Determination of the toxicity of standard dose cetuximab together with concurrent individualised, isotoxic accelerated radiotherapy and cisplatin - vinorelbine for patients with stage III non-small cell lung cancer (NSCLC): a phase I study.

At present, the prognosis of patients with locally advanced NSCLC is still
dismal. Although the introduction of concurrent chemo-radiation has improved
the survival significantly, most patients still die with persistent local tumor
as well as metastases.
Cetuximab is a monoclonal antibody with proven activity against EGFR positive
cancer cells, such as the majority of NSCLC. It has a toxicity profile that
mainly consists of skin reactions. In head and neck cancer, it was shown that
the concurrent administration of cetuximab and radiotherapy improved local
tumor control and survival with a favorable toxicity profile. However, much
remains to be learned about the concurrent administration of cetuximab and
radiotherapy in patients with NSCLC.

To determine the MTD toxicity of standard dose cetuximab together with
concurrent individualized, isotoxic accelerated radiotherapy and
cisplatin-vinorelbine.

Phase I trial with escalating doses of vinorelbine and standard doses of
radiotherapy, cisplatin and cetuximab.

Eligible patients receive 1 cycle of carboplatin (AUC 5) day 1 and gemcitabine
(1250 mg/m2) days 1,8. One cycle duration is 21 days.

Patients without progressive disease (PD) according to the RECIST criteria
(appendix 1) will be entered in the phase I dose-escalation part of the study.
Chest radiation is given concurrently with cetuximab, cisplatin and
vinorelbine. The latter drug will be escalated in three steps until
dose-limiting toxicity occurs.
On day 22, i.e. 14 days after the last gemcitabine delivery, radiotherapy is
started.
Radiotherapy: In all patients in every dose-step, the radiation will be given
as follows: first 3 weeks: 1.5 Gy BID to a dose of 45 Gy in 30 fractions, then
2 Gy QD to a mean lung dose (MLD, this is related to radiation-induced lung
damage) of 19 Gy. Maximum dose: 69 Gy given in 5.5 weeks. Maximum dose to the
spinal cord: 50 Gy.
Cetuximab: All patients will receive a starting dose 400 mg/ m2 7 days before
the beginning of radiotherapy (i.e. day 15), thereafter a weekly dose 250 mg/
m2 during the course of radiotherapy for 5 consecutive weeks. Cetuximab will be
delivered at the same days as chemotherapy.
Cisplatin: In all patients in every dose-step, cisplatin will be given as
follows: Step 1, 2 and 3: 50 mg/ m2 days 22, 29; 40 mg/m2 day 43.
Vinorelbine will be escalated in three steps:
Step 1: 10 mg/ m2 days 22, 29; 8 mg/m2 days 43 and 50.
Step 2: 20 mg/ m2 days 22, 29; 8 mg/m2 days 43 and 50.
Step 3: 20 mg/ m2 days 22, 29; 15 mg/m2 days 43 and 50.

Eligible patients receive 1 cycle of carboplatin (AUC 5) day 1 and gemcitabine
(1250 mg/m2) days 1,8. One cycle duration is 21 days.

Patients without progressive disease (PD) according to the RECIST criteria will
be entered in the phase I dose-escalation part of the study. Chest radiation is
given concurrently with cetuximab, cisplatin and vinorelbine. The latter drug
will be escalated in three steps until dose-limiting toxicity occurs.
On day 22, i.e. 14 days after the last gemcitabine delivery, radiotherapy is
started.
Radiotherapy: In all patients in every dose-step, the radiation will be given
as follows: first 3 weeks: 1.5 Gy BID to a dose of 45 Gy in 30 fractions, then
2 Gy QD to a mean lung dose (MLD, this is related to radiation-induced lung
damage) of 19 Gy. Maximum dose: 69 Gy given in 5.5 weeks. Maximum dose to the
spinal cord: 50 Gy.
Cetuximab: All patients will receive a starting dose 400 mg/ m2 7 days before
the beginning of radiotherapy (i.e. day 15), thereafter a weekly dose 250 mg/
m2 during the course of radiotherapy for 5 consecutive weeks. Cetuximab will be
delivered at the same days as chemotherapy.
Cisplatin: In all patients in every dose-step, cisplatin will be given as
follows: Step 1, 2 and 3: 50 mg/ m2 days 22, 29; 40 mg/m2 day 43.
Vinorelbine will be escalated in three steps:
Step 1: 10 mg/ m2 days 22, 29; 8 mg/m2 days 43 and 50.
Step 2: 20 mg/ m2 days 22, 29; 8 mg/m2 days 43 and 50.
Step 3: 20 mg/ m2 days 22, 29; 15 mg/m2 days 43 and 50.

The patients undergo six extra infusions with cetuximab. This will be
administered at the time of chemotherapy, except of the loading dose, which is
given one week before radiotherapy.
Rarely, allergic reactions at the time of infusion may occur. The most
important side effect is skin toxicity that is not increased by radiotherapy or
chemotherapy.