\- Hypothesis We hypothesise that intermittent dosing of the anti-angiogenic RTKI sunitinib or bevacizumab prior to systemic cisplatin and gemcitabine chemotherapy to transiently "normalise" tumour vasculature in patients with locally advanced or metastatic NPC will allow greater efficiency in drug and oxygen delivery, thus potentiating sensitivity to chemotherapy. We hypothesise that a loading dose of sunitinib for 7 days is required to achieve this sensitization effect prior to the first cycle of chemotherapy, and that this effect can subsequently be maintained by a 7 day course of sunitinib prior to each subsequent cycle of chemotherapy. The other hypothesis tested is that bevacizumab 7 days prior to chemotherapy will achieve normalization of tumor vasculature as well, and may induce changes in the tumor microenvironment that is beneficial for antitumour effect.
* Primary objectives 1. To determine the pathological CR\* rate of intermittent sunitinib or bevacizumab administered with combination cisplatin and gemcitabine as systemic therapy for locally advanced or metastatic NPC. 2. To determine the safety and tolerability of intermittent sunitinib or bevacizumab administered with combination cisplatin and gemcitabine as systemic therapy for locally advanced or metastatic NPC. * Secondary objectives 1. To determine the clinical RR (complete and partial response)+ of intermittent sunitinib or bevacizumab administered with combination cisplatin and gemcitabine as systemic therapy for locally advanced or metastatic NPC. 2. To evaluate the pharmacodynamic effects (imaging, circulating and tissue) of intermittent sunitinib or bevacizumab administered with combination cisplatin and gemcitabine as systemic therapy for locally advanced or metastatic NPC. 3. To evaluate the early pharmacodynamic effects (imaging, circulating and tissue) of 2 loading doses of sunitinib (ie., 12.5mg or 25mg) and 2 dose level of bevacizumab (ie. 7.5mg/kg or 2.5mg/kg) given 1 week prior to administration of cisplatin and gemcitabine chemotherapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
1\) Arm A Day -6 to Day 0 (total 7 days): Sunitinib 12.5mg daily Cycles 1 and 2 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 Day 15 to Day 21: Sunitinib 12.5mg daily Cycle 3 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2
Arm B Day -6 to Day 0 (total 7 days): Sunitinib 25mg daily Cycles 1 and 2 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 Day 15 to Day 21: Sunitinib 25mg daily Cycle 3 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2
Day -7: IV bevacizumab 7.5mg/kg diluted in normal saline over 30 minutes Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 For locally advanced patients, 3 cycles of treatment will be administered. For metastatic patients, up to 6 cycles would be administered.
Day -7: IV bevacizumab 2.5mg/kg diluted in normal saline over 30 minutes Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 For locally advanced patients, 3 cycles of treatment will be administered. For metastatic patients, up to 6 cycles would be administered
National University Hospital
Kent Ridge, Singapore
Clinical Response
1. Rates of clinical response (complete and partial clinical response). 2. Rates of pathological complete responses. 3. Progression-free survival. 4. Haematologic and non-haematologic toxicities, as well as serious adverse events.
Time frame: 2 years
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