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Clinical Cancer Research 13, 1769, March 15, 2007. doi: 10.1158/1078-0432.CCR-06-2233
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Phase I and Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin in Adult Patients with Refractory Advanced Cancers

Ramesh K. Ramanathan1,3, Merrill J. Egorin1,2,3, Julie L. Eiseman1,2, Suresh Ramalingam1,3, David Friedland1,3, Sanjiv S. Agarwala1,3, S. Percy Ivy5, Douglas M. Potter4, Gurkamal Chatta1,3, Eleanor G. Zuhowski3, Ronald G. Stoller1,3, Cynthia Naret3, Jianxia Guo3 and Chandra P. Belani1,3

Authors' Affiliations: 1 Division of Hematology/Oncology, Department of Medicine and 2 Department of Pharmacology, University of Pittsburgh School of Medicine; 3 Molecular Therapeutics/Drug Discovery Program and 4 Biostatistics Department, University of Pittsburgh Graduate School of Public Health and Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 5 Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Ramesh K. Ramanathan, University of Pittsburgh Medical Center Cancer Pavilion, #562, 5150 Centre Avenue, Pittsburgh, PA 15232. Phone: 412-648-6507; Fax: 412-648-6579; E-mail: ramanathanrk{at}upmc.edu.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week.

Experimental Design: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly x 3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 mg/m2 and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m2. Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins.

Results: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m2, DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m2 developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2.

Conclusions: The recommended phase II doses of 17AAG are 175 to 200 mg/m2 when given twice a week and consistently cause elevations in PBMC HSP70.

Heat shock protein (HSP) 90 constitutes 1% to 2% of all cytosolic proteins, and its primary function is to chaperone multiple client proteins involved in cell signaling, proliferation, and survival (1, 2). HSP90 plays an important role in mediating conformational folding and activation of oncoproteins, such as mutant p53, HER-2/neu, Raf-1, and Bcr-Abl (1–4). Geldanamycin and its analogues bind to HSP90 and prevent its chaperone function (5). The first geldamycin analogue to enter clinical trials is 17-(allylamino)-17-demethoxygeldanamycin (17AAG; refs. 6–10). Previous phase I studies of 17AAG in adults have evaluated weekly, daily x3 schedule, or daily x5 schedule (Table 1 ; refs. 6–10).The recommended phase 2 dose of 17AAG is 295 to 308 mg/m2 when administered weekly x3, every 4 weeks (7, 8), and 450 mg/m2 when administered weekly on a continuous schedule (6). In contrast, administration of 17AAG daily x5 or daily x3 is associated with dose-limiting toxicity (DLT) at substantially lower doses, and the DLT, which was primarily reversible hepatitis (9, 10), reflected preclinical animal toxicology studies (11).


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  		Table 1. Phase I studies of 17AAG in adults

 
17AAG is metabolized primarily by CYP3A, with the major metabolite, 17-(amino)-17-demethoxygeldanamycin, being equipotent to 17AAG in its ability to affect HSP90 (12–14). The pharmacokinetics of 17AAG in humans is now well characterized. 17AAG and 17-(amino)-17-demethoxygeldanamycin are excreted primary through the liver and biliary system, and urinary excretion accounts for <10% of a dose. (6–10, 15, 16).

Biomarkers that may be affected by 17AAG therapy have been evaluated in clinical trials (6–10). HSP90 has not shown a consistent increase or decrease in response to 17AAG therapy. However, several animal and human studies have shown HSP70 increases resulting from 17AAG-HSP90 interaction. (6–13).

Inhibition of HSP90 function seems to last only 1 to 5 days after a single dose of 17AAG (6). In addition, frequent administration of 17AAG is more effective in inhibiting tumor growth than is weekly 17AAG dosing (11). Based on these observations, we did a phase I study, in which 17AAG was administered on a twice-a-week schedule. The principal objectives of the study were to define the DLT and maximal tolerated dose (MTD) of 17AAG, recommend a dose for future phase II studies, and characterize the pharmacodynamics of 17AAG as reflected by changes in peripheral blood mononuclear cell (PBMC) content of HSP90 and client proteins.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient selection. Eligible patients had histologically confirmed, advanced cancer not curable by standard therapies. Other requirements were as follows: Eastern Cooperative Oncology Group performance status 0, 1, or 2; no chemotherapy or radiation therapy for at least 4 weeks before study entry; and a negative pregnancy test for women of child-bearing potential. Adequate organ function was required and was defined by the following: absolute neutrophil count >1500/µL; platelets >100,000/µL; serum creatinine <1.5 mg/dL, measured creatinine clearance >60 mL/min if serum creatinine was between 1.5 and 2.0 mg/dL; bilirubin <1.5 mg/dL; and serum aspartate aminotransferase (AST) <2x the upper limit of normal. Women of child-bearing potential were required to use an effective means of contraception.

The following were grounds for exclusion from the trial: pregnancy or lactation, untreated brain metastasis, active infections, or serious concomitant conditions. Because 17AAG is formulated in a diluent containing egg phospholipids, patients with a history of serious allergic reactions to eggs were excluded. Before entering the study, all patients gave written consent according to institutional and Federal guidelines.

Drug administration. 17AAG (NSC 330507) and EPL diluent (NSC 704057) were supplied by the Pharmaceutical Resources Branch of the National Cancer Institute (Rockville, MD). 17AAG was supplied in sterile vials that contained 50 mg 17AAG in 2.0 mL DMSO. EPL diluent was supplied in sterile, 50-mL flint glass vials that contained 48 mL of 2% egg phospholipids in 5% dextrose in water for injection. 17AAG was prepared for infusion by adding 2 mL 17AAG to 48 mL EPL diluent, thereby producing a 17AAG concentration of 1 mg/mL. The final 17AAG dosing solution was transferred to a glass bottle and administered within 6 h of preparation. Most 17AAG infusions were given over 1 h; however, if the volume of the infusion exceeded 500 mL, the infusion could be given over 2 h.

Patients were entered onto schedule A (Table 2 ) or B (Table 3 ) independently. The dose levels planned for schedule A (twice weekly x 3 weeks, repeated every 4 weeks) were 100, 125, 150, 175, and 200 mg/m2 and for schedule B (twice weekly x 2 weeks, repeated every 3 weeks) were 150, 200, and 250 mg/m2. A modified Fibonacci schema, with three to six patients per cohort, was used. No intrapatient dose escalation was allowed. At least three patients were to be enrolled at each dose level, assuming DLT did not occur in the first two patients enrolled at that level. The first three patients enrolled at a given dose level were observed for 4 weeks on schedule A and 3 weeks on schedule B. If none of the first three patients treated at a given dose level had a DLT, as defined below, patients were enrolled at the next dose level. If one of three patients experienced a DLT, up to three additional patients were accrued at the same dose level, and only if none of those additional three patients had a DLT was the next cohort of three patients accrued to the next higher dose. If two or more patients treated at any dose level experienced DLT, that level was considered the excessively toxic dose, and accrual to that dose level ceased. If only three patients had been treated at the dose level immediately below the excessively toxic dose, that dose level was expanded to six patients, assuming fewer than two of those six patients experienced a DLT. The highest dose level at which zero or one of six patients experienced a DLT was considered the MTD or the dose recommended for future phase II studies. At the MTD, cohorts could be expanded up to 12 patients.


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  		Table 2. Dose levels for schedule A

 

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  		Table 3. Dose levels for schedule B

 
DLTs. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. DLT was defined as any drug-related (possible, probable, or definite) grade 3 or greater nonhematologic toxicity, except alopecia, occurring in cycle 1. In addition, nausea or vomiting ≥grade 3 despite maximal antiemetic therapy, persistent decrease of creatinine clearance to <50% of baseline, or increase of serum creatinine to more than two times baseline were also considered a DLT. Hematologic criteria for a DLT were thrombocytopenia <25,000/µL or leucopenia <500/µL.

Dose modifications. If any grade 3 or greater nonhematologic toxicity occurred, 17AAG administration was withheld until resolution to grade <1 or baseline, at which time 17AAG dosing could be resumed at a dose one level below that which produced the toxicity. Weekly laboratory tests were done, and drug dosing was withheld, if serum creatinine was elevated to more than two times baseline. On recovery of the creatinine to <1.5 times baseline, reinitiation of treatment was allowed at a dose one level below that associated with the elevated creatinine. If grade 2 neuropathy developed, treatment was withheld until normalization of signs and symptoms. If the absolute neutrophil count nadir was <500/µL or platelet nadir was <100,000/µL, subsequent 17AAG treatment could be resumed after hematologic recovery to an absolute neutrophil count >1500/µL or platelet count >100,000/µL but at a 17AAG dose one level below that which produced the hematologic toxicity. A dose delay of up to 4 weeks was permitted before treatment discontinuation was required.

Study requirements and assessments. A history and physical examination were done prestudy and before every cycle. A complete blood count, serum electrolytes, and chemistries were evaluated prestudy and once weekly. Radiographs to follow response were done prestudy and after every two cycles. The WHO response criteria were used (16).

We reported previously on the pharmacokinetic characteristics of 17AAG given on a weekly schedule (7, 15), as the 17AAG doses were similar in this study, pharmacokinetic sampling was omitted.

Assessment of HSP90 and client proteins in PBMCs. During cycle 1, 8-mL blood samples were collected in heparinized Vacutainer tubes or Vacutainer CPT cell preparation tubes before the start of 17AAG treatment, 4 h after the day 1 dose, and before dosing on days 4, 8, and 11. Patients treated on schedule A also had samples obtained before dosing on days 15 and 18. When possible, samples were also obtained at the same times during cycle 2. PBMCs were isolated from heparinized blood by centrifugation over Histopaque (density 1.077, Sigma-Aldrich, St. Louis, MO). PBMCs were isolated from blood collected in Vacutainer CPT cell preparation tubes by centrifugation at 1,500 x g for 25 min. All PBMC isolations were done at room temperature. Isolated PBMCs were washed twice with PBS at 4°C and stored at –80°C.

Before analysis by Western blot, PBMC pellets were thawed and lysed, on ice, by incubation for 40 min in 100 µL lysis buffer [50 mmol/L Tris-HCl (pH 7.9), 2 mmol/L EDTA, 100 mmol/L NaCl, 1% NP40, 10 mmol/L NaF, 10 mmol/L sodium vanadate] that contained the following freshly prepared protease inhibitors: 1 µg/mL pepstatin, 10 µg/mL aprotin, 5 µg/mL leupeptin, 5 mmol/L phenylmethylsulfonyl fluoride, 0.1 µmol/L microcystin, and 5 mmol/L sodium pyrophosphate. The cell lysates were centrifuged at 13,000 x g for 10 min, and protein concentrations in the resulting supernatants were determined using the Bio-Rad protein assay (Hercules, CA) and bovine albumin standards for calibration curves. Equal amounts of protein from each lysed supernatant (40 µg) were denatured in 3x modified Laemmli sample buffer (Bio-Rad), loaded onto 4% to 15% gradient gels (Bio-Rad), and electrophoresed at 100 V. The separated proteins were transferred onto polyvinylidene difluoride membranes that were blotted with 5% nonfat dry milk in TBS (Bio-Rad) for 1 h and then incubated overnight at 4°C with antibodies against HSP70 (Stressgen Biotechnologies, Victoria, British Columbia, Canada), HSP90 (Stressgen Biotechnologies), Akt (Cell Signaling Technology, Danvers, MA), phosphorylated Akt (Ser473, 587F11, Cell Signaling Technology), Raf-1 (C-12, Santa Cruz Biotechnology, Inc., Santa Cruz, CA), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Chemicon International, Inc., Temecula, CA). The immunoreactive signals were detected with ELC detection reagents (Perkin-Elmer Life Sciences, Boston, MA) following the manufacturer's instructions. The density of each signal was quantitated using UN-Scan-It software (Silk Scientific, Inc., Orem, UT). Densities of the same-sized areas from each band, as well as selected background, were digitized. The ratio between each band of interest and the loading control band (GAPDH) were calculated. These ratios were then further normalized by comparing the ratio from each time point after 17AAG treatment with the corresponding density ratio for that specific patient's pretreatment sample. Other PBMC samples had their HSP70 content determined by ELISA (StressXpress HSP70 ELISA kit, Stressgen Biotechnologies) using reagents and instructions provided by the manufacturer.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics. Patient characteristics are detailed in Table 4 . Forty-four patients were enrolled between February 2003 and November 2004. On schedule A (Table 2), 32 patients were enrolled to dose levels between 100 and 200 mg/m2 and received 56 cycles (median of one cycle per patient). On schedule B (Table 3), 12 patients were enrolled to dose levels between 150 and 250 mg/m2 and received 18 cycles (median of two cycles per patient). Forty-three patients received at least one dose of drug and were evaluable for toxicity.


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  		Table 4. Patient characteristics

 
Toxicity. On schedule A (Table 2), DLTs were seen at three dose levels. At dose levels 1 and 4 (100 and 175 mg/m2), one patient each developed a reversible grade 3 elevation in hepatic transaminases detected on day 10. At dose level 5 (200 mg/m2), two DLTs were documented. One patient exhibited grade 3 thrombocytopenia on day 21, and the other developed grade 3 abdominal pain on day 16. The abdominal pain was constant and of severe intensity, required narcotics for relief, and could not be attributed to causes other than treatment. The dose of 175 mg/m2 was therefore determined to be the MTD for schedule A, and 12 evaluable patients were treated at this dose. On schedule B (Table 3), DLTs were seen at the 250 mg/m2 dose level. Both patients treated at this dose developed severe headache with nausea and/or vomiting and required hospital admission immediately following their first or second dose of 17AAG. The headaches and associated nausea and vomiting subsided over 1 to 2 days. The headaches, which required narcotic administration for relief, were attributed to drug administration after extensive evaluation revealed no other cause. Therefore, the dose of 200 mg/m2 was determined to be the MTD for schedule B, and a total of six evaluable patients were treated at that dose.

The most common drug-related toxicities reported were grades 1 or 2 fatigue, anorexia, weight loss, diarrhea, nausea, constipation, and vomiting (Table 5 ). Reversible elevations of liver enzymes (mainly alkaline phosphatase, AST, and {gamma}-glutamyl transpeptidase) were the most common grade 3/4 toxicities seen, occurring in 20 (47%) patients. Hematologic toxicity was minimal, with the exception of one episode of grade 3 thrombocytopenia. (Table 5). As in our previous phase I study of weekly 17AAG administration, a mildly unpleasant odor that usually lasted for a few days after each dose of 17AAG was consistently noticed by family members and nursing staff (7).


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  		Table 5. Drug-related toxicity

 
Antitumor activity. There were no objective responses observed. Stable disease was documented in a patient with adenocystic cancer, who was treated on schedule A at the dose of 100 mg/m2 and received eight cycles of therapy.

Assessment of HSP90 and client proteins in PBMCs. Concentrations of HSP90, HSP70, Akt, phosphorylated Akt, Raf-1, and GAPDH were assessed by Western blot analysis in PBMCs isolated from 11 patients on schedule A. Six of the patients had been treated with 100 mg/m2 17AAG, three had been treated with 125 mg/m2 17AAG, and two had been treated with 150 mg/m2 17AAG during both cycles 1 and 2. There was great interpatient variability in the cycle 1 predose values for these proteins. Even with equivalent protein loading on the gels, the predose ratios for HSP70 to GAPDH varied from 0.25 to 1.38. Similarly, the values for HSP90, phosphorylated Akt, Akt, and Raf-1 ratios to GAPDH in predose PBMC samples ranged from 0.26 to 0.96, 0.37 to 1.51, 0.34 to 0.76, and 0.32 to 0.92, respectively. Representative Western blots from PBMCs of a patient treated with 100 mg/m2 17AAG are shown in Fig. 1 .


Figure 1
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  		Fig. 1. Protein expression of HSP90, HSP70, phosphorylated Akt (p-Akt), Akt, and Raf-1 in PBMCs from a patient receiving 100 mg/m2 17AAG. GAPDH served as the loading control.

 
The only consistent change observed in Western blots of PBMCs from the 11 patients studied after receiving 17AAG on schedule A was an increase in HSP70, which occurred by 4 h after treatment on day 1 and remained elevated (between 2-and 4-fold over predose) in all patients throughout the treatment period. The normalized concentrations of HSP70 in all patients returned to predose cycle 1 concentrations or slightly lower in the predose samples from cycle 2. There were no consistent changes in PBMC phosphorylated Akt, Akt, HSP90, or Raf-1 during treatment with 17AAG. Because increases in HSP70 were the only consistent changes observed, no additional Western blots were done. PBMCs from the remainder of patients were only assayed for HSP70, and those assays were done by ELISA, which had a larger dynamic range in addition to being easier and requiring less time to do than the Western blot analysis. Consequently, the ELISA method was used to determine HSP70 concentrations in PBMCs from an additional 15 patients treated on schedule A (1 treated with 125 mg/m2, 7 treated with 150 mg/m2, and 7 treated with 200 mg/m2) and 3 patients treated with 150 mg/m2 on schedule B. As seen with Western blot analysis, there was great variation in HSP70 content of PBMCs obtained from patients before treatment in cycle 1. HSP70 concentrations in the predose samples ranged from 0.91 to 14.16 ng/mg protein. In all patients whose PBMC HSP70 was assessed with the ELISA, the response and time course of HSP70 increase was qualitatively similar to those shown with Western blots. In those patients for whom PBMCs were monitored in cycle 2, increases in HSP70 concentrations were quantitatively similar to those increases observed in that patient during cycle 1 (Fig. 2 ).


Figure 2
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  		Fig. 2. Concentrations of HSP70 measured in PBMCs from two patients receiving 150 mg/m2 17AAG (A), two patients receiving 175 mg/m2 17AAG (B), and two patients receiving 200 mg/m2 17AAG (C). Concentrations of HSP70 were normalized by dividing the concentrations by the pretreatment values obtained just before the start of cycle 1. The concentrations of HSP70 were measured by ELISA.

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
Our evaluation of a twice-a-week dosing schedule for 17AAG was based on reports that inhibition of HSP90 function seems to last only for 1 to 5 days after a single dose of 17AAG (6) and preclinical studies indicating that frequent administration of 17AAG was more effective than weekly dosing in inhibiting tumor growth (11). Our results indicate that administration of 17AAG doses between 100 and 175 mg/m2 on schedule A and between 150 and 200 mg/m2 on schedule B is safe and associated with manageable toxicity. The MTDs and recommended doses for future single-agent phase II studies are 175 mg/m2 (twice a week for 3 weeks) and 200 mg/m2 (twice a week for 2 weeks) on schedules A and B, respectively. These doses differ by only 25 (14%) mg/m2, and this difference is probably not clinically relevant, as the weekly dose intensity of 17AAG over a 12-week period is similar for both schedules. The MTD of another study, in which 17AAG was administered twice a week for 2 weeks was 220 mg/m2, which is only slightly higher than the 200 mg/m2 MTD defined in our study (17).

The DLT of headache and abdominal pain has not been reported in other trials of 17AAG (6–10). The etiology of the severe headache seen in two patients remains unclear. It is notable that much higher doses of 17AAG have been administered in other studies and have not caused headaches. The etiology for abdominal pain is also unclear. Pancreatitis following 17AAG therapy has been reported previously (7), but laboratory and radiological evaluations of the patients in the current study were not consistent with that diagnosis. Some of these side effects may be due to DMSO, which is needed for formulation of 17AAG. Although reversible elevations of liver enzymes were often seen, they were not dose limiting.

A twice-a-week schedule of 17AAG was associated with a persistent increase of HSP70, which may be a useful biomarker. However, a correlation between increase in HSP70 levels and clinical variables of activity, such as response, time-to-progression, or survival, has not been shown to date. Consequently, other biomarkers of 17AAG treatment are being investigated. Plasma concentrations of insulin-like growth factor binding protein-2 and the extracellular domain of erb-B2 are decreased in human tumor xenograft-bearing mice after treatment with17AAG (18), but this pharmacodynamic response does not occur in the plasma of patients treated with 17AAG (19).

In summary, administration of 17AAG by a twice-a-week schedule is well tolerated. Because in vitro and in vivo preclinical studies have shown an additive or synergistic effect when 17AAG is combined with several traditional and targeted antitumor agents (11), phase I studies of 17AAG combined with agents, such as taxanes, imatinib, trastuzumab, and bortezomib, have been initiated (2, 20–22). The results of the current single-agent phase I study should allow greater flexibility in expanding these combination strategies.


   Acknowledgments
 
We thank Jeremy Hedges and Alicia DePastino for excellent secretarial assistance and the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for constructive suggestions about this manuscript.


   Footnotes
 
Grant support: National Cancer Institute grants UO1-CA099168, UO1-CA69855, and P30CA47904 and NIH/National Center for Research Resources/General Clinical Research Centers #5M01 RR 00056 (University of Pittsburgh Cancer Institute and Medical Center).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 2005.

Received 9/ 6/06; revised 11/10/06; accepted 12/ 5/06.


   References
Top
 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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Commentary

Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells
Wanping Xu and Len Neckers
Clin. Cancer Res. 2007 13: 1625-1629. [Full Text] [PDF]



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S. S. Ramalingam, M. J. Egorin, R. K. Ramanathan, S. C. Remick, R. P. Sikorski, T. F. Lagattuta, G. S. Chatta, D. M. Friedland, R. G. Stoller, D. M. Potter, et al.
A Phase I Study of 17-Allylamino-17-Demethoxygeldanamycin Combined with Paclitaxel in Patients with Advanced Solid Malignancies
Clin. Cancer Res., June 1, 2008; 14(11): 3456 - 3461.
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W. Xu and L. Neckers
Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells
Clin. Cancer Res., March 15, 2007; 13(6): 1625 - 1629.
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