Clinical Trial: Lenvatinib in Recurrent and/or Metastatic Adenoid Cystic Carcinomas of the Salivary Glands: ACC-LEN14

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Phase II Study on Lenvatinib in Recurrent and/or Metastatic Adenoid Cystic Carcinomas of the Salivary Glands of the Upper Aerodigestive Tract

Brief Summary: ACC is rare and represent approximately 25% of salivary gland carcinomas. The standard treatment is surgical excision followed by radiotherapy in selected cases. The disease is characterized by a progressive course with local and distant recurrences. First-line treatment is palliative chemotherapy that had modest results. Expression of the epidermal growth factor receptor in ACC of salivary origin has been reported. Several papers report that a high percentage of ACCs carries a chromosome translocation that results in the overexpression of the oncogene MYB, which is involved in cell proliferation, apoptosis, differentiation and in upregulation of several growth and angiogenetic factors contributing to the autocrine activation of the FGFR and VEGFR-mediated angiogenesis. Recently two whole genome sequencing of several ACC tumor/normal pairs have found mutations in genes involved in the FGF/IGF/PI3K pathway corroborating the hypothesis that this subset might benefit from inhibitors of this pathway. Based on these premises several antiangiogenic drugs and FGFR inhibitors are currently under investigation and a response rate of 11% was observed in ACC. Lenvatinib is an oral multiple RTK inhibitor targeting VEGFR-1-3, FGFR-1-4, RET, c-KIT, and PDGFR. On February 13, 2015 the drug has been approved by FDA for the treatment of patients with locally recurrent or metastatic, radioactive iodine-refractory differentiated thyroid cancer. Based on preclinical and clinical data, the investigators believe that targeting angiogenesis, FGFR pathway and tumor microenvironment might represent a rational basis to test Lenvatinib in patients with relapsed and/or metastatic ACC.

Detailed Summary:

Carcinomas of the salivary glands (SGCs) are rare, (less than 1% of all cancers of the head and neck and include more than 20 malignant histotypes. They can occur both in major and minor salivary glands, are locally aggressive, demonstrating invasiveness that leads to involvement of the facial nerve, skin, bone and surrounding soft tissue. The standard treatment is surgical excision, followed by radiotherapy in selected cases such as high-grade histotypes, advanced disease and neck nodes diffusion. Loco-regional recurrence occurs in 16% to 85%, it can be managed in very selected cases with further surgery and/or radiotherapy, although the prognosis of these patients remains poor. Adenoid cystic cancer (ACC) is the most common SGC histotype observed in metastatic subjects (60%) and distant metastases are the principal cause of failure, being diagnosed in 25-55% of the patients. First-line treatment is palliative chemotherapy that is typically not associated with any benefit neither in response rate nor in outcome. In preclinical models, VEGF seems to contribute to tumor aggressiveness as well as to distant metastasization, in particular in ACC. Moreover, about 80% of ACC are characterized by MYB-NFIB fusion gene. Deregulation of MYB involves several genes including those associated with apoptosis, cell cycle control and angiogenesis. Clinical evidences support the use of antiangiogenic compounds in ACC. Sorafenib a multi-tyrosine kinase inhibitor (TKI) (VEGFR1-3; PDGFR, RET, cKIT FLT3) and axitinib a potent TKI anti VEGFR1-3 have been tested in advanced ACC, obtaining a 1% of response rate, suggesting some activity agents of this class of drug.

Recently two whole genome sequencing of ACC tumor/normal pairs have found mutations in genes involved in the FGF/IGF/PI3K pathway (up to 30% of the cases) corroborating the hypothesis that this subset might benefit from agents targe
Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Current Primary Outcome: Objective response rate (CR+PR) [ Time Frame: 2 years and 5 months ]

Objective response rate (CR+PR) will be evaluated according to RECIST response evaluation criteria 1.1 at any subsequent re-evaluation


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Progression free survival [ Time Frame: 2 years and 5 months ]
    PFS according to RECIST criteria 1.1
  • Overall survival [ Time Frame: 2 years and 5 months ]
    After study drug treatment ends, patients will be contacted each 6 months to determine survival
  • Safety and toxicity profile of lenvatinib (according to CTCAE v 4.0) [ Time Frame: 2 years and 5 months ]
    Incidence of adverse events (AEs), will be graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0, laboratory values, physical examinations, vital signs.
  • Duration of response [ Time Frame: 2 years and 5 months ]
    The duration of response will be evaluated to assess the duration of activity of lenvatinib (CR+PR+SD)


Original Secondary Outcome: Same as current

Information By: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Dates:
Date Received: August 2, 2016
Date Started: June 2015
Date Completion: May 2018
Last Updated: May 15, 2017
Last Verified: May 2017