Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer.
BACKGROUND
Everolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in nonsmall cell lung cancer (NSCLC). The authors conducted a phase 1 and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC.


METHODS
Patients with advanced stage NSCLC and progression after prior platinum-based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel (Day 1) and everolimus (orally daily, Days 1-19) every 3 weeks. Pharmacokinetic sampling of everolimus and docetaxel was done in Cycle 1. The primary endpoint was determination of the recommended phase 2 doses of the combination.


RESULTS
Twenty-four patients were enrolled (median age, 62 years; women, 11; number of prior regimens, 1 [n=13], 2 [n=6], >or=3 [n=5]; Eastern Cooperative Oncology Group performance status, 0 [n=6], 1 [n=17]). The dose-limiting toxicities (DLTs) were fever with grade 3/4 neutropenia, grade 3 fatigue, and grade 3 mucositis. None of the 7 patients treated at the recommended phase 2 dose (docetaxel 60 mg/m2 and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m2 docetaxel. Mean+/-standard deviation AUC-based accumulation factors for everolimus on Days 8 and 15 were 1.16+/-0.37 and 1.42+/-0.42, respectively. Docetaxel Day 1 half-life was 9.4+/-3.4 hours. Among 21 patients evaluable, 1 had a partial response, and 10 had disease stabilization.


CONCLUSIONS
The recommended phase 2 doses of docetaxel and everolimus for combination therapy are 60 mg/m2 and 5 mg orally daily, respectively. Promising anticancer activity has been noted.
Ramalingam
Suresh S
SS
Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia 30322, USA. ssramal@emory.edu
Harvey
R Donald
RD
Saba
Nabil
N
Owonikoko
Taofeek K
TK
Kauh
John
J
Shin
Dong M
DM
Sun
Shi-Yong
SY
Strychor
Sandra
S
Tighiouart
Mourad
M
Egorin
Merrill J
MJ
Fu
Haian
H
Khuri
Fadlo R
FR
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D043823:Taxoids; D000077143:Docetaxel; D000068338:Everolimus; D020123:Sirolimus