Phase I/II Study on Induction Chemotherapy Followed by Chemoradiation With or Without Lapatinib, a Dual EGFR/ErbB2 Kinase Inhibitor, in Patients With Locally Advanced Larynx and Hypopharynx Squamous Cell Carcinoma
- Determine the maximum tolerated dose and recommended dose for phase II of lapatinib
ditosylate in patients with locally advanced squamous cell carcinoma of the larynyx or
hypopharynx who are concomitantly treated with neoadjuvant induction chemotherapy
comprising docetaxel, cisplatin, and fluorouracil, followed by chemoradiotherapy
comprising carboplatin and radiotherapy. (Phase I)
- To document the feasibility, in the framework of an organ preservation program, of this
regimen in these patients. (Phase II)
- To look at the role of PET in patients with N1-3 disease, in terms of PET being used as
a reliable method to spare patients from planned neck dissection. (Phase II)
OUTLINE: This is a multicenter, dose-escalation phase I study followed by a randomized phase
II study. Patients are stratified by institution and EGFR status (negative vs positive).
- Phase I:
- Neoadjuvant chemotherapy: Patients receive neoadjuvant chemotherapy comprising
docetaxel IV and cisplatin IV on day 1 and fluorouracil IV continuously on days
1-5. Treatment repeats every 21 days for up to 4 courses in the absence of disease
progression or unacceptable toxicity. Patients with a complete or partial response
after 4 courses of neoadjuvant chemotherapy proceed to chemoradiotherapy. Patients
with less than a partial response after course 2 or course 4 proceed to surgery,
including total laryngectomy.
- Chemoradiotherapy: Within 3 weeks after completion of neoadjuvant chemotherapy,
patients undergo radiotherapy on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and
43-47 and receive carboplatin IV on days 1, 8, 15, 22, 29, 36, and 43.
- Concurrent lapatinib ditosylate: Patients receive oral lapatinib ditosylate once
daily during neoadjuvant chemotherapy, during the break between neoadjuvant
chemotherapy and chemoradiotherapy, and during chemoradiotherapy.
- Phase II: Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive neoadjuvant chemotherapy and undergo chemoradiotherapy as
in phase I.
- Arm II: Patients receive neoadjuvant chemotherapy and undergo chemoradiotherapy as
in phase I. Patients also receive concurrent lapatinib ditosylate as in phase I at
the recommended dose determined in phase I.
In both phases, treatment continues in the absence of disease progression or unacceptable
Patients with node-positive disease (initially) undergo tumor and blood sample collection
for biological studies. Samples are analyzed for ErbB-related activation via
immunohistochemistry, in situ hybridization, and PCR/sequencing of genes/proteins, to detect
DNA amplification and polysomy (for AKT, ErbB2, EGFR) and genomic losses (for PTEN) via
FISH, and the ratio between EGFR and EGFRvIII via QRT-PCR. Patients with node-positive
disease undergo at least elective neck dissection to evaluate the negative predictive value
of PET scanning.
Patients are followed every 3 months for one year and then every 6 months thereafter.
Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of lapatinib ditosylate (Phase I)
Ahmad Awada, MD, PhD
Institut Jules Bordet
United States: Federal Government