Phase I study evaluating the combination of lapatinib (a Her2/Neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: South West Oncology Group (SWOG) Study S0528.
OBJECTIVE
Everolimus, an oral inhibitor of mammalian target of rapamycin, can augment the efficacy of HER inhibitors in preclinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus and to describe its anti-tumor activity in the Phase I setting.


METHODS
In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction.


RESULTS
Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis, and fatigue. The MTD of the combination was 1,250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44 %, and mean clearance was decreased by 25 % when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response [thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months)]; 11 patients attained stable disease of at least 4 months.


CONCLUSIONS
Lapatinib and everolimus are well tolerated at doses of 1,250 and 5 mg po daily, respectively. Stable disease ≥4 months/PR was achieved in 13 of 78 patients (17 %).
Karmanos Cancer Institute, Wayne State University, 4100 John R, 4 HWCRC, Detroit, MI, 48201, USA, gadgeels@karmanos.org.
Shirish M
SM
Gadgeel
Danika L
DL
Lew
Timothy W
TW
Synold
Patricia
P
LoRusso
Vincent
V
Chung
Scott D
SD
Christensen
David C
DC
Smith
Laura
L
Kingsbury
Antje
A
Hoering
Razelle
R
Kurzrock
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000068338:Everolimus; D005260:Female; D006801:Humans; D015994:Incidence; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014481:United States / Q000453:epidemiology; D055815:Young Adult
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068338:Everolimus; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases