|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 34 (December 1), 2007: pp. 5410-5417 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.7960 Combination of Trastuzumab and Tanespimycin (17-AAG, KOS-953) Is Safe and Active in Trastuzumab-Refractory HER-2–Overexpressing Breast Cancer: A Phase I Dose-Escalation Study
From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA Address reprint requests to Shanu Modi, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: modis{at}mskcc.org
Purpose This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes. Patients and Methods Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels.
Results Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease Conclusion Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.
Heat shock protein (Hsp) 90 is a molecular chaperone that is required for the refolding of proteins under conditions of environmental stress and for the conformational maturation of a subset of key signaling proteins.1-3 Hsp90 clients include steroid receptors, RAF-1, cdk4, AKT and other key mitogenic proteins.1-3 Geldanamycin, an antitumor antibiotic, binds selectively to the amino terminal ADP/ATP pocket of Hsp90, inhibiting its function.4 Hsp90 inhibition by this mechanism causes the ubiquitination of Hsp90 client proteins and their trafficking to the proteasome, where they are degraded. Human epidermal growth factor receptor 2 (HER-2) is the most sensitive Hsp90 client, and HER-2–amplified breast cancer cells are potently inhibited by geldanamycin.5,6 Tanespimycin (17-allylamino-17-demethoxy-geldanamycin [17-AAG]), is a geldanamycin derivative that inhibits Hsp90 function in tumors in a variety of murine models.6-9 In human xenograft and murine transgenic HER-2–driven breast cancers, tanespimycin causes the rapid degradation of HER-2, with attendant loss of phosphorylated AKT and significant antitumor activity, with both stable disease and regression noted, depending on the dose and schedule employed.5 In phase 1 trials using dimethyl sulfoxide (DMSO)-solubilized tanespimycin, toxicity was schedule and dose-dependent, and included elevation of hepatic enzymes, diarrhea, and thrombocytopenia.10-15 Although preclinical models suggest that weekly administration of tanespimycin has inferior antitumor activity compared with more frequent schedules,7 clinical antitumor activity in melanoma was noted on this schedule, so it has been studied more extensively, yielding recommended phase II doses of 295 mg/m2, 308 mg/m2, and 450 mg/m2, the latter because of constraints on volume and formulation, not toxicity.11,12,15 A formulation of tanespimycin, KOS-953, that contains Cremophory EL (polyethoxylated castor oil; BASF Corp, Ludwigshafen, Germany) rather than DMSO has been developed. Preclinical experiments demonstrate that both formulations achieve comparable pharmacokinetics of 17-AAG and an active metabolite, 17-aminogeldanamycin (17-AG).16 Additionally, both formulations had similar activity in murine xenograft models of human tumors.16 The combination of tanespimycin with trastuzumab is conceptually appealing because it represents combined inhibition of important cell proliferation and survival pathways by different mechanisms. In animal models, enhanced antitumor effects were seen for the two agents administered together compared with either one alone.17 Moreover, given trastuzumab's long half-life18 (leading to continued exposure even after cessation of active treatment) and the expectation that any new HER-2–targeting agent would be used after failure of trastuzumab, we designed this phase I study to test tanespimycin with concurrent administration of the antibody, and we prospectively planned to target patients with HER-2+ disease for accrual. The primary aim was to evaluate the safety and toxicity and recommend a phase II dose of tanespimycin in combination with trastuzumab in patients with advanced solid tumors refractory to standard therapies. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were undertaken to evaluate the effects of treatment on Hsp90 client proteins in peripheral-blood lymphocytes (PBLs) as a surrogate for the biologic effects of tanespimycin.
Eligibility Eligibility requirements included age at least 18 years, histologic documentation of a nonhematologic malignancy (irrespective of HER-2 expression) with evidence of progression during treatment with standard therapy, Karnofsky performance status of at least 70%, negative pregnancy test, 2 weeks' removal from prior radiation or chemotherapy (6 weeks for nitrosoureas), hemoglobin of at least 8.5 g/dL, absolute neutrophil count (ANC) of at least 1.5 x 109cells/L, platelet count of at least 75 x 109/L, serum bilirubin no more than 2x the upper limit of normal (ULN), AST and ALT no more than 2x ULN, and creatinine no more than 2x ULN. Patients continuing on weekly trastuzumab were permitted to continue without break. Patients were excluded for prior severe hypersensitivity reaction to Cremophor-containing therapy or trastuzumab, active CNS metastases, severe dyspnea at rest, or a need for supportive oxygen; New York Heart Association class III/IV congestive heart failure, left ventricular ejection fraction less than 50%, a history of prior radiation including the heart in the field, myocardial infarction or active ischemia within 12 months, history of uncontrolled dysrhythmias, requirement for antiarrhythmics, or left bundle branch block. Additionally, on the basis of two reports from ongoing trials with tanespimycin showing QTc prolongation, this study was amended to exclude patients with QTcF more than 450 ms (males) or 470 ms (females), congenital long QTc syndrome, or medications causing QTc prolongation. The study protocol was reviewed and approved by the institutional review boards of each participating center. Before study entry, each patient signed a written informed consent form.
Treatment
Evaluation of Tumor Response and Toxicity Assessment
Before each treatment, patients were required to meet eligibility criteria with respect to performance status and hepatic, bone marrow, and renal function; all toxicities had to have returned to baseline or grade
Patients were assessed for dose-limiting toxicity (DLT) during cycle 1. DLT was defined using the National Cancer Institute Common Toxicity Criteria Version 3.0 (NCI-CTC) as any of the following: grade 4 neutropenia lasting 7 days or longer, or febrile neutropenia (ANC < 1.0 x 109/L, fever
Twenty-five patients were enrolled into four tanespimycin dose groups (225, 300, 375, and 450 mg/m2). Demographics are presented in Table 1. Although the trial allowed patients to enroll irrespective of HER-2 status, the majority of patients (n = 15) had HER-2+ metastatic breast cancer. In these patients, the median number of prior trastuzumab-based therapies was 2. Median time since primary diagnosis for all 25 patients equaled 5 years, with a range of approximately 1 to 19 years.
A total of 326 weekly infusions were delivered, with the median number of weekly infusions equal to 8 (range, 1 to 42). Median weekly infusions administered per dose level equaled 7, 27, 15, and 8, respectively, for the four dose groups.
Overall Safety Two patients at the 450 mg/m2 dose level were considered nonassessable for toxicity because they received only one dose of study drug and then discontinued for reasons unrelated to study drug. Adverse events by toxicity grade are summarized in Table 2. Diarrhea, fatigue, and nausea were the most frequent toxicities, with 64% of the patients experiencing at least one grade 1 event. In contrast to prior phase I studies of tanespimycin, severe liver function test abnormalities were rare (overall, 8%), without any obvious dose dependency. There were two cases of grade 3 nausea/vomiting at the 375 mg/m2 dose that prompted prophylactic administration of antiemetics to all subsequent patients at this dose level. Patients with prophylactic antiemetic (typically consisting of 5HT3 antagonists with aprepitant) had excellent control without grade 3 or 4 episodes. Despite routine antihistamine and steroid premedication, there were two cases of grade 3 hypersensitivity reactions that resulted in discontinuation of patients from the trial. Hypersensitivity is a known adverse effect of the Cremophor component of tanespimycin. These reactions were attributed to the diluent and were not considered DLTs. All cases of hypersensitivity responded to additional steroids and antihistamines. Two patients were noted to have occlusion of venous access devices, possibly caused by tanespimycin crystallization within the device. Additional venous access device management was implemented (sites were instructed to use a larger-volume postinfusion flush with normal saline).
Myelosuppression, cardiovascular toxicity (including QTc prolongation), neurotoxicity, and alopecia were not observed. Age and performance status did not predict for toxicity. One patient with a pre-existing autoimmune disorder (Hashimoto's disease) was noted to have grade 4 thrombocytopenia after 11 cycles on study.
Pharmacokinetics
Two patients were admitted to the study already receiving trastuzumab maintenance therapy and were not included in the PK cohort, giving a total 23 patients with serum trastuzumab results after the 4.0 mg/kg loading dose. Aside from the shorter half-life, underestimated because of the abbreviated sampling period, the kinetics of trastuzumab were similar to those shown in published data.18 AUC extrapolation from the last measured plasma concentration to infinity was 38% ± 17%, indicating that a large part of the trastuzumab AUC0-  was not quantified. Trough levels of trastuzumab collected before the weekly maintenance dose averaged 30.8 ± 7.2 µg/mL, excluding four patients who had results below the level of detection of the analytic method (20 µg/mL; Figure A2, online only). For these four patients, the low trastuzumab trough levels is not felt to be related to an interaction between trastuzumab and tanespimycin but rather to the low sensitivity of the assay used. Additionally, theoretical minimum effective trastuzumab trough levels are proposed to be between 10 and 20 µg/mL.20 There was no significant difference in PK parameters between patients who experienced grade 3/4 toxicities and those who did not.
Pharmacodynamics
Antitumor Affects Five patients responded and all had HER-2+ metastatic breast cancer (Table 4; Fig 2). By investigator assessments, one patient had a partial response by RECIST and the remaining patients with tumor regressions (n = 4) remained on study for 4 to 12 months. An independent radiologic assessment of these five patients with tumor regression upgraded this result to two patients with a confirmed partial response. Additionally, three patients with metastatic breast cancer (one HER-2+, one HER-2 unknown, and one HER-2 1+) and one patient with metastatic thymus cancer had stable disease and remained on study for 4 to 10 months. All patients with tumor regression had demonstrated radiographic progression of disease immediately before study entry. Of note, patients with objective tumor regressions did not stop study treatment for progression of disease. These patients were all withdrawn due to the following: hypersensitivity reactions (two), drug-induced thrombocytopenia, secondary acute leukemia related to prior chemotherapy drugs, and occlusion of a venous access device.
This is the first trial in solid tumors where the administration of an Hsp90 inhibitor has produced objective tumor regressions and demonstrated meaningful anticancer activity. Moreover, these results were achieved in a heavily pretreated patient population that received weekly therapy that had only modest activity in preclinical studies. One patient achieved a partial response, with 59% regression in pulmonary metastases. She stopped study treatment after 3 months for a grade 3 hypersensitivity reaction. Another four patients also had significant reductions in measurable disease, although did not achieve RECIST criteria for response. The durations of these best responses were between 4 and 12 months. It is striking that all of these patients had HER-2+ metastatic breast cancer with evidence of progressive disease during prior trastuzumab-based therapies. We cannot assess the role of trastuzumab in these responses, but note that prior experiments with inert single agents combined with this antibody in patients with refractory HER-2–overexpressing breast cancer have not demonstrated activity.21 Although the mechanisms of trastuzumab-resistance are at present unknown, this study and recent data from the lapatinib/capecitabine trial demonstrate that some HER-2–amplified tumors that are clinically resistant to trastuzumab remain HER-2 dependent.22 We conclude that tanespimycin is active after progression with trastuzumab. Whether degradation of HER-2 or other effects of Hsp90 inhibition synergized with trastuzumab or resensitized tumors to its effects is unknown. Examination of this question in preclinical models will require a better understanding of the molecular mechanisms responsible for the sensitivity and resistance of tumors to trastuzumab. The most common adverse effects of the treatment (nausea, vomiting, diarrhea, headache, fatigue, and anorexia) were generally mild to moderate in nature and manageable with supportive measures. Notably, previously reported reversible transaminitis was not a DLT in this study. Only three patients had grade 2 or 3 hepatic enzyme elevation attributed to study treatment, and this was reversible with treatment delays. There was no neurotoxicity, alopecia, cardiotoxicity, or any significant myelosuppression, although one patient did develop an idiosyncratic drug-induced thrombocytopenia after 11 months on study. The PK findings were comparable to those seen in the five phase I trials of the DMSO formulation demonstrating increasing exposure to tanespimycin and its active metabolite KOS-1297 over the dose ranges tested.10-15 No correlation was observed between PK profiles and grade 3/4 toxicities, although this analysis was limited by the small number of patients who had severe toxicity. An examination of the effects of tanespimycin treatment on Hsp90 client proteins in PBLs revealed a reactive increase in intracellular Hsp70 levels within 24 hours of drug administration at all dose levels, suggesting that the drug achieves biologically active plasma concentrations and affects its target. Other Hsp90 clients examined (RAF-1, cdk4, and AKT) were inhibited to varying degrees, and inconsistently across dose levels. The utility of these studies is, however, limited given the previous observations that 17-AAG accumulates in tumors and has a higher affinity for tumor Hsp90 versus that found in normal tissues.23 Although these data do suggest that we have reached a dose at which 17-AAG can modulate Hsp90 function, they do not obviate the need for direct measurements of the clients in tumors. The MTD was not achieved in this trial. However, dose escalation was terminated at 450 mg/m2, with this being the recommended weekly dose for phase II studies based on the following factors: although there was only one observed DLT at 450 mg/m2 (of eight assessable patients), there was additional toxicity seen with two other patients requiring dose delays in subsequent cycles, and PK results comparing 450 mg/m2 with lower dose levels showed an asymptote for overall drug exposure. Although 450 mg/m2 is recommended as the dose for further testing, higher doses or alternative schedules of administration might be more effective. On the basis of these data, we are conducting a phase II study of weekly tanespimycin at 450 mg/m2 in combination with trastuzumab for patients with HER-2+ metastatic breast cancer who have progressive disease after one line of trastuzumab-based therapy. Additional studies are needed to determine the optimal dose and schedule of these agents, whether they sensitize tumors to cytotoxic chemotherapy, and whether trastuzumab is an active component of the regimen.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Gillian F. Cropp, Kosan Biosciences Inc; Robert G. Johnson, Kosan Biosciences Inc Leadership: Robert G. Johnson, Kosan Biosciences Inc Consultant: Michael S. Gordon, Genentech; Neal Rosen, Kosan Biosciences Inc; Gillian F. Cropp, Kosan Biosciences Inc; Alison L. Hannah, Kosan Biosciences Inc; Clifford A. Hudis, Genentech Stock: Gillian F. Cropp, Kosan Biosciences Inc; Robert G. Johnson, Kosan Biosciences Inc Honoraria: Shanu Modi, Genentech; Michael S. Gordon, Genentech; Larry Norton, Genentech; Clifford A. Hudis, Genentech Research Funds: Shanu Modi, Kosan Biosciences, Inc; Alison T. Stopeck, Kosan Biosciences Inc; Michael S. Gordon, Kosan Biosciences Inc; David Mendelson, Premiere Oncology; Clifford A. Hudis, Kosan Biosciences Inc Testimony: N/A Other: N/A
Conception and design: Robert G. Johnson, Alison L. Hannah, Clifford A. Hudis Financial support: Robert G. Johnson Administrative support: Robert G. Johnson, Alison L. Hannah, Clifford Hudis Provision of study materials or patients: Shanu Modi, Alison T. Stopeck, Michael S. Gordon, David Mendelson, David B. Solit, Rochelle Bagatell, Larry Norton, Clifford A. Hudis Collection and assembly of data: Shanu Modi, Alison T. Stopeck, Michael S. Gordon, David Mendelson, David B. Solit, Rochelle Bagatell, Jennifer Wheler, Neal Rosen, Gillian F. Cropp, Alison L. Hannah Data analysis and interpretation: Shanu Modi, Alison T. Stopeck, Michael S. Gordon, David B. Solit, Rochelle Bagatell, Weining Ma, Jennifer Wheler, Neal Rosen, Larry Norton, Gillian F. Cropp, Robert G. Johnson, Alison L. Hannah, Clifford A. Hudis Manuscript writing: Shanu Modi, David B. Solit, Neal Rosen, Alison L. Hannah, Clifford A. Hudis Final approval of manuscript: Shanu Modi, David B. Solit, Neal Rosen, Clifford A. Hudis
Pharmacokinetic Sampling and Bioanalytical Methods Trastuzumab. Limited sampling for trastuzumab serum quantitation was performed during cycle 1 at the following times: before dosing; immediately before the end of infusion (EOI); 2, 4, 24, and 48 hours after the first infusion; and preinfusion on days 8 and 15. Serum samples were frozen at –70°C and analyzed by a commercial laboratory using a validated enzyme-linked immunosorbent assay (PPD Development, Richmond, VA) with calibration range from 20 to 200 µg/mL. Tanespimycin and 17-AG. Heparinized blood samples for tanespimycin and its major metabolite 17-AG were collected before dosing; 30 minutes after the start of the infusion; immediately before EOI; and 5, 15, and 30 minutes and 1, 2, 4, 8, 24, and 48 hours after the first and fourth infusion. Blood samples were centrifuged at 4°C, with the plasma separated and frozen at –70°C pending analysis. Plasma concentrations of tanespimycin and 17-AG were determined by a fully validated, liquid chromatography (LC)/ tandem mass spectrometry (MS) method. The assay generated a linear response over the concentration range 10 to 2,500 ng/mL for tanespimycin and 5 to 1,250 ng/mL for 17-AG. The method in brief is as follows; human plasma samples (standards, quality control specimens and clinical samples) were allowed to thaw at ambient temperature. Samples were vortexed for approximately 5 seconds and 100 µL of each human plasma sample were transferred into a 96-well plate (2-mL capacity, round bottom). Subsequently, 400 µL of internal standard working solution (KOS-1761, 200 ng/mL) or 400 µL of acetonitrile for blanks were added. Samples were capped, vortexed at 1,100 osc/min for 1 minute using pulsation mode of the plate shaker and centrifuged for 5 minutes at 2,862 RCF (speed 4000 rpm) on a sigmafuge at ambient temperature. Next, 100 µL of 10 mmol/L ammonium acetate was added to a clean 96-well plate (1.1 mL capacity, round bottom). Supernatants (200 µL) were manually transferred or automatically transferred (by Sciclone ALH 3000 [Caliper Life Sciences, Hopkinton, MA]or TOMTEC Quadra 96 [TOMTEC, Hamden, CT]). Plates were covered and vortexed at 1,100 osc/min for 1 minute using pulsation mode of the plate shaker. Samples were then stored at 5°C until injection onto the LC. High-performance LC conditions: mobile phase, 65/35 (v/v) [20/80 (v/v) methanol/acetonitrile]/10 mmol/L ammonium acetate; flow rate 1.0 mL/min; analytic column XTerra RP18 (Waters Corp, Milford, MA) 50 x 4.6 mm, 3.5 µm; injection volume 15 µL; injection temperature 5°C. MS: PE Sciex API 3000 (Applied Biosystems, Thornhill, Ontario, Canada); detection mode, Selected reaction monitoring (SRM); quantitation by peak area ratio using linear weighting 1/concentration. Under these conditions, the retention times of interest were as follows: tanespimycin, 1.58 minutes; 17-AG, 0.97 minutes; and internal standard KOS-1761, 1.10 minutes, for a total run time 3.00 minutes. PBMCs. PBMCs were assessed for changes in Hsp90 client protein levels. Samples were obtained during cycle 1 of therapy (day 1 pretreatment, 4 hours after the KOS-953 infusion), day 2, day 3, pretreatment weeks 2 and 3. Blood (8 mL) was collected into room temperature Vacutainer CPT tubes (Becton Dickinson, Franklin Lakes, NJ) and PBMCs were isolated by centrifugation. PBMCs were assessed for changes in Hsp70, RAF-1, cdk4, AKT, and p85 PI3 kinase by immunoblot. p85 PI3 kinase, a protein whose expression is unaffected by tanespimycin, was used as a control. Cells were lysed in NP40 lysis buffer and immunoblots were performed as previously described.14
Concentration versus time data for tanespimycin, 17-AG, and trastuzumab were analyzed by noncompartmental methods (Kinetica version 4.4, Electron Corporation, Philadelphia, PA). Because of the maintenance dose administration on day 8, the time period for blood sampling to 8 days postinfusion was insufficient to wholly measure the trastuzumab AUC0-
We thank Rajeet Pannu, PhD, for his critical reading of the manuscript.
Supported in part by Kosan Biosciences Inc. Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 2005; American Association of Cancer Research Meeting, Washington, DC, 2006; American Society of Clinical Oncology Meeting, Atlanta, GA, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Schneider C, Sepp-Lorenzino L, Nimmesgern E, et al: Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90. Proc Natl Acad Sci U S A 93:14536-14541, 1996 2. Solit DB, Rosen N: Hsp90: A novel target for cancer therapy. Curr Top Med Chem 6:1205-1214, 2006[CrossRef][Medline] 3. Maloney A, Workman P: Hsp90 as a new therapeutic target for cancer therapy: The story unfolds. Expert Opin Biol Ther 2:3-24, 2002[CrossRef][Medline] 4. Whitesell L, Mimnaugh EG, De Cost B, et al: Inhibition of heat shock protein Hsp90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: Essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91:8324-8328, 1994 5. Basso A, Solit DB, Munster PN, et al: Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER-2. Oncogene 21:1159-1166, 2002[CrossRef][Medline] 6. Solit DB, Zheng FF, Drobnjak M, et al: 17-allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 8:986-993, 2002 7. Solit DB, Basso AD, Olshen AB, et al: Inhibition of heat shock protein 90 function downregulates akt kinase and sensitizes tumors to taxol. Cancer Res 63:2139-2144, 2003 8. Banerji U, Walton M, Raynaud F, et al: Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin Cancer Res 11:7023-7032, 2005 9. Burger AM, Fiebig HH, Stinson SF, et al: 17-(allylamino)-17-demethoxygeldanamycin activity in human melanoma models. Anticancer Drugs 15:377-387, 2004[CrossRef][Medline] 10. Nowakowski GS, McCollum AK, Ames MM, et al: A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clin Cancer Res 12:6087-6093, 2006 11. Banerji U, O'Donnell A, Scurr M, et al: Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23:4152-4161, 2005 12. Ramanathan RK, Trump DL, Eiseman JL, et al: Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 11:3385-3391, 2005 13. Grem JL, Morrison G, Guo XD, et al: Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23:1885-1893, 2005 14. Solit DB, Ivy P, Kopil C, et al: Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Clin Cancer Res 13:1775-1782, 2007 15. Goetz MP, Toft D, Reid J, et al: Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23:1078-1087, 2005 16. Investigators Brochure: Tanespimycin, January 2007 17. Solit DB, Basso A, Smith-Jones P, et al: Inhibitors of Hsp90 induce the degradation of HER-2 and inhibit the growth of HER-2-dependent breast tumors. Presented at the 28th Annual San Antonio Breast Cancer Symposium, December 8-11, 2005, San Antonio, TX 18. Leyland-Jones B: Dose scheduling: Herceptin. Oncology 61:31-36, 2001 (suppl)[CrossRef][Medline] 19. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 20. Cobleigh M, Frame D: Is trastuzumab every three weeks ready for prime time? J Clin Oncol, 21:3900-3901, 2003 21. Dang CT, Dannenberg AJ, Subbaramaiah K, et al: Phase II study of celecoxib and trastuzumab in metastatic breast cancer patients who have progressed after prior trastuzumab-based treatments. Clin Cancer Res 10:4062-4067, 2004[CrossRef][Medline] 22. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER-2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 23. Chiosis G, Neckers L: Tumor selectivity of Hsp90 inhibitors: The explanation remains elusive. ACS Chem Biol 1:279-284, 2006[CrossRef][Medline] Submitted March 26, 2007; accepted August 27, 2007.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. 
2 or better, except for alopecia. In addition, cardiac function was monitored with multiple gated acquisition scans every 8 weeks and ECGs before and after the first and fourth infusions in cycle 1. 
