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43rd Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2007

As researchers unravel the molecular defects that give rise to human malignancy, new targets are being identified against which novel anti-tumour agents can be fashioned. Perhaps this is nowhere more eloquently illustrated than in the new class of agents known as the histone deacetylase (HDAC) inhibitors, now in clinical trials across a spectrum of solid and hematological cancers. As explained by Dr. Peter Jones, Professor of Biochemistry and Molecular Biology, Keck School of Medicine, Los Angeles, California, DNA methylation, histone modification and nucleosome remodelling all interact in such a way as to cause silencing of genes.

“This process is critical for normal human development,” Dr. Jones noted, but if the process goes wrong—for example, tumour suppressor genes that control cell growth become pathologically methylated as in cancer cells—it can turn a gene permanently off. Once silenced, cells continue to grow indefinitely. Tumour suppressor genes can be silenced by DNA methylation but they can also be expressed through preservation of acetylation of the histone. DNA methylation and histone deacetylation induce a closed chromatin configuration and transcriptional repression; histone acetylation and demethylation of DNA relaxes chromatin and allows transcriptional activation. Consequently, agents which block HDAC preserve acetylation of the histone, promote tumour suppressor gene expression and ultimately control cell growth. Indeed, HDAC inhibition causes acetylated nuclear histones to accumulate in both tumour and normal tissue, thereby serving as a surrogate marker for the biological activity of this novel class of inhibitors.

Wide Spectrum of Anti-tumour Potential

The extent of HDAC inhibitor activity potential was demonstrated in several early-phase studies. One of the many studies cited here during the scientific sessions was an evaluation of vorinostat in cutaneous T-cell lymphoma (CTCL). Also known as suberoylanilide hydroxamic acid (SAHA), vorinostat is the first HDAC inhibitor to receive regulatory approval in the US for the treatment of CTCL.

In this phase II study of 74 patients who had failed systemic therapies, the overall response rate was approximately 30%, the median time to response was 55 days and the median duration of response had not been reached in the majority of patients by study end. “Even more impressive,” reported Dr. Owen O’Connor, Chief, Lymphoma Service, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, “good responses were seen across various types of CTCL including patients with bulky disease and Sézary syndrome”—the leukemic variant of mycosis fungoides. Responses to vorinostat have also been seen in laryngeal, papillary and thyroid cancer, as well as mesothelioma and granulosa cell ovarian cancer, he added.

Although rare, results from another phase II study in recurrent glioblastoma multiforme (GBM) presented by Dr. Evanthia Galanis, Mayo Clinic College of Medicine, Rochester, New York, showed that nine out of the first 52 patients treated with vorinostat 200 mg b.i.d. for two or three weeks, with dose escalation up to 300 mg b.i.d. in the second cycle if toxicity proved acceptable, were free of disease progression at six months. The median duration during which disease remained stable was 11.2 months (range up to 17.5 months) and median overall survival (OS) was 5.7 months, numerically longer than has been seen in other trials in the same patient population, where median OS is in the range of four months, Dr. Galanis observed.

In animal models, there is evidence of central nervous system penetration with vorinostat at doses that inhibit HDAC activity and evidence of histone acetylation in the brain. In a second group of patients who were scheduled for surgery in the same GBM study, patients received six doses of vorinostat pre-operatively and treatment was resumed after recovery. Histone acetylation analysis as well as RNA array analysis suggested that vorinostat does indeed target pathways in GBM, Dr. Galanis observed, adding, “Given its radiosensitizing properties, vorinostat could be incorporated into regimens for newly diagnosed GBM patients.”

Another phase I trial evaluating the HDAC inhibitor LBH589 in advanced solid tumours and non-Hodgkin’s lymphoma (NHL) also showed that at the maximum tolerated dose of 20 mg every other day, complete responses (CRs) were produced in two CTCL patients at five and seven months while partial responses (PRs) were seen in four others. Disease stabilized in seven patients using the same HDAC inhibitor. The cancers treated in this study included melanoma, mesothelioma, parotid gland cancer and renal cell carcinoma. “We also showed rapid and robust changes in gene expression,” reported Dr. Miles Prince, Peter MacCallum Cancer Institute, Melbourne, Australia. The genes involved were those that control cell proliferation, immune regulation and apoptosis, among other cancer-promoting functions.

Another HDAC inhibitor known as MGCDO103 was tested in patients with relapsed or refractory Hodgkin’s lymphoma. Out of 20 evaluable patients for efficacy, a CR was achieved in two patients, while six others achieved a PR. Disease stabilized in 40% of patients for six months or less and in 5% for more than six months, for an overall disease control rate of 45%. As noted by Dr. Anas Younes, M.D. Anderson Cancer Center, Houston, Texas, evidence of tumour reduction was seen in 75% of the group and 60% of them had a greater than 30% reduction in their tumour burden. Seven out of nine evaluated patients also had evidence of significant inhibition of HDAC activity, he added, again suggesting that oral monotherapy with this particular HDAC inhibitor has “significant anti-tumour activity” in this relapsed and refractory setting of NHL where there are currently no approved therapies.

Of note, even though the HDAC inhibitors currently in clinical trials are structurally different and have different selectivities for different enzymes, the toxicity profile of the class is similar. Fatigue, nausea, vomiting and diarrhea are the most common non-hematological toxicities and thrombocytopenia the most common hematological toxicity; the majority of toxicities that do occur are mild in severity.

Combination Therapy

As active as the HDAC inhibitors may be as a single agent in advanced malignant disease, their use in combination with other cytotoxic agents is gaining considerable attention as well. For example, in one study of patients with advanced solid tumours, vorinostat was given in combination with capecitabine. Out of 24 patients, there were four PRs and 18 patients (69%) had stable disease—“a pretty high response rate in patients with advanced disease,” remarked Dr. Eric Chen, UHN-Princess Margaret Hospital, Toronto, Ontario. The combination was also “reasonably well tolerated,” he added, especially considering how much treatment these patients had already received. The most common side effects were hand-foot syndrome with capecitabine and fatigue with vorinostat.

As discussed by Dr. Adil Daud, H. Lee Moffitt Cancer Center, Tampa, Florida, the use of vorinostat first might cause chromatin to move to an open configuration which in turn might enhance DNA access, providing a rationale to treat advanced solid tumour malignancies with vorinostat, followed by doxorubicin.

Researchers studied this in some 15 patients with a variety of cancers, including breast, melanoma, pancreatic and other tumour types, at escalating doses of vorinostat (up to 500 mg b.i.d.) followed by doxorubicin 20 mg/m² on day 3 of three out of four weeks. One PR was achieved in a breast cancer patient, while three others had either stable disease or minor responses. Again, the fact that histone hyperacetylation occurred in peripheral blood mononuclear cells at all doses suggests that the sequence is worth exploring in at least breast cancer and melanoma, according to Dr. Daud.

Pre-clinical work suggests there are synergies between the HDAC inhibitors and other cytotoxic agents, including capecitabine, idarubicin and 5-fluoro-uracil, as well as the proteasome inhibitor bortezomib. In general, all of these combinations are proving to be active, as results in small series of patients showed, and they also appeared to be reasonably well tolerated, especially given the advanced stage of disease in which the combinations are being evaluated.

Overcoming Resistance to Tyrosine Kinase Inhibitors

Unlike most other malignancies, oncologists now have the ability to offer prolonged, disease-free survivals and an excellent quality of life for most chronic myeloid leukemia (CML) patients in chronic-phase disease, noted Dr. Francis Giles, Professor of Medicine, University of Texas Health Science Center, San Antonio. Nevertheless, outcomes are still poor for those who move into accelerated phase (AP) and blast crisis (BC), especially if they develop the T315I mutation that mediates resistance to all tyrosine kinase inhibitors (TKIs) to date.

This mutation does not harbour resistance to MK-0457, an aurora kinase inhibitor with additional anti-tumour properties which inhibits not only bcr-abl-resistant disease, but also aurora kinases A, B and C, FLT3 and JAK2. “As such, it should correctly be considered a multi-targeted inhibitor,” Dr. Giles indicated.

In a phase I study in 44 relapsed/refractory leukemia or JAK2 myeloproliferative patients, there was predictable myelosuppression at all dose levels but it was very rapidly reversible and there were no neutropenia-attributable deaths in this study—“a startling observation in a cohort of over 40 advanced CML patients,” he told delegates.

At treatment onset, all patients were in either AP BC disease phase and all had failed imatinib and a second-generation TKI. In the 15 patients who had failed on second-generation TKIs because of the T315I mutation, one patient achieved a complete cytogenic response and there were two partial and one minor response. The first patient to go on study went into chronic-phase CML following treatment with MK-0457, “literally unheard of in patient with T315I disease,” Dr. Giles commented.

He also noted that there were patients who achieved significant responses to MK-0457 but who did not necessarily have bcr-abl phosphorylation inhibition, “raising the distinct possibility that either aurora kinase inhibition itself or some other target were involved in the clinical responses of these patients.” Importantly, the dose of MK-0457 is 70 mg b.i.d. but in studies to date, the median daily dose approximated only about 100 mg/day. Studies are now underway to determine if this dose decrement—required because of side effects—delivers the same responses as are seen with the usual dose. Nevertheless, as Dr. Giles concluded, “This is an extremely potent agent and we may need to give it at lower than usual doses in many patients.”

Chemotherapy-induced Nausea and Vomiting

Even with modern anti-emetic regimens, over 50% of patients undergoing stem-cell transplantation experience acute or delayed chemotherapy-induced nausea and vomiting (CINV). However, the addition of aprepitant, a neurokinin-1 receptor antagonist, to a standard anti-emetic regimen significantly improves CINV control. In a study presented by Joseph Bubalo, PharmD, Oregon Health and Science University, Portland, a total of 40 patients undergoing either total body irradiation (TBI) plus cyclophosphamide (CYC) or targeted busulfan (BU) plus CYC were treated with aprepitant or placebo on day 1 of conditioning. Treatment was continued until four days after patients had undergone allogeneic or autologous stem-cell transplantation for a total of 10 to 12 days. Both groups also received standard anti-emetics consisting of ondansetron 8 mg every six hours on days patients received BU, and 8 mg b.i.d. on TBI days. Intravenous ondansetron was also given on CYC days. Dexamethasone 20 mg/day was given on both CYC and TBI days.

Compared with placebo, patients undergoing the BU/CYC regimen who were given additional aprepitant did “significantly better” in terms of achieving either a CR (no emesis and mild-to-moderate nausea) or a major response (one to two emesis episodes on one day with any level of nausea or no emesis with severe nausea). Interestingly, however, there did not appear to be any difference in the incidence of CINV between the aprepitant-containing arm and the placebo-controlled arm when patients underwent TBI/CYC, “which is somewhat puzzling,” observed Dr. Bubalo, “because in animal models, radiation-induced nausea and vomiting does respond to aprepitant.”

The lack of superior response in the TBI/CYC arm might be explained by the fact that substance P—which is blocked by aprepitant—may not be invoked as much by TBI as it is by focal radiation, a hypothesis the group intends to explore further.

Lastly, a simple and convenient anti-emetic regimen consisting of three compounds given on one day led to excellent anti-emetic control in 41 patients undergoing moderately emetogenic chemotherapy.

As explained by Dr. Steven Grunberg, Professor of Medicine, University of Vermont College of Medicine, Burlington, palonosetron, a 5HT3 antagonist, has a 40-hour half-life, “so we know that the drug would last at least five days with a single dose.” In earlier trials, aprepitant was tested at much higher doses that it is currently used (125 mg, 80 mg and 80 mg on days 1, 2 and 3, respectively) and it was shown to be safe at higher doses, so they gave it at a dose of 285 mg on day 1 as well.

Aprepitant also inhibits the metabolism of dexamethasone and doubles systemic exposure to it so a single, high dose of aprepitant can be used to simulate treatment exposure to that achieved with a common multiple-day anti-emetic regimen, he observed. Defining CR as no emesis and no rescue medication, results showed that almost 75% of patients achieved a CR, while 100% had no emesis on day 1.

“Almost 95% of patients did not vomit on the latter days either and nausea levels were quite reasonable—60 to 80% of patients had no more than mild nausea,” Dr. Grunberg said, adding that “overall, we felt that these were very promising results and the regimen was easier for patients to take and allowed for better compliance.”

Questions and Answers

The following question-and-answer session was conducted during interviews with Dr. William Schelman, Medical Oncology Fellow, University of Wisconsin, Madison; and Joseph Bubalo, PharmD, Oregon Health and Science University, Portland.

Q: Is stable disease a promising result in patients with advanced refractory cancers, as many of the HDAC inhibitors appear to accomplish?

Dr. Schelman: Certainly. I think that story was best exemplified by the erlotinib story in non-small cell lung cancer, where the majority of patients had stable disease but treatment improved quality of life and patients lived longer. So I think with refractory diseases, treating it like a chronic illness and palliating symptoms and achieving a good quality of life is a reasonable goal.

Q: Does aprepitant have properties that differ from standard anti-emetics?

Dr. Bubalo: Yes. Aprepitant blocks the neurokinin-1 receptor which is a substance P receptor. And in other high-dose chemotherapies, it has been shown that the addition of aprepitant to 5HT3 antagonists and corticosteroids improves control of not only acute but delayed nausea and vomiting. In this stem-cell transplant population, they have both acute and delayed-phase CINV but standard anti-emetics do not address the delayed component of CINV at all. In addition, we are very hesitant to use any kind of dexamethasone taper in patients such as these, since they are already going to be profoundly immunosuppressed.