Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors.
OBJECTIVE
To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of 17-AAG, gemcitabine and/or cisplatin. Levels of the proteins Hsp90, Hsp70 and ILK were measured in peripheral blood mononuclear cell (PMBC) lysates to assess the effects of 17-AAG.


METHODS
Phase I dose-escalating trial using a "3 + 3" design performed in patients with advanced solid tumors. Once the MTD of gemcitabine + 17-AAG + cisplatin was determined, dose escalation of 17-AAG with constant doses of gemcitabine and cisplatin was attempted. After significant hematologic toxicity occurred, the protocol was amended to evaluate three cohorts: gemcitabine and 17-AAG; 17-AAG and cisplatin; and gemcitabine, 17-AAG and cisplatin with modified dosing.


RESULTS
The 39 patients enrolled were evaluable for toxicity and response. The MTD for cohort A was 154 mg/m(2) of 17-AAG, 750 mg/m(2) of gemcitabine, and 40 mg/m(2) of cisplatin. In cohort A, DLTs were observed at the higher dose level and included neutropenia, hyperbilirubinemia, dehydration, GGT elevation, hyponatremia, nausea, vomiting, and thrombocytopenia. The MTD for cohort C was 154 mg/m(2) of 17-AAG and 750 mg/m(2) of gemcitabine, with one DLT observed (alkaline phosphatase elevation) observed. In cohort C, DLTs of thrombocytopenia, fever and dyspnea were seen at the higher dose level. The remaining cohorts were closed to accrual due to toxicity. Six patients experienced partial responses. Mean Hsp90 levels were decreased and levels of Hsp70 were increased compared to baseline.


CONCLUSIONS
17-AAG in combination with gemcitabine and cisplatin demonstrated antitumor activity, but significant hematologic toxicities were encountered. 17-AAG combined with gemcitabine is tolerable and has demonstrated evidence of activity at the MTD. The recommended phase II dose is defined as 154 mg/m(2) of 17-AAG and 750 mg/m(2) of gemcitabine, and is currently being investigated in phase II studies in ovarian and pancreatic cancers. There is no recommended phase II dose for the cisplatin-containing combinations.
Hubbard
Joleen
J
Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Erlichman
Charles
C
Toft
David O
DO
Qin
Rui
R
Stensgard
Bridget A
BA
Felten
Sara
S
Ten Eyck
Cynthia
C
Batzel
Gretchen
G
Ivy
S Percy
SP
Haluska
Paul
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016227:Benzoquinones / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002945:Cisplatin / Q000627:therapeutic use*; D015331:Cohort Studies; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D000093542:Gemcitabine; D000099200:Scaffold Protein ILK
D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D002945:Cisplatin; D003841:Deoxycytidine; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017346:Protein Serine-Threonine Kinases; D000093542:Gemcitabine; D000099200:Scaffold Protein ILK; C112765:tanespimycin