PMID- 24323026
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20220331
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 32
IP  - 2
DP  - 2014 Jan 10
TI  - Phase I study of neratinib in combination with temsirolimus in patients with 
      human epidermal growth factor receptor 2-dependent and other solid tumors.
PG  - 68-75
LID - 10.1200/JCO.2012.47.2787 [doi]
AB  - PURPOSE: Human epidermal growth factor (HER) -mediated signaling is critical in 
      many cancers, including subsets of breast and lung cancer. HER family members 
      signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase 
      B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for 
      the expression of multiple contributors to tumor growth and invasion. On the 
      basis of preclinical data suggesting synergy of HER2 inhibition and mTOR 
      inhibition in breast and lung cancer models, we conducted a phase I combination 
      study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase 
      inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid 
      tumors. PATIENTS AND METHODS: This study enrolled patients to dosing combinations 
      of neratinib and temsirolimus. The primary objective was to estimate the toxicity 
      contour of the combination and establish recommended phase II doses. RESULTS: 
      Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea 
      was the most common drug-related (93%) and dose-limiting toxicity (DLT), 
      constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were 
      also observed. Other frequent drug-related toxicities included nausea, stomatitis 
      (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were 
      identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 
      mg of temsirolimus. Responses were noted in patients with HER2-amplified breast 
      cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and 
      tumor types without identified mutations in the HER-PI3K-mTOR pathway. 
      CONCLUSION: The combination of neratinib and temsirolimus was tolerable and 
      demonstrated antitumor activity in multiple tumor types, warranting further 
      evaluation.
FAU - Gandhi, Leena
AU  - Gandhi L
AD  - Leena Gandhi, Sara M. Tolaney, James M. Cleary, and Geoffrey I. Shapiro, 
      Dana-Farber Cancer Institute; Eunice L. Kwak, Massachusetts General Hospital; 
      Shuchi S. Pandya, Beth Israel Deaconess Medical Center, Boston; Anna Berkenblit 
      and Mizue Krygowski, Aveo Pharmaceuticals; Revathi Ananthakrishnan and Kathleen 
      W. Turnbull, Inventiv Health, Cambridge, MA; Rastislav Bahleda, Antoine 
      Hollebecque, and Jean-Charles Soria, Insitut Gussav Roussy, Villejuif, France; 
      Richat Abbas and Yali Liang, Pfizer, Collegeville, PA.
FAU - Bahleda, Rastislav
AU  - Bahleda R
FAU - Tolaney, Sara M
AU  - Tolaney SM
FAU - Kwak, Eunice L
AU  - Kwak EL
FAU - Cleary, James M
AU  - Cleary JM
FAU - Pandya, Shuchi S
AU  - Pandya SS
FAU - Hollebecque, Antoine
AU  - Hollebecque A
FAU - Abbas, Richat
AU  - Abbas R
FAU - Ananthakrishnan, Revathi
AU  - Ananthakrishnan R
FAU - Berkenblit, Anna
AU  - Berkenblit A
FAU - Krygowski, Mizue
AU  - Krygowski M
FAU - Liang, Yali
AU  - Liang Y
FAU - Turnbull, Kathleen W
AU  - Turnbull KW
FAU - Shapiro, Geoffrey I
AU  - Shapiro GI
FAU - Soria, Jean-Charles
AU  - Soria JC
LA  - eng
SI  - ClinicalTrials.gov/NCT00838539
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131209
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Quinolines)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - JJH94R3PWB (neratinib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - J Clin Oncol. 2014 Jan 10;32(2):65-7. PMID: 24323038
MH  - Aged
MH  - Anemia/chemically induced
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Area Under Curve
MH  - Breast Neoplasms/drug therapy/genetics/metabolism
MH  - Diarrhea/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gene Amplification
MH  - Humans
MH  - Lung Neoplasms/drug therapy/genetics/metabolism
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Nausea/chemically induced
MH  - Neoplasms/*drug therapy/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Quinolines/administration & dosage/adverse effects/pharmacokinetics
MH  - Receptor, ErbB-2/*genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/administration & dosage/adverse effects/analogs & 
      derivatives/pharmacokinetics
MH  - Stomatitis/chemically induced
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Treatment Outcome
EDAT- 2013/12/11 06:00
MHDA- 2014/03/04 06:00
CRDT- 2013/12/11 06:00
PHST- 2013/12/11 06:00 [entrez]
PHST- 2013/12/11 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
AID - JCO.2012.47.2787 [pii]
AID - 10.1200/JCO.2012.47.2787 [doi]
PST - ppublish
SO  - J Clin Oncol. 2014 Jan 10;32(2):68-75. doi: 10.1200/JCO.2012.47.2787. Epub 2013 
      Dec 9.