Lenvatinib in Recurrent and/or Metastatic Adenoid Cystic Carcinomas of the Salivary Glands: ACC-LEN14
Condition: Adenoid Cystic Carcinomas of the Salivary Glands
MeSH terms: Carcinoma; Carcinoma, Adenoid Cystic; Salivary Gland Neoplasms
Study type: Interventional
Phase: Phase 2

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 description: 
      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 targeting this pathway. Dovitinib, a small
      molecule that inhibits FGFR, is currently under investigation. Preliminary results indicate
      that the drug produces objective partial responses and prolonged tumor stabilization in
      patients with progressive ACCs. Lenvatinib has a stronger antiangiogenic effect compared to
      sorafenib and axitinib and has also a higher potency with regard to inhibition of FGFR-1,
      offering a potential opportunity to block one of the well known mechanisms of resistance to
      VEGF/VEGFR inhibitors. Lenvatinib also has a direct oncogenic effect of controlling tumor
      cell proliferation by inhibiting RET, c-KIT, and PDGFR beta, as well as an effect on the
      tumor microenvironment by blocking FGFR and PDGFR beta.

      Lenvatinib has been investigated in thyroid cancer and hepatocellular carcinoma (phase III
      trials) and in other malignancies, showing high rates of activity.

      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.
    

Intervention name(s): Lenvatinib
Intervention type(s): Drug
Intervention description(s): Lenvatinib will be self orally administered at 24 mg daily, on a continuous basis in 4 week cycles until tumour progression, unacceptable toxicity or other criteria for discontinuation is met. Study drug should be taken at approximately the same time each morning.
Other intervention name(s): Lenvima
Intervention MeSH terms: Lenvatinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment