR-TKI, however, confers no benefits to patients who are EGFR wildtype (HR = 1.06, 95% CI=0.94-1.19). A phase III trial of crizotinib has also demonstrated the superiority of crizotinib to standard chemotherapy in ALK-positive NSCLC patients (HR = 0.49; 95% CI=0.37-0.64).

In Hong Kong, as

Detailed Summary:

Although EGFR- and ALK-TKIs can achieve a response rate as high as 70%, all patients treated with TKIs invariably develop resistance to the therapy. The median progression-free survival is 10-16 months. The most common mechanism of acquired resistance to TKIs is the therapy-induced clonal selection of a minor subpopulation of resistant cancer cells that were present in the original tumor. Emergence of the EGFR mutation T790M occurs in about 50-70% of patients with acquired resistance to EGFR-TKIs. Other EGFR mutations and mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and B-Raf Proto-Oncogene (BRAF) are also associated with EGFR-TKI resistance, but they occur at low frequencies. Resistance to ALK-TKI is more complex and involves various resistant mutations.

TKI resistance remains a major problem in clinical management of NSCLC. Patients with acquired resistance can be treated with second generation TKIs, though none are FDA approved yet, or by combination therapy strategies. Therefore, molecular characterization of tumor throughout the course of disease is helpful to match new drugs to the tumor's evolving genomic profile and guide effective personalized therapies. However, serial tissue sampling to monitor molecular signatures of tumor is invasive, impractical, and not a routine clinical practice. Obtaining sufficient tissue materials for genotyping is also a major hurdle in tissue sampling. There is a need to develop a technology that permits non-invasive serial analysis of the tumor genomic profiles.

Cell-free circulating DNA is fragmented DNA found in circulation that is not associated with cells or cell fragments. When tumor cells die, they release tumor DNA into the bloodstream. The cell-free circulating DNA derived from tumors, known as circulating tumor DNA (ctDNA), car
Sponsor: The University of Hong Kong

Current Primary Outcome:

  • ctDNA mutation [ Time Frame: an average of one year ]
    Types of ctDNA mutations
  • Any new ctDNA mutations [ Time Frame: an average of one year ]
    Types of new ctDNA mutations


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • ctDNA levels [measured as copy number] [ Time Frame: an average of one year ]
    Quantity of ctDNA mutations
  • Any new ctDNA levels [measured as copy number] [ Time Frame: an average of one year ]
    Quantity of new type ctDNA


Original Secondary Outcome: Same as current

Information By: The University of Hong Kong

Dates:
Date Received: March 30, 2016
Date Started: February 2016
Date Completion: December 2017
Last Updated: March 20, 2017
Last Verified: March 2017