Retaspimycin Hydrochloride Research Articles

Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models.

Retaspimycin hydrochloride (IPI-504), an Hsp90 (heat shock protein 90) inhibitor, has shown activity in multiple preclinical cancer models, such as lung, breast and ovarian cancers. However, its biological effects in gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the expression pattern of Hsp90α/β mRNA in stable glioma cell lines, multiple glioma-derived primary cultures and human neural stem/progenitor cells. The effects of IPI-504 on cell proliferation, apoptosis, motility and expression of Hsp90 client proteins were evaluated in glioma cell lines. In vivo activity of IPI-504 was investigated in subcutaneous glioma xenografts. Our results showed Hsp90α and Hsp90β expression levels to be patient-specific, higher in high-grade glioma-derived primary cells than in low-grade glioma-derived primary cells, and strongly correlated with CD133 expression and differentiation status of cells. Hsp90 inhibition by IPI-504 induced apoptosis, blocked migration and invasion, and significantly decreased epidermal growth factor receptor levels, mitogen-activated protein kinase and/or Akt activities, and secretion of vascular endothelial growth factor in glioma cell lines. In vivo study showed that IPI-504 could mildly attenuate tumor growth in immunocompromised mice. These findings suggest that targeting Hsp90 by IPI-504 has the potential to become an active therapeutic strategy in gliomas in a selective group of patients, but further research into combination therapies is still needed.

A Phase I Study of the HSP90 Inhibitor Retaspimycin Hydrochloride (IPI-504) in Patients with Gastrointestinal Stromal Tumors or Soft-Tissue Sarcomas

Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.

Geldanamycin and its derivatives as Hsp90 inhibitors

The Hsp90 molecule, one of the most abundant heat shock proteins in mammalian cells, maintains homeostasis and prevents stress-induced cellular damage. Hsp90 is expressed under normal conditions at a level of about 1-2 Percent of total proteins, while its expression increases 2-10 fold in cancer cells. The two main constitutively expressed isoforms of Hsp90 are known as Hsp90-alpha and Hsp90-beta, and their upregulation is associated with tumor progression, invasion and formation of metastases, as well as development of drug resistance. The Hsp90 is a key target for many newly established, potent anticancer agents containing Hsp90 N-terminal ATP binding inhibitors, such as geldanamycin, and its analogues 17AAG and 17DMAG. The therapeutic usage of geldanamycin has been limited due to its poor water solubility and severe hepatotoxicity. Therefore, its analogues, including 17AAG, 17DMAG, Tanespimycin and Retaspimycin hydrochloride, with improved pharmacokinetic profiles, have been developed.

The Heat Shock Protein 90 Inhibitor IPI-504 Induces KIT Degradation, Tumor Shrinkage, and Cell Proliferation Arrest in Xenograft Models of Gastrointestinal Stromal Tumors

The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib and sunitinib are very effective in advanced GIST, but have no curative potential. The observation that heat shock protein 90 (HSP90) inhibition results in KIT degradation prompted us to assess the efficacy of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) alone or in combination with imatinib or sunitinib in two GIST xenografts with distinctive KIT mutations. Nude mice were grafted with human GIST carrying KIT exon 13 (GIST-882; n = 59) or exon 11 (GIST-PSW; n = 44) mutations and dosed with imatinib (50 mg/kg twice daily), sunitinib (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504 + imatinib, or IPI-504 + sunitinib. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as adverse events during treatment. Treatment with IPI-504 alone resulted in tumor regression, proliferation arrest, and induction of tumor necrosis. We documented downregulation of KIT and its signaling cascade in IPI-504-treated animals. Treatment effects were enhanced by combining IPI-504 with imatinib or sunitinib. On histologic examination, liver damage was frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 shows consistent antitumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with imatinib or sunitinib. The sequence of drug administration in the combination arms warrants further studies.

A phase 1 study of IPI-504 (retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma

A phase 1 study of IPI-504 (retaspimycin hydrochloride) administered intravenously twice weekly for 2 weeks at 22.5, 45, 90, 150, 225, 300 or 400 mg/m2 followed by 10 days off-treatment was conducted to determine the safety and maximum tolerated dose (MTD) of IPI-504 in patients with relapsed or relapsed/refractory multiple myeloma (MM). Anti-tumor activity and pharmacokinetics were also evaluated. Eighteen patients (mean age 60.5 years; median 9 prior therapies) were enrolled. No dose-limiting toxicities (DLTs) were reported for IPI-504 doses up to 400 mg/m2. The most common treatment-related adverse event was grade 1 infusion site pain (four patients). All other treatment-related events were assessed as grade 1 or 2 in severity. The area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2–4 h for IPI-504 and its metabolites. Four patients had stable disease, demonstrating modest single-agent activity in relapsed or relapsed/refractory MM.

Multicenter Phase II Trial of the Heat Shock Protein 90 Inhibitor, Retaspimycin Hydrochloride (IPI-504), in Patients With Castration-resistant Prostate Cancer

To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC). A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ≥1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout. A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively. Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.

Efficacy and safety of retaspimycin hydrochloride (IPI-504) in combination with trastuzumab in patients (pts) with pretreated, locally advanced or metastatic HER2-positive breast cancer.

590 Background: Retaspimycin hydrochloride (IPI-504) is a potent, intravenously-administered heat shock protein 90 (Hsp90) chaperone inhibitor. Hsp90 helps maintain the stability of key oncoproteins, including HER2. Preclinical studies have demonstrated the activity of IPI-504 plus trastuzumab in xenograft mouse models using trastuzumab-sensitive and trastuzumab-resistant HER2-positive cell lines. Methods: In our single-arm, phase 2 study, the overall response rate and tolerability of IPI-504 plus trastuzumab in pts with previously treated, locally advanced or metastatic HER2-positive breast cancer were evaluated. Prior treatment with trastuzumab was required and no limit of previous lines was specified. The trial used a Simon two-stage design; if the DLT rate was ≤25% and at least 2 responses were observed, the trial would be expanded. Results: 26 pts were initially treated with 300 mg/m2 IPI-504 once weekly in combination with 6 mg/kg trastuzumab once every 3 weeks. The median age was 52.5 years (range 33-72) and the median number of prior regimens received was 6 (range 2-20). Pts received a median of 3 cycles (range 1-12) of IPI-504. No DLTs were reported. The majority of AEs were grade 1 or 2, and the most common treatment-related adverse events were fatigue (46%), nausea (31%), and diarrhea (23%). Related serious adverse events were reported in 2 pts; one pt had Grade 1 diarrhea and Grade 3 hypokalemia, and the other pt had Grade 3 vomiting. Only 1 (4%) Grade 3 transaminase elevation was noted on trial, in a pt with metastatic disease to the liver. Among the 20 pts evaluable for efficacy, 1 partial response was observed (based on central, independent radiology review). Stable disease was observed in 14 pts (70%), including 1 pt (4%) with stable disease for more than 6 months. Conclusions: IPI-504 300 mg/m² IV weekly in combination with trastuzumab was well tolerated, without significant hepatic toxicity. Treatment resulted in modest clinical activity in heavily pretreated pts previously exposed to trastuzumab, but did not meet the prespecified efficacy criteria for trial expansion.

Safety and activity of IPI-504 (retaspimycin hydrochloride) and docetaxel in pretreated patients (pts) with metastatic non-small cell lung cancer (NSCLC).

7516 Background: IPI-504, a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17-AAG), is an intravenously (IV) administered heat shock protein 90 (Hsp90) inhibitor that causes degradation of a variety of mutated or amplified oncoproteins. The combination of IPI-504 with taxanes has demonstrated additive activity in murine xenograft tumor models. Methods: An expansion of a Phase Ib trial was undertaken to evaluate IPI-504 in combination with docetaxel in pts with NSCLC and Karnofsky performance status of ≥70. Pts had pathologically confirmed metastatic NSCLC; all had received 1 to 2 prior chemotherapy regimens without prior docetaxel. Docetaxel 75 mg/m2 IV was given once every three weeks (wks), while IPI-504 300 mg/m² IV was administered once per wk. All pts were evaluated for safety, pharmacokinetics and tumor response (RECIST). Archival tissue samples were required for KRAS genotyping. Results: The 23 pts included in this analysis received an average of 4 cycles (range 1-13) on study. Median age was 61 years, 13 (57%) were female, and 18 (78%) were current or former smokers, with a median tobacco exposure of 30 pack-years. The majority of adverse events were Grade 1 or 2, and the most common treatment-related adverse events were fatigue (57% total, 4% ≥Grade 3), diarrhea (35%, 9%), nausea (30%, 13%), vomiting (30%, 13%), neutropenia (30%, 30%), and anemia (26%, 4%). Docetaxel pharmacokinetics were unaltered by IPI-504 co-administration. 6 of the 23 pts (26%) had a partial response (PR), including 3 of 7 pts with squamous cell carcinoma. Efficacy analysis in overall population and exploratory subgroups is below (Table). Conclusions: IPI-504 in combination with docetaxel was well tolerated and resulted in clinical activity in pts with pretreated, metastatic NSCLC. A randomized trial is ongoing to evaluate this combination compared to docetaxel plus placebo in this pt population. Clinical activity. Patients n ORR n, (%) Previously treated NSCLC 23 6 (26) Current or former smokers 18 6 (33) Squamous cell carcinoma 7 3 (43) KRAS wild type 13 4 (31) Abbreviation: ORR, overall response rate (all PRs).

Abstract 2827: Activity of the proprietary Hsp90 inhibitor IPI-493 in models of colorectal cancer correlates with RAS pathway activation

Abstract Heat shock protein 90 (Hsp90) plays a role in regulating the stability of key cancer-causing proteins through its role as a protein chaperone. Proteins chaperoned by Hsp90, known as client proteins, include cancer-causing forms of ALK, BCR-ABL, EGFR, FLT3, and HER2. Infinity is developing two drug candidates in its Hsp90 chaperone inhibitor program: IPI-504 (retaspimycin hydrochloride), an intravenously-administered small molecule, and IPI-493, which is administered orally. To investigate the activity of IPI-493 in colorectal cancer (CRC), we performed in vitro growth inhibition (GI) studies on a CRC cell line panel. IPI-493 demonstrated GI50s in the range of 10-100nM in cell lines harboring either kRAS or bRAF mutations. To explore the in vivo potency of IPI-493, several mutant bRAF, mutant kRAS, as well as a wild-type kRAS/bRAF xenograft models were developed. Administration of IPI-493 at 100 mg/kg three times weekly demonstrated dramatic effects in all of the mutant models tested, with tumor growth inhibition (TGI) values between 70 and 90% and regression in one mutant bRAF model. Importantly, when IPI-493 was evaluated in combination with irinotecan, the combination resulted in greater tumor regression than seen with either agent alone with complete regressions observed in 4 of 10 animals. Interestingly, in the wild-type kRAS/bRAF models, IPI-493 administration did not lead to tumor growth inhibition. These results suggest that activation of the MAPK pathway may predispose these cells to sensitivity to Hsp90 inhibition. To investigate the effect of IPI-493 on MAPK pathway activity, we performed pharmacodynamic analysis after a single dose of IPI-493 in multiple xenograft models differing in their RAF/RAS mutation status. In mutant bRAF models, pathway activity was high, and IPI-493 administration resulted in downregulation of the activity of both bRAF and MEK. In models containing no mutations in kRAS or bRAF, we detect low baseline levels of both p-bRAF and p-MEK and little effect of IPI-493 administration. When Ras pathway activity in all CRC xenografts was compared with IPI-493 efficacy, there was a clear correlation between pathway activation and tumor growth inhibition by IPI-493. Our finding that Ras pathway activation predisposes CRC cells to sensitivity to IPI-493 and our combination data with irinotecan provide a clear rationale for the evaluation of Hsp90 inhibitors in colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2827. doi:10.1158/1538-7445.AM2011-2827

Abstract 1601: Hsp90 inhibition results in a significant delay in tumor progression in a model of emerging EGFR TKI resistance in non-small cell lung cancer

Abstract Heat shock protein 90 (Hsp90) plays a role in regulating the stability of key cancer-causing proteins through its role as a protein chaperone. Proteins chaperoned by Hsp90, known as client proteins, include cancer-causing forms of ALK, BCR-ABL, EGFR, FLT3 and HER2. Infinity is developing two drug candidates in its Hsp90 chaperone inhibitor program: IPI-504 (retaspimycin hydrochloride), an intravenously-administered small molecule, and IPI-493, which is administered orally. EGFR tyrosine kinase inhibitors (TKIs) are an effective treatment for lung cancer patients with activating mutations in EGFR. After a dramatic initial response, however, most patients become resistant to drug treatment and progress. In about half of these cases, resistance is due to a second point mutation in EGFR (T790M). It is believed that in at least some of these cases, the TKI resistance mutations are pre-existing and that treatment with TKIs selects for the resistant cells. In an effort to model the emergence of resistance to TKIs from pre-existing mutations, we developed a novel in vivo model, where gefitinib treatment initially leads to tumor regression followed by rebound of tumor growth and outgrowth of drug resistant clones containing the T790M mutation. We show that in this model, treatment with IPI-493 alone and IPI-493 following gefitinib resulted in tumor growth inhibition of 61 and 77%, respectively, when compared with gefitinib treatment alone. Treatment with IPI-493 alone also resulted in a significant delay in time to tumor progression with ∼40% of animals still on study 45 days following tumor implant; all animals treated with either vehicle or gefitinib had been removed due to tumor progression. Interestingly, treatment with IPI-493 following gefitinib resulted in an even more impressive delay in time to progression, with >50% of animals still on study on day 65 post-implant. These results suggest that further studies with Hsp90 inhibitors in EGFR mutant NSCLC patients who have been pre-treated with a TKI may be warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1601. doi:10.1158/1538-7445.AM2011-1601

210 EML4-ALK is a sensitive client protein of Hsp90, and rearrangements of the ALK locus are associated with clinical response to IPI-504 (retaspimycin hydrochloride), a novel Hsp90 chaperone inhibitor, in patients with non-small cell lung cancer

210 EML4-ALK is a sensitive client protein of Hsp90, and rearrangements of the ALK locus are associated with clinical response to IPI-504 (retaspimycin hydrochloride), a novel Hsp90 chaperone inhibitor, in patients with non-small cell lung cancer

Pharmaceutical development of IPI-504, an Hsp90 inhibitor and clinical candidate for the treatment of cancer

IPI-504 (retaspimycin hydrochloride) is an Hsp90 inhibitor that is the subject of multiple clinical trials for the treatment of cancer. IPI-504 is an aqueous soluble (>200 mg/ml) hydroquinone hydrochloride salt of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a quinone derivative also undergoing clinical evaluation, albeit with suboptimal formulations that address its inferior aqueous solubility (∼50 µg/ml). IPI-504 interconverts with 17-AAG in vivo through oxidation-reduction reactions that result in a dynamic redox equilibrium. The development challenges associated with redox active molecules are significant due to the pH, oxygen, and temperature sensitivities associated with such chemotypes. The API and sterile drug product manufacturing processes thus warrant the monitoring and control of these key variables. Furthermore, the pharmaceutical development challenges associated with cancer agents that are often fast-tracked due to unmet medical needs mandate a rapid development cycle with associated regulatory hurdles. Drug Dev Res 71: 429–438, 2010. © 2010 Wiley-Liss, Inc.

Association between anaplastic lymphoma kinase rearrangements (rALK) and the clinical activity of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with non-small cell lung cancer (NSCLC).

7517 Background: Oncogenic ALK gene rearrangements (rALK) recently have been identified in approximately 3-5% of all NSCLC, particularly in non-smoking patients (pts) with epidermal growth factor r...

Abstract A215: Hsp90 inhibitor IPI-504 demonstrates antitumor activity against a panel of neuroendocrine/carcinoid cell lines in vitro and in vivo

Abstract Heat shock protein 90 (Hsp90), an emerging target in cancer, is a chaperone protein that contributes to tumorigenesis by maintaining the stability and activity of multiple oncogenic proteins. Infinity Pharmaceuticals is currently developing two Hsp90 inhibitors: IPI-504 (retaspimycin hydrochloride), an intravenous agent that has entered several phase II clinical trials, and IPI-493, an orally administered compound that is currently being tested in a phase I dose-escalation trial. In pre-clinical animal models, IPI-504 and IPI-493 have demonstrated anti-tumor activity against a wide variety of tumor types. Neuroendocrine tumors form a heterogeneous group of malignancies, which differ from each other in their biology, prognosis, and genetics. They mainly occur in the gastrointestinal tract and bronchopulmonary system. Conventional cytotoxic therapy has failed to demonstrate effective treatment of neuroendocrine/carcinoid cancers over the past 4 decades, resulting in an unmet need for improved pharmacological treatment of these tumors. To date, no data have been reported on the activity of Hsp90 inhibitors against carcinoid cancer cells. Herein we describe the activity of the Hsp90 inhibitors IPI-504 and IPI-493 against a panel of neuroendocrine tumors including: BON-1, a cell line derived from a metastasis of a primary pancreatic neuroendocrine tumor, NCI-H720, a lung carcinoid, QGP-1, a pancreatic carcinoma of islet cells and HC-45, an ileal carcinoid. In vitro, most of the carcinoid cell lines are sensitive to the Hsp90 inhibitors with EC50 values between 10 and 189 nM for IPI-493 and 49 and 930 nM for IPI-504. In vivo, IPI-504 dosed twice weekly inhibits the tumor growth of BON-1 cells in mice. To identify the potential mechanism of action of IPI-504 in BON-1 cells we have determined that IGF-1R, a tyrosine kinase receptor and an Hsp90 client protein, is constitutively activated in these cells suggesting that it could participate in the unregulated growth of these tumor cells. Upon treatment of BON-1 cells with IPI-504, phospho-IGF-1R is degraded in a dose-dependent manner. The EC50 of the protein degradation and the in vitro growth inhibitory activity of IPI-504 are similar (∼50 nM), suggesting that the anti-tumor activity of IPI-504 could be due, in part, to the inactivation of this growth factor receptor. In conclusion, we demonstrated that the Hsp90 inhibitors IPI-504 and IPI-493 potently inhibit the growth of neuroendocrine tumor cell lines both in vitro and in vivo and identified IGF-1R as a potential client protein. These data suggest further exploring IPI-504 for the possible treatment of neuroendocrine tumors in the clinic. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A215.

Ansamycin Inhibitors of Hsp90: Natures Prototype for Anti-Chaperone Therapy

The ansamycin class of natural products is well known for its anti-tumor effects and has been extensively studied by cancer researchers for nearly four decades. The first description of geldanamycin in the scientific literature appeared in 1970 and nearly thirty years later the semi-synthetic derivative 17-AAG, or tanespimycin, entered Phase 1 clinical trials. In the subsequent years, three additional geldanamycin derivatives have entered clinical evaluation. Kosan Biosciences developed 17-DMAG or alvespimycin hydrochloride for clinical evaluation as both an intravenous and oral product. Infinity Pharmaceuticals is developing IPI-504 or retaspimycin hydrochloride as an intravenous product, which is in several Phase 2 clinical trials; IPI-504 is the hydroquinone hydrochloride salt of 17-AAG. More recently, Infinity Pharmaceuticals initiated a Phase 1 clinical trial with an oral formulation of 17-AG (IPI-493), the major metabolite of 17-AAG and IPI-504. Since a vast amount of scientific literature exists regarding the ansamycin field and Hsp90 inhibition, this review will survey key milestones in the development of the natural product class as anti-cancer drugs including discovery of the compounds and their anti-tumor effects, identification of Hsp90 as their biological target, the structure-activity relationships that have been identified in this interesting class of compounds, and development of clinical candidates for the treatment of cancer patients. A brief overview of important pre-clinical development data from each clinical lead is also provided.

Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent

Heat shock proteins are vital to cell survival under conditions of stress. They bind client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes and recovery of proteins from aggregates. Heat shock protein inhibitors are a diverse group of novel agents that have been demonstrated to have pro-apoptotic effects on malignant cells through inhibition of ATP binding on the ATP/ADP-binding pocket of the heat shock protein. Initial development of heat shock protein 90 inhibitors, geldanamycin and 17-AAG, were limited by hepatotoxicity and the need for solvent carrying agents. In contrast, retaspimycin, or IPI-504, a derivative of geldanamycin and 17-AAG, is highly soluble in water and generally well tolerated. In Phase I/II trials, retaspimycin has shown activity in NSCLC and gastrointestinal stromal tumor. The most promising activity was observed in gastrointestinal stromal tumors. Phase I/II trials are currently underway to evaluate the dosing schedules and activity of IPI-504 in breast cancer. Given the in vitro activity in diffuse large B-cell lymphoma, mantle cell lymphoma, melanoma, leukemia and pancreatic cancer, current and future trials are of clinical interest. This article reviews IPI-504 and its utility in a wide variety of cancer phenotypes.

A phase II trial of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with relapsed and/or refractory stage IIIb or stage IV non-small cell lung cancer (NSCLC) stratified by EGFR mutation status

8073 Background: IPI-504 (retaspimycin hydrochloride) is a potent, water-soluble heat shock protein 90 (Hsp90) inhibitor. IPI-504 causes the degradation of mutated epidermal growth factor receptor (mtEGFR) kinase and cMET in NSCLC cell lines. IPI-504 also significantly reduces tumor growth in murine xenograft models, including tumors resistant to tyrosine kinase inhibitors (TKIs). Methods: This phase II trial is investigating the safety and antitumor activity of intravenous (IV) 400 mg/m2 IPI-504 given twice weekly for 2 out of 3 weeks. Eligible patients (pts) had stage IIIb (w/ malignant effusion) or stage IV NSCLC that progressed after TKI treatment. EGFR mutation analysis was performed on all pts. Two cohorts (n=10 each) were initially enrolled and stratified by EGFR status (mtEGFR or wtEGFR). Planned cohort expansion to 29 pts occurred if ≥ 1 pt from that cohort had a best response of stable disease (SD) ≥12 wks or partial response (PR). Pts were evaluated for safety and RECIST response every 6 weeks. Central, independent radiology review was performed for all imaging studies. Results: 43 pts have been enrolled: 10 mtEGFR, 17 wtEGFR, 12 pending analysis, and 4 EGFR-failed samples. 19 pts are currently on study. Median age is 62 yrs (range 31–77). Median no. of prior therapies is 3. Common related adverse events are fatigue, nausea, and diarrhea. Anti-tumor activity has been observed, see table. Both cohorts have been expanded. Conclusions: IPI-504 monotherapy has been well tolerated, with evidence of anti-tumor activity, particularly and unexpectedly in the wtEGFR cohort. These data suggest that IPI-504 may have antitumor activity in heavily pretreated pts with advanced NSCLC. Further evaluation continues in the expansion phase of the trial. [Table: see text] [Table: see text]

Cardiovascular safety profile of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor: Results from two independent phase I trials in patients with advanced cancer

e14539 Background: Heat shock protein 90 (Hsp90) is a protein chaperone that regulates the proper folding, stability, and function of multiple mutated and wild type signaling proteins that promote malignant phenotypes. Numerous clinical trials are investigating the activity of the Hsp90 inhibitor IPI-504. Since Hsp90 is a novel cancer target that is ubiquitously expressed in normal cells, a comprehensive evaluation of potential cardiac effects, including the risk of ventricular arrhythmia, was performed in two Phase I trials. Methods: ECG data were pooled and analyzed from 60 pts in two-open label Phase I trials of patients with advanced cancers. Pts received 90 to 400 mg/m2 of IPI-504 IV twice weekly for 2 out of 3 weeks. Subset analyses for 35 pts who received the MTD of 400 mg/m2 were performed. ECGs were obtained in triplicate at 5, 60, and 360 minutes after IPI-504 infusion. Interpretation was conducted at a central, independent laboratory. Results: Over 6,500 ECGs were obtained from 60 pts. At the MTD 3,000 ECGs were obtained from 35 patients. No ventricular arrhythmias or changes in QTcF of ≥60 msec were noted, and no statistically significant relationship between the concentration or dose of IPI-504 and QTcF was observed. At the MTD 5 minutes post infusion, changes from baseline were observed in QTcF (5.4 ms increase), heart rate (15.2 bpm decrease), and PR interval (27.9 ms increase). All of these changes reversed by 6 hours post-infusion and no clinical hemodynamic disturbances were observed. Conclusions: In phase I studies, IPI-504 was not associated with any significant ventricular arrhythmia and no clinically significant QTcF interval changes were noted. These studies did show however that IPI-504 administration was associated with transient, dose-related bradycardia and PR interval lengthening, suggestive of autonomic effects associated with the drug infusion. No clinically significant and IPI-504 related cardiac safety events were observed at the MTD dose of 400 mg/m2. Given these findings, appropriate monitoring of heart rate immediately post-infusion is recommended during further studies with IPI-504. [Table: see text]

A phase Ib trial of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in combination with docetaxel

3547 Background: IPI-504 is a water-soluble heat shock protein 90 (Hsp90) inhibitor. IPI-504 causes the degradation of a variety of mutated or amplified oncoproteins, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The combination of IPI-504 and docetaxel demonstrates additive efficacy in murine xenograft models. This Phase 1b trial was undertaken to identify the maximum tolerated dose (MTD) of IPI-504 in combination with docetaxel. Methods: Eligible patients (pts) had advanced solid tumors that were either refractory to available therapies or for which docetaxel alone was an appropriate therapy. Intravenous (IV) 75 mg/m2 docetaxel was given once every three weeks (q 3- weekly). IPI-504 was administered IV q 3-weekly, with 3 pts per cohort and inter-cohort dose escalation. All pts were evaluated for safety, pharmacokinetics (PK), and tumor response. Results: 16 pts have been enrolled at 3 dose levels of IPI-504 (7 at 300 mg/m2, 6 at 450 mg/m2, and 3 at 550 mg/m2). 6 pts had non-small cell lung cancer (NSCLC). Median age was 59 yrs (range 33–77). Median number of cycles received was 3 (1–11), with 5 pts currently on study. There have been 4 dose-limiting toxicities (DLTs): 1 at 300 mg/m2 (Grade 3 febrile neutropenia); 1 at 450 mg/m2 (Grade 3 fatigue); and 2 at 550 mg/m2 (Grade 1 asymptomatic sinus bradycardia requiring hospitalization for observation, and Grade 3 elevated AST with Grade 3 acute respiratory distress syndrome). All DLTs resolved on trial. No PK interactions between docetaxel and IPI-504 have been observed. The regimen of IPI-504 450 mg/m2 with docetaxel 75 mg/m2 has been identified as the recommended phase 2 dose on a q 3-weekly schedule. Conclusions: In this Phase 1b trial, the MTD of IPI-504 plus docetaxel q 3-weekly was identified. Toxicities were reversible and similar to those seen with docetaxel or IPI-504 alone in this patient population. Given the activity of single-agent IPI-504 against NSCLC and the standard use of docetaxel in that disease, an expanded evaluation of this regimen in pts with previously treated NSCLC is on-going. The combination of IPI-504 and docetaxel on a weekly schedule is also being explored. [Table: see text]