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Clinical Cancer Research 14, 3456, June 1, 2008. doi: 10.1158/1078-0432.CCR-07-5088
© 2008 American Association for Cancer Research
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Cancer Therapy: Clinical

A Phase I Study of 17-Allylamino-17-Demethoxygeldanamycin Combined with Paclitaxel in Patients with Advanced Solid Malignancies

Suresh S. Ramalingam1,2, Merrill J. Egorin1,2, Ramesh K. Ramanathan1,2, Scot C. Remick4, Rachel P. Sikorski2, Theodore F. Lagattuta2, Gurkamal S. Chatta1,2, David M. Friedland2, Ronald G. Stoller2, Douglas M. Potter2,3, S. Percy Ivy5 and Chandra P. Belani1,2

Authors' Affiliations: 1 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine; 2 Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; 3 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; 4 Developmental Therapeutics Program, Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Cleveland, Ohio; and 5 Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland

Requests for reprints: Suresh S. Ramalingam, Emory University Winship Cancer Institute, 1365 Clifton Road, Suite #C-5090, Atlanta, GA 30322. Phone: 404-778-5961; Fax: 404-778-5550; E-mail: suresh.ramalingam{at}emory.edu.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
Background: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel.

Methods: Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1.

Results: Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 ± 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 ± 0.51.

Conclusions: The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.

Heat shock proteins are molecular chaperones that facilitate conformational changes in newly synthesized proteins and mediate the translocation of the newly synthesized proteins to their functional location (1, 2). Heat shock protein 90 (Hsp90), a member of the heat shock protein family of proteins, is the chaperone for a number of oncogenic client proteins such as ERB-B2 (3), BCR-ABL (4), AKT/protein kinase B, C-RAF (5), cyclin-dependent kinase 4 (6), steroid hormone receptors (cortisol, estrogen, and androgen), survivin, and telomerase (7). Expression of heat shock protein is induced by heat, heavy metals, or oxidative stress (1). In addition to the chaperone function, heat shock proteins also play a role in the degradation of impaired proteins. Based on its ability to affect important cellular functions such as growth, differentiation, and survival, Hsp90 has emerged as a target for the treatment of cancer, and pharmacologic inhibition of Hsp90 is currently under evaluation in a number of preclinical and clinical studies (8–13).

Geldanamycin is an ansamycin antibiotic that binds to and inhibits Hsp90. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an analogue of geldanamycin, is active against a variety of solid and hematologic malignancies in preclinical models and has entered clinical evaluation (14–16). We previously conducted phase I studies of 17-AAG that evaluated two different schedules of 17-AAG in patients with advanced solid malignancies (9, 17). The recommended phase II dose of 17-AAG was 295 mg/m2 when given on a weekly schedule, and 175 to 200 mg/m2 when given on a twice-weekly schedule (2 or 3 weeks of dosing followed by a week of rest; refs. 9, 17). In these studies, the salient toxicities associated with 17-AAG included fatigue and elevation of hepatic transaminases. Although disease stabilization was noted in a minority of patients, no objective responses were seen in our phase I studies.

Preclinical studies have shown synergistic interactions between 17-AAG and paclitaxel (18). Breast cancer cell lines exposed to 17-AAG were sensitized to the apoptotic effects of paclitaxel by the activation of caspase-3 and caspase-9. Furthermore, cells with intact retinoblastoma gene (RB) that were exposed to 17-AAG followed by paclitaxel underwent G1 arrest and enhanced apoptosis. Schedule dependence was not seen in cells with mutated RB because both agents block cells in mitosis (18). In another study, 17-AAG enhanced the cytotoxicity of paclitaxel against lung cancer cells that overexpressed p185 (an erbB-2 gene product; ref. 19). In vivo experiments have also shown synergy between 17-AAG and paclitaxel. Nguyen et al. (20) showed a 5- to 22-fold enhancement of paclitaxel cytotoxicity when combined with 17-AAG in mice bearing H358 human non–small–cell lung cancer xenografts. A profound decrease in vascular endothelial growth factor expression and an associated decrease in microvasculature were noted in tumors treated with 17-AAG (19). Solit et al. (15) also showed synergy between 17-AAG and paclitaxel against breast cancer xenografts when both agents were administered at their maximally tolerated doses, and the synergy was maximal when both agents were administered on the same day. Based on the in vitro and in vivo preclinical evidence of synergy between 17-AAG and paclitaxel, we conducted a phase I study to evaluate the recommended doses of 17-AAG and paclitaxel that could be administered as a combination to patients with advanced solid malignancies. We hypothesized that combining the weekly schedule of paclitaxel with the twice-weekly schedule of 17-AAG would allow for maximal exposure to both agents. Furthermore, the weekly schedule of paclitaxel may be associated with enhanced efficacy and a better tolerability profile when compared with every-3-week administration (21).


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 Disclosure of Potential...
 References
 
The objectives of the study were to (a) determine the recommended dose for phase II studies evaluating the combination of twice-weekly 17-AAG and weekly paclitaxel in patients with advanced solid malignancies; (b) define the dose-limiting and non–dose-limiting toxicities; (c) evaluate potential pharmacokinetic interactions between 17-AAG and paclitaxel; and (d) document and describe any anticancer activity associated with the regimen.

Patient eligibility
Patients with histologic or cytologic confirmation of malignancy, for which standard curative or palliative measures did not exist or were no longer effective, were eligible. Eastern Cooperative Oncology Group performance status ≤2 was required. Qualifying laboratory criteria were leukocytes ≥3,000/µL; absolute neutrophil count ≥1,500/µL; platelet count ≥100,000/µL; serum total bilirubin less than or equal to institutional upper limit of normal; serum transminases ≤2.5 x upper limit of normal; and serum creatinine less than or equal to upper limit of normal. Patients with serum creatinine levels greater than or equal to upper limit of normal were eligible if their creatinine clearance was ≥60 mL/min/1.73 m2. At least 4 wk had to have elapsed since prior radiation or chemotherapy. Patients with grade >1 peripheral neuropathy; allergy to egg, paclitaxel, or 17-AAG; prior therapy with 17-AAG; or uncontrolled severe comorbid disease were excluded. Patients with known brain metastases were ineligible. Other pertinent exclusion criteria were history of congenital long QT syndrome; concomitant medications that might prolong QT interval on electrocardiogram; significant cardiac disease; serious ventricular arrythmias; prior radiotherapy that potentially included the heart; left bundle branch block; active antiarrhythmic therapy; and therapeutic anticoagulation with warfarin. Pregnant women were excluded, and women with reproductive potential were required to use contraception. All patients provided written informed consent before enrollment into the study. The study was approved by the Institutional Review Boards of University of Pittsburgh and University Hospitals Case Medical Center.

Treatment plan
17-AAG was provided by the Cancer Therapy Evaluation Program of the National Cancer Institute. Treatment was administered on an outpatient basis. Paclitaxel was administered on days 1, 8, and 15 of each 4-wk treatment cycle. 17-AAG was given on days 1, 4, 8, 11, 15, and 18 of each cycle (twice a week for 3 of 4 wk). Each agent was administered i.v. over 60 min. On days 1, 8, and 15, the sequence of administration was 17-AAG followed by paclitaxel. On day 1 of cycle 1, paclitaxel was administered alone (the dose of 17-AAG was omitted on that day) to compare single-agent pharmacokinetic analysis of each agent against the pharmacokinetic parameters when given as a combination. The dose escalation scheme is outlined in Table 1 . Premedications for paclitaxel included dexamethasone (20-mg oral doses 12 and 6 h before the paclitaxel), diphenhydramine (50 mg i.v.), a histamine receptor-2 antagonist, and a 5-hydroxytryptamine-3 antagonist. The dose of dexamethasone was reduced from 20 to 10 mg orally if the patient tolerated the first two doses of paclitaxel without allergic reactions. An electrocardiogram was obtained before and immediately after the first infusion of 17-AAG to evaluate for assessment of QT interval and cardiac arrhythmias.


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  		Table 1. Dose escalation scheme

 
Treatment was continued to a maximum of 6 cycles or until disease progression or unacceptable toxicity. Dose modifications for toxicity were done as follows: For grade 4 neutropenia or thrombocytopenia, the dose of paclitaxel was reduced in 20 mg/m2 decrements. For clinically significant grade ≥3 nonhematologic toxicity, the dose of the appropriate drug was reduced by 20 mg/m2 decrements. The dose of 17-AAG was reduced for grade ≥3 nausea, emesis, hepatic toxicity, or cardiac arrhythmia. No more than two dose reductions were allowed for each patient. Treatment was held for toxicity grade >1 and resumed only after resolution of toxicity to grade ≤1. Treatment delay of >2 wk led to discontinuation of the patient from the study. Patients were monitored for symptoms and signs of pulmonary toxicity attributable to 17-AAG.

Definition of dose-limiting toxicity
Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Dose-limiting toxicity (DLT) was defined as occurrence of ≥1 of the following events attributable to the study drug(s) during the first cycle of therapy: grade ≥3 nonhematologic toxicity except nausea, vomiting, or alopecia; grade ≥3 nausea or vomiting that lasted >48 h despite maximal medical therapy; absolute neutrophil count <1,000/µL lasting >7 d; grade ≥3 neutropenia associated with fever; grade 4 thrombocytopenia; delay in starting cycle 2 by >2 wk due to toxicity; and grade ≥3 QTc change. Abnormal nonhematologic laboratory criteria (grade ≥3) were considered a DLT if clinically significant and deemed drug related. If a baseline value was elevated before drug therapy, an increase was not considered to be a DLT unless there was an elevation by >2 grades and was of clinical significance.

An "up and down" dose escalation scheme, with cohorts of 3 patients, was used. The first cohort was treated at dose level 1. If 1 of the 3 patients in a cohort experienced DLT, 3 more patients were added at the same level. If 0 of 3 or only 1 of 6 patients in an expanded cohort experienced DLT, the dose for the next cohort was escalated by one level. Escalation was stopped and de-escalation by one dose level was begun as soon as 2 patients at a dose level experienced DLT. If only 3 patients had been treated at the previous dose level, 3 additional patients were to be entered. Dose de-escalation continued until ≤1 of 6 patients at a dose level experienced DLT, and that level was defined as the recommended phase II dose. Intrapatient dose escalation was not permitted.

Patient evaluation
Pretreatment evaluations were history and physical examination, assessment of performance status, complete blood count, and hepatic and renal function tests. If clinically indicated, a multigated acquisition scan was obtained at baseline. Women of reproductive age underwent a serum pregnancy test. Patients were evaluated weekly with complete blood count and hepatic and renal function tests. Serum chemistry tests were done on day 1 of each cycle from cycle 2 onward. Radiologic studies to assess response were done after every 2 cycles of therapy. History and physical examination and assessment of performance status were done before initiation of each cycle. Responses were assessed with Response Evaluation Criteria in Solid Tumors criteria (22).

Pharmacokinetic studies
Sampling. Pharmacokinetic studies were done during the first cycle. On day 1, samples for paclitaxel pharmacokinetics were obtained before the infusion and at 10, 90, 240 min, and 24 h after the initiation of the paclitaxel infusion. On day 4, pharmacokinetic samples for 17-AAG were obtained before the infusion, at the end of the 60-min infusion, and at 24 h after the end of the infusion. On day 8, samples were obtained before the infusion, at the end of the 17-AAG infusion (this specimen also served as preinfusion for paclitaxel pharmacokinetics), and at 10, 90, 240 min, and 24 h after the initiation of paclitaxel infusion. This sampling schedule allowed for comparison of single-agent pharmacokinetic parameters for both agents with that noted when administered as a combination. Samples were collected in 10-mL heparinized vacutainer CPT tubes (Becton-Dickinson) and were centrifuged for 25 min at room temperature at 1,500 to 1,800 x g. Approximately 4 mL of plasma were aspirated and stored at –20°C until time of assay.

Analytic chemical methods. Concentrations of 17-AAG and its metabolite 17-(amino)-17-demethoxygeldanamycin (17-AG) were quantitated by a high-performance liquid chromatography assay with absorbance detection that was developed and validated in our laboratory (23). Concentrations of paclitaxel in plasma were quantitated with a liquid chromatography-mass spectrometry assay that was developed and validated in our laboratory (24).

Pharmacokinetic data analysis. Day 4 and day 8 end-of-infusion and 24-h concentrations of 17-AAG and 17-AG were analyzed by descriptive statistics as reflected in their means and SDs. In addition, the ratio of day 4 end-of-infusion 17-AAG or 17-AG concentration to the corresponding day 8 value was calculated for each patient, and the means and SDs of those ratios were calculated. Paclitaxel pharmacokinetics on days 1 and 8 were analyzed using a previously published limited sampling strategy (25). Specifically, paclitaxel area under the concentration to time curve (AUC) was calculated according to the following formula:

Formula

The duration that plasma paclitaxel concentrations remained >0.05 µmol/L was calculated according to the following formula:

Formula

The ratio of paclitaxel AUC on day 1 to that on day 8 was calculated for each patient. Similar ratios were calculated for the duration that plasma paclitaxel concentration remained >0.05 µmol/L after the day 1 and day 8 doses of paclitaxel.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 Disclosure of Potential...
 References
 
Patients. Twenty-five patients were enrolled at the University of Pittsburgh and Case Western Reserve University between June 2004 and July 2006 (Tables 1 and 2 ). The median age was 61 years, and 18 patients were male. Twenty-four patients were Caucasians. Fourteen patients had an Eastern Cooperative Oncology Group performance status of 0, and 10 had a Eastern Cooperative Oncology Group performance status of 1. A total of 54 cycles of therapy were initiated (median, 2; range, 1-6). Five patients received ≥4 cycles of therapy. The most common primary tumors were prostate, non–small-cell lung, and esophageal carcinomas. Other tumor types included ovarian, uterine, breast, colon, and parotid malignancies. Twenty-four patients had received prior chemotherapy regimens (median, 2; range, 1-6).


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  		Table 2. Patient baseline characteristics (N = 25 patients)

 
DLT and recommended phase II dose. The dose escalation schedule is outlined in Table 1. One patient enrolled to dose level 1 experienced grade 3 elevation of hepatic transaminases and met the criteria for DLT. The cohort was expanded to seven patients (one inevaluable) and no DLT was noted thereafter. Dose escalation proceeded until dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel), at which the first two patients experienced DLT. One patient had grade 3 fatigue and chest pain (musculoskeletal) and the other had grade 3 myalgia. Six patients were treated at dose level 5 (130 mg/m2 17-AAG and 100 mg/m2 paclitaxel). Although none experienced protocol-specified DLT, three of six patients required neutropenia-related paclitaxel dose reductions during cycle 1. Therefore, this dose level was deemed undeliverable. Dose level 3 (175 mg/m2 17-AAG and 80 mg/m2 paclitaxel) was defined as the recommended phase II dose. Seven patients were treated at this dose level without any DLT. The non–dose-limiting toxicities are described in Table 3 and included elevation of liver enzymes, nausea, emesis, diarrhea, arthralgia, myalgia, and neuropathy.


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  		Table 3. Adverse events

 
Antitumor activity. Sixteen patients completed at least 2 cycles of therapy and were considered evaluable for response. One patient, with metastatic soft tissue sarcoma of the thigh, experienced reduction in size of the pulmonary nodules after 2 cycles of therapy, but progressed following the fourth cycle (unconfirmed partial response). He had progressed with a prior chemotherapy regimen consisting of ifosfamide, doxorubicin, and mesna. Disease stabilization was noted in five other patients (two esophageal carcinomas, one non–small-cell lung cancer, one cholangiocarcinoma, and one parotid gland carcinoma). One patient with metastatic esophageal adenocarcinoma that had progressed after three prior chemotherapy regimens experienced reduction in the size of retroperitoneal lymph nodes following 4 cycles of therapy with 17-AAG and paclitaxel and received the maximum of 6 cycles on study. Five of the six patients with benefit were treated at doses that were deemed safe. Disease progression led to treatment discontinuation in 16 patients.

Pharmacokinetics. On both days 4 and 8, end-of-infusion concentrations of 17-AAG increased with 17-AAG dosage (Table 4 ). There was no dose-related increase in end-of-infusion concentrations of 17-AG (Table 4). There was no consistent intrapatient change in the ratio of day 4 to day 8 end-of-infusion concentrations of either 17-AAG or 17-AG (Table 4). Data on paclitaxel pharmacokinetics are shown in Table 5 . There was no clear relationship between paclitaxel dose and paclitaxel AUC or the duration that plasma paclitaxel remained >0.05 µmol/L. This likely reflects the interpatient variability observed and the relatively narrow range of paclitaxel doses studied (Table 5). The ratio of day 1 to day 8 paclitaxel AUC and the duration that plasma paclitaxel remained >0.05 µmol/L did not indicate any consistent difference between paclitaxel pharmacokinetics on days 1 and 8 (Table 5).


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  		Table 4. 17-AAG pharmacokinetics

 

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  		Table 5. Paclitaxel pharmacokinetics

 

   Discussion
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 Abstract
 Patients and Methods
 Results
 Discussion
Disclosure of Potential...
 References
 
Inhibition of members of the heat shock protein family, particularly Hsp90, is a novel strategy to treat cancer (26). After extensive preclinical studies (12, 13, 15), clinical studies have now been initiated with multiple Hsp90 inhibitors, either as monotherapy or as part of combination regimens. 17-AAG, the first Hsp90 inhibitor to enter the clinic, has been studied as monotherapy on various treatment schedules (9–11, 17). Although the safety of 17-AAG has been shown, there has been no evidence of robust anticancer activity. Therefore, studies of 17-AAG combined with proven or novel anticancer agents are currently under way. Paclitaxel has anticancer activity against a broad range of solid organ malignancies (21, 27) and therefore represents an ideal drug to study in combination with 17-AAG. Based on preclinical evidence of supra-additive or synergistic interactions between 17-AAG and paclitaxel (15, 18), we conducted a phase I study to define the combined doses of the two agents that can be administered safely and recommended for use in phase II studies. Our study showed that 17-AAG and paclitaxel can be administered safely in combination. There were no DLTs in the seven patients treated at the recommended dose for phase II studies.

The regimen evaluated builds on our extensive previous experience with both 17-AAG and paclitaxel (9, 17, 23, 25, 28–30). The twice-weekly schedule of 17-AAG was safe and tolerated well in our previous phase I study of single agent 17-AAG (17). The weekly schedule of paclitaxel has several advantages over the conventional every-3-week schedule. It is associated with a favorable tolerability profile, and the frequent, low-dose administration may result in antiangiogenic effects. In patients with metastatic breast cancer, the weekly schedule of paclitaxel is superior to every-3-week administration (21, 31). In patients with advanced non–small-cell lung cancer, we showed that a weekly regimen of paclitaxel in combination with carboplatin was associated with a favorable nonhematologic toxicity profile when compared with the standard every-3-weekly regimen of carboplatin and paclitaxel (32). Therefore, we hypothesized that the weekly paclitaxel regimen in combination with twice-weekly 17-AAG would not only allow for maximal interaction between the two agents but would also have a favorable tolerability profile.

Solit et al. (33) presented the preliminary results of an ongoing phase I study of 17-AAG and docetaxel administered every 3 weeks to patients with advanced solid malignancies. That regimen has been tolerated well, and disease stabilization has been noted in 3 of 16 patients enrolled. There are also several ongoing studies evaluating the combination of 17-AAG with other molecularly targeted agents. A recent study noted promising anticancer activity with the combination of 17-AAG and trastuzumab in patients with trastuzumab-refractory metastatic breast cancer (34). These encouraging data provide new avenues for exploration of 17-AAG–based combinations for the treatment of various malignancies.

The pharmacokinetic data generated in this study gave no indication of drug-drug interactions between 17-AAG and paclitaxel. For individual patients, the data generated for paclitaxel on day 1 and for 17-AAG on day 4, when each drug was administered as a single agent, were not consistently different than the values obtained on day 8, when the two drugs were delivered in combination. Furthermore, the data generated for paclitaxel AUC and the duration that plasma paclitaxel remained >0.05 µmol/L are consistent with data previously published for patients receiving paclitaxel doses between 60 and 100 mg/m2 (30). Similarly, the end-of-infusion concentrations of 17-AAG and 17-AG observed on days 4 and 8 are consistent with previously published end-of-infusion 17-AAG and 17-AG concentrations in patients receiving 17-AAG doses comparable to those used in the current study (9).

The anticancer activity noted in our study was modest, at best. One potential explanation for the lack of strong anticancer activity could be the fact that several tumor types that are not known to be sensitive to paclitaxel were represented in our study. Overall, it is disappointing that the promising preclinical data did not translate into a clinical benefit. Thus, the therapeutic potential of Hsp90 inhibitors remains yet to be fully realized in the clinical setting. In conclusion, our study shows the safety and feasibility of combining 17-AAG with paclitaxel and defines the doses of the two agents that can be evaluated in phase II studies.


   Disclosure of Potential Conflicts of Interest
Top
 Abstract
 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
References
 
No potential conflicts of interest were disclosed.


   Acknowledgments
 
We thank Cindy Naret and Lori Musguire for their role in coordination of the study, Jeremy Hedges for excellent secretarial assistance, and the University of Pittsburgh Hematology/Oncology Writing Group for constructive criticism regarding the manuscript.


   Footnotes
 
Grant support: University of Pittsburgh: National Cancer Institute grants U01 CA099168 and P30 CA47904, NIH/National Coalition for Cancer Research/General Clinical Research Center grant 5M01-RR 00056, and American Society of Clinical Oncology Foundation Clinical Research Career Development Award (S.S. Ramalingam); University Hospitals Case Medical Center: National Cancer Institute grant U01 CA 62502 and NIH/General Clinical Research Center grant M01-RR00080.

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.

Received 12/ 6/07; revised 1/29/08; accepted 1/31/08.


   References
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 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 

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