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Meeting Highlights

15th International Congress of Parkinson’s Disease And Movement Disorders and Inaugural Melanoma and Cutaneous Malignancy Meeting

Walter Alexander

15th International Congress Of Parkinson’s Disease And Movement Disorders

This year’s gathering in Toronto, from June 4 to 9, 2011, featured approximately 70 sessions led by more than 170 faculty members from around the world. Approximately 3,750 clinicians, researchers, trainees, and industry supporters attended. This article includes key sessions on incobotulinumtoxinA for blepharospasm and cervical dystonia, as well as discussions of a rotigotine patch for restless legs syndrome and a carbidopa/levodopa capsule for Parkinson’s disease.

Transdermal Rotigotine (Neupro) in Restless Legs Syndrome: The SP790 Trial

  • Ralf Kohnen, PhD, Professor of Neurology, University of Erlangen–Nuremberg, Nuremberg, Germany

Rotigotine (Neupro, UCB Pharma), a dopamine agonist with activity in D1 through D5 receptors and at adrenergic and serotonergic sites, is indicated for the treatment of restless legs syndrome (RLS) and Parkinson’s disease. This drug has been shown to maintain stable plasma levels over 24 hours after a single daily application via a transdermal patch.

Dr. Kohnen’s study, which included 458 patients with moderate-to-severe idiopathic RLS (IRLS), defined as having an IRLS sum score of 15 or above and a Clinical Global Impression (CGI) Item 1 score of 4 or above, addressed the question: “To what degree do pains in arms or legs impair your well-being or your normal daily activities?”

The post hoc analysis of item 8 on the Restless Legs Syndrome–Quality of Life (RLS–QOL) instrument was performed with data from the phase 2, randomized, double-blind placebo-controlled trial (SP790) of transdermal rotigotine at 1, 2, or 3 mg per 24 hours in this population. More than half of patients with RLS experienced moderate-to-severe pain that had a negative effect on QOL. Subjects receiving the rotigotine patch at doses of 1, 2, or 3 mg every 24 hours achieved significant reductions in the International Restless Legs Syndrome Rating Scale sum scores by 2.09 to 2.55 points compared with a reduction of 1.34 points for the placebo patients.

Quality of life was also improved with rotigotine, Dr. Kohnen said. At baseline, 60% of subjects rated themselves as being moderately to extremely impaired because of pain. In this subgroup, after 6 months of treatment, the mean change in RLS–QOL for item 8 in the rotigotine groups was significantly greater than that observed with placebo (P < 0.01). Among rotigotine-treated patients, 60% reported improvement of at least 2 points compared with 44% in the placebo group. Among the rotigotine group, one-third no longer reported impairment from pain compared with 19% in the placebo group.

“Rotigotine works in restless legs syndrome,” Dr. Kohnen concluded, “and those who have pain and resulting mood problems can expect that these symptoms will decrease or disappear.”

The Neupro patch is currently available in Europe but was removed from the U.S. market in 2008 because of a formulation problem. The patch is expected to be approved in the U.S. again in 2012.1

IncobotulinumtoxinA (Xeomin) Injections For Cervical Dystonia: A Repeated-Dose Study

  • Hubert Fernandez, MD, Head, Movement Disorders, The Cleveland Clinic Foundation, Cleveland, Ohio

Although the customary interval for cervical dystonia injections in clinical trials of incobotulinumtoxinA (Xeomin, NT-201, Merz) has been 3 months, the effect and importance of flexible injection intervals with botulinum toxin are unknown, Dr. Fernandez said in an interview. He noted that when patients are receiving injections at fixed intervals, they often comment that they either don’t need an injection yet or that they needed one sooner.

IncobotulinumtoxinA is purified botulinum toxin type A, free from accessory proteins with a low immunogenic potential. To compare the safety and efficacy of incobotulinumtoxinA across flexible dosing intervals in a repeated-dose, double-blind study in adults with cervical dystonia, Dr. Fernandez enrolled 214 patients (mean age, 53 years) in an open-label extension trial. All of the subjects had primary cervical dystonia of a predominantly rotation form. They were randomly assigned to receive either 120-unit or 240-unit doses at freely chosen intervals based on the perceived need for re-treatment. The maximum extended treatment period was 48 weeks, and safety was evaluated for up to an additional 20 weeks.

The primary outcome measure was the mean change in scores on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS–Total) 4 weeks after each of five injection sessions. The TWSTRS–Total score comprises three scales based on severity, pain, and disability.

Dr. Fernandez reported that 22.5% of patients requested injection intervals with a median of 10 weeks or less; 46.8%, between 10 and 12 weeks, 19.4%; between 12 and 14 weeks; and 33.5%, 14 weeks or more. Mean TWSTRS-Total scores were significantly improved with both doses (P < 0.001). He said:

Low and high doses were generally equally tolerated and equally efficacious on the TWSTRS–Total score—except that with the higher dose, the severity subscale was better. Patients who got the lower dose, one much lower than Americans are used to, were equally satisfied with their pain and disability improvements. So you don’t need that high a dose to improve disability and pain.

The overall occurrence of treatment-emergent adverse events (AEs) was similar between the groups (P = 0.1117). Dysphagia, the main side effect, was more common with the higher dose.

“The need to consider the advantages of customizing the frequency of injections is one take-home message, and the other is that you need to listen to your patients when they say ‘I don’t need it yet’ or ‘I need it sooner,’ ” Dr. Fernandez said.

The study was supported by Merz Pharmaceuticals. Dr. Fernandez disclosed that he is chair of the Merz publication committee and is on the Merz speaker’s bureau.

IncobotulinumtoxinA (Xeomin) Injections For Blepharospasm: A Repeated-Dose Study

  • Matthew Brodsky, MD, Assistant Professor of Neurology, Oregon Health & Science University, Portland, Ore.

Blepharospasm, the involuntary contraction of eyelid muscles, can be very disabling, with some patients rendered functionally blind. In previously presented results of a placebo-controlled clinical trial of initial treatment lasting for up to 20 weeks, incobotulinumtoxinA (Xeomin) provided significant improvements in blepharospasm clinical scores and was well tolerated compared with placebo. Data on long-term blepharospasm treatment with botulinum toxin type A have been lacking, Dr. Brodsky said.

Injection intervals in prospective trials have typically been 12 weeks. Third-party payers, Dr. Brodsky commented in an interview, often do not pay for injections given more often than every 91 days, in part out of concern that immunogenicity may evolve or loss of effect may occur. Treatment effects seem to wear off, however, no matter how well treatment has been optimized in some patients, at 6 or 8 weeks or even earlier.

“We were interested to see if more frequent injections would create immunogenicity or loss of effect,” Dr. Brodsky said.

In a 48- to 69-week treatment extension trial (plus up to 20 weeks for a safety evaluation), patients were treated at five or fewer injection sessions (50 units or less per eye per session) at intervals of 6 weeks or more, as determined by the discretion of the physician and patient. All patients had Jankovic Rating Scale (JRS) severity subscores of 2 or higher. In a post hoc analysis, 102 patients (mean age, 62.2 years; 64.7% women) were stratified into median injection intervals of 10 weeks or less, between 10 and 12 weeks, between 12 and 14 weeks, and less than 1 week.

The primary outcome was the mean change in JRS sum scores from each injection session to a control visit 6 weeks later. Significant improvements were observed for all interval groups (P < 0.001). The baseline mean JRS sum score of 5.9 was reduced to approximately 3.5 at the control visits. Treatment-emergent AEs were experienced by 79.4% of subjects in each interval group; the most frequently occurring AEs were eyelid ptosis, dry eye, visual disturbances, nasopharyngitis, and upper respiratory tract infections. Treatment-emergent AEs were experienced by 95.7% of patients receiving injections at intervals of between 12 and 14 weeks and by 81.8% of patients receiving injections at intervals of 10 weeks or less.

Dr. Brodsky commented:

... We found that patients continued to have a significant response going out to five treatments. We saw also that those who were re-injected in under a 10-week interval over a year had no loss of clinical response—which should be encouraging for patients who require treatment more frequently.

Dr. Brodsky expressed hope that payers will reimburse health care providers for the injections at more frequent intervals after prospective clinical trials with sensitive antibody assays have been conducted.

Carbidopa/Levodopa (IPX066) in Advanced Parkinson’s Disease: The ADVANCE–PD Trial

  • Robert A. Hauser, MD, MBA, Professor of Neurology, University of South Florida, Tampa, Fla.

Whereas immediate-release (IR) carbidopa/levodopa has a half-life of 1.5 hours, IPX066 (Impax/GlaxoSmithKline) is a carbidopa/levodopa extended-release capsule formulation that rapidly attains therapeutic concentrations and maintains them for a prolonged period, Dr. Hauser said.

Dr. Hauser and colleagues conducted a phase 3 randomized trial among 393 patients with advanced Parkinson’s disease (PD) (mean age, 63 years) with motor fluctuations. For all patients, the IR doses were converted to the extended-release (ER) doses of IPX066 over a 6-week open-label phase. The patients were then entered into a 13-week double-blind, randomized, parallel-group study of IPX066 in comparison with IR carbidopa/levodopa.

The primary efficacy measure was the percentage of “off-time” (periods with PD symptoms) during waking hours based on the subjects’ diaries. At the end of the study, mean reductions in off-time were 35.4% in the IPX066 group and 17.2% in the IR carbidopa/levodopa group (P < 0.0001). Mean off-time, which had improved by more than 2 hours in the open-label phase, was maintained at 2.2 hours in subjects who received IPX066, but worsened significantly by 1 hour in those receiving IR carbidopa/levodopa at all measured time points (P < 0.0001). Other significant reductions with IPX066, compared with IR carbidopa/levodopa, were as follows:

  • Unified Parkinson’s Disease Rating Scale (UPDRS) (−5.7 vs. −2.1; P < 0.0001)
  • Patient Global Impression (PGI) Scale (67.5% vs. 42.3%; P < 0.0001)
  • Clinical Global Impression (CGI) Scale (66% vs. 44.2%; P < 0.0001)

The improvements, Dr. Hauser noted, were not associated with clinically significant worsening of dyskinesia, and the frequency of AEs was similar in groups during the double-blind phase. The mean dosing frequency of IPX066 was 3.6 times per day, and that of IR carbidopa/levodopa was 5.1 times per day.

“For moderate-to-advanced Parkinson’s disease patients who are experiencing fluctuations on immediate-release carbidopa/levodopa,” Dr. Hauser said in an interview, “you should be able to switch them over to IPX066, dose it less frequently, and patients will do better with more ‘on-time’ and less ‘off-time’ through the day—and, I think, the effect is large.”

He concluded, “IPX066 significantly improved efficacy over immediate-release carbidopa/levodopa in key Parkinson’s disease measures.”

Inaugural Melanoma and Cutaneous Malignancy Meeting

On June 25 and 26, 2011, a new annual Continuing Medical Education (CME) meeting, “HemOnc Today: Melanoma and Cutaneous Malignancies,” was introduced in New York City with the goal of updating oncologists and dermatologists. This first gathering included 115 specialists. Three key sessions are reviewed, two on interferon and one on novel intralesional therapies—Allovectin, OncoVex, and Rose Bengal.

Adjuvant Therapy With Intermediate-Dose Interferon in Melanoma: The NORDIC IFN Trial

  • Johan Hansson, MD, PhD, Senior Physician and Associate Professor, Karolinska Institute, Stockholm, Sweden

Results from the European Organization for Research and Treatment of Cancer (EORTC 18952) trial of postsurgical adjuvant therapy with intermediate-dose interferon (IFN) alfa 2b, when compared with observation, showed little benefit for extending treatment to 2 years at doses of 10 million Inter -national Units (IU) once daily for 4 weeks, 10 million IU three times weekly for 12 months versus 10 million IU once daily for 4 weeks, and 5 million IU three times weekly for 24 months.

Enrolled patients (n = 1,286) had resected stage IIB or TxN1–2M0 melanoma. Although there was no benefit in survival or distant metastasis-free survival, the primary endpoint of the distant metastasis-free interval was met marginally (hazard ratio [HR], 0.83; P = 0.05) for the 24-month treatment group compared with observation.

A subgroup analysis showed an overall survival benefit in the stage IIb group (no lymph node metastases, HR = 0.54), a lesser advantage in the stage III N1 patients (microscopic lymph node metastases, HR = 0.73), and no benefit in stage III N2 patients (clinically palpable nodal involvement, HR = 0.97).

The phase 3 Nordic Adjuvant Interferon Melanoma Trial (NORDIC IFN), conducted in Denmark, Finland, Norway, and Sweden, used the same protocol as EORTC 18952, but the maintenance phase was at 10 million IU in both the 12- and 24-month arms, and the primary endpoint was overall survival.2 No overall survival benefit was seen compared with observation; however, relapse-free survival was significantly improved with 1 year of treatment (P = 0.034) but not with 2 years of treatment (P = 0.178).

Relapse-free survival benefits were also noted in patients with palpable nodal metastases (stage III) and in those with more than one metastasis. Unlike some other trials, NORDIC IFN did not demonstrate any beneficial effects on ulceration. Dr. Hansson emphasized that these subgroup findings are merely hypothesis-generating.

He concluded, “Intermediate-dose interferon has significant effects on relapse-free survival but not on overall survival.”

He added, “Clearly, interferon has some effect, but it is a very limited, diluted one. It would be very advantageous to be able to do personalized, adjuvant IFN therapy.”

The search for predictive markers of benefit is ongoing, he said, and includes cytokine panels, serum markers, and tumor gene expression profiles.

The study drug was later approved as Sylatron. The study was funded by Merck.

Optimal Adjuvant Interferon Therapy For Melanoma: 1 Month, 1 Year, or 5 Years?

  • Vernon K. Sondak, MD, Chair, Department of Cutaneous Oncology, Moffit Cancer Center; and Professor, Departments of Surgery and Oncologic Sciences, University of South Florida College of Medicine, Tampa, Fla.

As recently as 2009, there was no approved therapy that consistently prolonged the survival of patients with metastatic melanoma, and all that could be acknowledged about adjuvant therapy was that it was “the best potential way to alter the natural history of high-risk melanoma patients,” Dr. Sondak said. (High-risk melanoma refers to a tumor larger than 4 mm or positive lymph nodes.) In 2011, however, the human monoclonal antibody ipilimumab (Yervoy, Bristol-Myers Squibb) and targeted therapy (for oncogene-mutated tumors) have been shown to prolong survival consistently in patients with metastatic disease. An understanding of their optimal use is still evolving. Furthermore, it is clear that adjuvant therapy is now the “bridge” between treatment of primary and stage IV disease.

Attention also needs to be directed, Dr. Sondak emphasized, to patients with intermediate-risk melanoma (sentinel-node negative and tumor thickness, 2 to 3.5 mm). Although these individuals have only a 15% risk of death, they outnumber sentinel node–positive patients by a factor of five.

Reviewing data on the various durations of IFN regimens, Dr. Sondak said that 1 year of high-dose IFN improved relapse-free survival compared with observation or ganglioside vaccine in patients with metastatic melanoma. Further, in a meta-analysis of 14 studies, IFN improved relapse-free survival by 18% (P < 0.001).3

An 840-patient trial of low-dose IFN (Roferon-A, Roche; discontinued in the U.S.) that compared 18 months and 60 months of treatment found virtual equivalence (P = 0.72) for the two approaches.4 Another trial comparing 1 month of IFN with observation in 975 patients revealed median relapse-free survival of 7.3 and 7.8 years, respectively (P = 0.690), with 5-year overall survival rates of 0.82 and 0.85, respectively (P = 0.387).5

Dr. Sondak stated, “The available data suggest that 1 year of high-dose interferon, several years of lower-dose interferon, and 5 years of peginterferon are all associated with significant improvement in relapse-free survival.”

He noted further that head-to-head data comparing these options are insufficient—even though the large-scale phase 3 Eastern Cooperative Oncology Group (ECOG) Study E1690 favored 1 year of high-dose IFN—and that the available data do not support 1 month of intravenous IFN.

“It cannot be recommended,” he said.

Meta-analyses of the impact of high-dose IFN on overall survival at 2 years and of adjuvant IFN at various doses and durations on overall survival revealed significant improvements at 15% (P = 0.03) and at 11% (P = 0.002).

Dr. Sondak pointed out that although additional comparative trials are clearly needed, results are years away.

“Adjuvant interferon still has a role to play, even in an era of new drugs that improve survival for stage IV melanoma patients,” he said.

Regarding new adjuvant therapies, he noted that those treatments that improve overall survival will clearly find a role, regardless of toxicity. Those that improve only relapse-free survival will also find a role, depending on toxicity. Finally, preference will be given to those agents for which there are reliable pretreatment predictors of benefit or resistance.

Intralesional Therapies With Allovectin, OncoVex, and Rose Bengal: Locoregional Control and Systemic Response

  • Merrick Ross, MD, M.D. Anderson Cancer Center, Houston, Texas

Patients with unresectable, multiple, or advanced locally and regionally metastatic stage IIIb/c or stage IV M1a melanoma, whose tumors are accessible for direct injection, are candidates for intralesional therapy, whether or not they have metastatic disease. They represent 2.3% to 6.5% of patients with primary melanomas and include high-risk groups with thick or ulcerated lesions, positive sentinel lymph nodes, and lower-extremity tumors. Morbidity is significant, and the risk of metastases and death is greater than 50%.

After injections of bacille Calmette-Guérin (BCG) into intracutaneous metastases induced resolution of 17 injected and 47 non-injected tumors in a 77-year-old man, initial interest in intralesional therapy waned when disseminated BCG led to anaphylactic reactions and death in a subsequent trial.6

Other agents and approaches have included carbon dioxide lasers, cryotherapy, electrochemotherapy (electroporation), and cytokines, such as interleukin-2 (IL-2) and IFN alfa-2a and alfa-2b. IL-2 produced overall response rates of 70% to 80% and complete response rates of 62.5% to 69%. However, this approach was time-intensive and costly, and it failed to demonstrate regression of non-injected lesions.

Recent interest has been intensified by three promising agents that are locally ablative and systemically active:

  • Allovectin-7 (Vical, Inc.) is an HLA-B7/beta2-microglobulin plasmid formulated with cationic lipids. Potential mechanisms of action include induction of allogeneic responses against HLA-B27, up-regulation and restoration of major histo-compatibility complex (MHC) molecules, and induction of pro-inflammatory responses by the plasmid DNA/lipid complex. In a phase 2 trial of 133 patients, the overall response rate was 12%, with no grade 3 or higher toxicities. A phase 3 trial is ongoing.
  • OncoVexGM–CSF (Amgen/BioVex) is an oncolytic Herpes simplex virus encoding granulocyte–macrophage colony-stimulating factor (GM–CSF). This agent is thought to work by replicating only in tumor cells and by lysing injected tumors. Lysed cells are then taken up by antigen-presenting cells (APCs). An adaptive anti-melanoma response, enhanced by local expression of GM–CSF, may also occur. In a phase 2 trial, the objective response rate was 28%, with regression of injected and non-injected lesions. A phase 3 trial is ongoing.
  • PV-10, made by Provectus, is a sterile, non-pyrogenic solution of Rose Bengal disodium (10% solution). This small-molecule, fluorescein derivative has been used as a hepatic diagnostic agent, 131I-radiolabeled Rose Bengal and Robengatope (Bracco, discontinued), and as a topical ophthalmic diagnostic (Rosettes and Minims).
  • PV-10 accumulates only in lysosomes of cancer cells, eliciting acute autophagy within 30 to 60 minutes. The “bystander” (anticancer) effect is thought to occur after acute exposure of antigenic tumor fragments to APCs.

    In phase 2 testing among 80 subjects with stage III/IV melanoma at seven centers in Australia and the U.S., loco-regional control (complete response + partial response + stable disease) was reported in 71% of patients and in 55% of those with bystander lesions. The complete response rate was 24% in both target and bystander lesions. Bystander responses correlated highly with positive objective responses in the target lesions. No grade 4 or 5 adverse events were reported. A phase 3 trial of PV-10 is being designed.

    Trials of novel combinations (e.g., PV-10 injections for bulky disease, followed by external beam radiotherapy)7 or high-dose intralesional IL-2 with topical imiquimod (Aldara, 3M) and retinoid cream8 may be followed by combinations with new agents targeting BRAF (proto-oncogene B-Raf) mutations; anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4); or programmed cell death protein-1 (PD-1). PD-1, which is encoded by the PDCD1 gene, is also known as CD279 (cluster of differentiation 279).

    Dr. Ross said in an interview:

    These agents have heightened interest into a field that people have become kind of ‘ho-hum’ about. Some of the data are relatively compelling and there’s special interest with regard to patients with comorbidities who can’t tolerate other aggressive therapies—for example, elderly patients who can’t tolerate any level of toxicity, which these drugs rarely have.

    References

    1. Okun M. National Parkinson Foundation: Update on Neupro Patch, April 26, 2010. Available at: www.parkinson.org/About-Us/Press-Room/Press-Releases/2010/April/A-Message-from-NPF-on-Neupro-Reformulation. Accessed August 10, 2011
    2. Hansson J, Aamdal S, Bastholt L, et al. Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN Trial): A randomised phase 3 trial. Lancet Oncology 2011;12:144–152.
    3. Mocellin S, Pasquali S, Rossi CR, et al. Interferon alpha adjuvant therapy in patients with high-risk melanoma: A systematic review and meta-analysis. J Natl Cancer Inst 2010;102:493–501.
    4. Hauschild A, Weichenthal M, Rass K, et al. Efficacy of low-dose interferon alfa-2a 18 versus 60 months of treatment in patients with primary melanoma of ≥1.5-mm tumor thickness: Results of a randomized phase III DeCOG [Dermatologic Cooperative Study Group] trial. J Clin Oncol 2010;28:841–846.
    5. Agarwala SS, Lee SJ, Flaherty LE, et al. Randomized phase III trial of high-dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with intermediate- and high-risk melanoma (Intergroup trial E 1697) (Abstract 8505). American Society of Clinical Oncology meeting, 2011. J Clin Oncol 2011;29;(Suppl):
    6. Mastrangelo MJ, Bellet RE, Berkelhammer J, et al. Regression of pulmonary metastatic disease associated with intralesional BCG therapy of intracutaneous melanoma metastases. Cancer 1975;36;(4):1305–1308.
    7. Foote MC, Burmeister BH, Thomas J, et al. A novel treatment for metastatic melanoma with intralesional rose bengal and radio-therapy: A case series. Melanoma Res 2010;20;(1):48–51.
    8. Garcia MS, Ono Y, Martinez SR, et al. Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream. Melanoma Res 2011;21;(3):235–243.