BOLETIN DE INFORMACIÓN ONCOLÓGICO

Abril 2015 Vol 5 (3) Biblioteca INOR

MELANOMA

El melanoma es un tumor maligno compuesto por melanocitos, células que producen el pigmento melanina y se derivan de la cresta neural. Aunque la mayoría de melanomas se presentan en la piel, también pueden surgir en las superficies mucosas o en otros sitios a los que migran las células de la cresta neural, incluida la vía uveal. Los melanomas uveales difieren, en gran medida, del melanoma cutáneo en la incidencia, los factores pronósticos, las características moleculares y el tratamiento.

El melanoma representa menos de 5% de los casos de cáncer de piel, pero es la causa de la mayoría de muertes. La incidencia de cáncer de piel se ha triplicado en las tres últimas décadas. En el mundo se registran anualmente de 2 a 3 millones de casos de cáncer de piel no melanoma y 160,000 casos de melanoma maligno Los hombres de edad avanzada tienen el riesgo más alto; sin embargo, el melanoma es el cáncer más frecuente en los adultos jóvenes entre 25 y 29 años, y el segundo cáncer más frecuente en aquellos entre 15 y 29 años

En Cuba, se notifican alrededor de mil casos de cáncer no melanoma, basocelular y espinocelular, que ocupan el segundo lugar en la tabla general de tumores malignos. Según informes estadísticos de salud, en el 2010 fallecieron 388 personas por esta causa, para una tasa de 4 x 100 000 habitantes, con predominio del sexo masculino y mayores de 60 años. El carcinoma basocelular es el más frecuente y menos agresivo, el melanoma es menos frecuente pero de alta agresividad, siendo mortal rápidamente en ocasiones, y el espinocelular, intermedio entre los 2 anteriores

Más de 50% de los casos surgen en áreas aparentemente normales de la piel. Aunque el melanoma puede surgir en cualquier sitio, incluidas las superficies mucosas y la úvea, en

las mujeres se presenta, con mayor frecuencia, en las extremidades y, en los hombres, en el tronco, la cabeza o el cuello. El melanoma ocular es el cáncer de ojo más frecuente; cada año, se diagnostican aproximadamente 2.000 casos.

Los factores de riesgo del melanoma son tanto intrínsecos (genéticos y fenotípicos) como extrínsecos (ambientales o de exposición):

Exposición solar. Características pigmentarias. Nevos múltiples. Gran número de lunares (en especial si superan los 100). Antecedentes familiares y personales de melanoma. Inmunodepresión.

El diagnóstico histopatológico de la enfermedad en estadios tempranos, permite diagnosticar precozmente la misma y brinda mayor posibilidad de tomar decisiones efectivas, en cuanto a la conducta a seguir para mejorar la supervivencia de la enfermedad, con mejoras en la calidad de vida de los pacientes.

A continuación presentamos diferentes secciones: Libros digitalizados que se encuentran el la biblioteca, Referencias con resúmenes y artículo completo.

Lic . Sol María López.

Ref: Día del lunar en Cuba.Rev.Ciencias. Med. 2012sept-oct 2014;18 (5)

http://www.cancer.gov

Libros y capítulos digitalizados, sobre melanoma, que posee nuestra bibliotecay los que usted puede copiar.

From melanomacytes to melanoma. The progression to malignancy 2006 Human Press.

Oncología Médica 2005 Capítulos:

Tumores de piel. Cáncer de piel no melanoma. Melanoma Maligno. Melanoma ocular.

Referencias :

MELANOMA AND RADIOTHERAPY

1.Middle East Afr J Ophthalmol. 2015 Jan-Mar;22(1):103-7. doi: 10.4103/0974-

9233.148358.

Regression rate of posterior uveal melanomas following iodine-125 plaque radiotherapy.

Demirci H1, Saponara F1, Khan A1, Niziol LM1, Lee C2, Hayman JA2, Comer G1, Musch DC3.

Abstract

AIM: melanoma following radioactive iodine-125 (I-125) plaque.

2.J Transl Med. 2014 Sep 23;12:262. doi: 10.1186/s12967-014-0262-6.

Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.Ridolfi L, de Rosa F, Ridolfi R, Gentili G, Valmorri L, Scarpi E, Parisi E, Romeo A, Guidoboni M.

Abstract

BACKGROUND: melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines.

3.J Transl Med. 2014 Jul 22;12:209. doi: 10.1186/1479-5876-12-209.

Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN- in patients with metastatic melanoma: a randomised α"proof-of-principle" phase II study.

de Rosa F, Ridolfi L1, Ridolfi R, Gentili G, Valmorri L, Nanni O, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E, Soldati V, Cassan S, Riccobon A, Parisi E, Romeo A, Turci L, Guidoboni M.

Abstract

BACKGROUND: melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed.

4.BMC Res Notes. 2014 Jun 30;7:412. doi: 10.1186/1756-0500-7-412.

Accrual to a randomised trial of adjuvant whole brain radiotherapy for treatment of melanoma brain metastases is feasible.

Fogarty GB1, Hong A, Jacobsen KD, Reisse CH, Shivalingam B, Burmeister B, Haydu LE, Paton E, Thompson JF.

Abstract

BACKGROUND:

melanoma patients. Adjuvant whole brain radiotherapy (WBRT) following local treatment of intracranial melanoma metastases with neurosurgery and/or stereotactic radiosurgery is controversial. A randomised trial is needed. However, accrual to WBRT trials has been problematic. A pilot study by Australia and New Zealand Melanoma Trials Group (ANZMTG) was conducted to see if accrual was feasible.

MELANOMA AND DRUG THERAPY1.Cancer Cell. 2015 Jan 12;27(1):85-96. doi: 10.1016/j.ccell.2014.11.006. Epub 2014 Dec 11.

Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.

Girotti MR1, Lopes F2, Preece N2, Niculescu-Duvaz D2, Zambon A2, Davies L2, Whittaker S2, et all.

Abstract

melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.

2.JAMA. 2014 Nov 5;312(17):1744-53. doi: 10.1001/jama.2014.13943.

Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial.

Hodi FS1, Lee S2, McDermott DF3, Rao UN4, Butterfield LH5, Tarhini AA5, Leming P6, Puzanov I7, Shin D2,

Kirkwood JM5.

Abstract

IMPORTANCE: melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade.

OBJECTIVE: melanoma.

DESIGN, SETTING, AND PARTICIPANTS: melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1.

INTERVENTIONS:

MAIN OUTCOMES AND MEASURES:

RESULTS:

CONCLUSION AND RELEVANCE: melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up.

3.Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12722-7. doi: 10.1073/pnas.1413027111. Epub 2014 Aug 19.

Refilling drug delivery depots through the blood.

Brudno Y1, Silva EA2, Kearney CJ3, Lewin SA4, Miller A5, Martinick KD4, Aizenberg M4, Mooney DJ6.

Abstract

drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN-carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.

4.Biomed Res Int. 2014;2014:895986. doi: 10.1155/2014/895986. Epub 2014 Jul 2.

Drug delivery nanoparticles in skin cancers.

Dianzani C1, Zara GP1, Maina G2, Pettazzoni P3, Pizzimenti S2, Rossi F4, Gigliotti CL5, Ciamporcero ES2, Daga M2,

Barrera G2.

Abstract

drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported.

MELANOMA AND SURGERY

1.Int J Surg Oncol. 2014;2014:987170. doi: 10.1155/2014/987170. Epub 2014 Oct 28.

Emergency surgery for metastatic melanoma.

Mantas D1, Tsaparas P1, Charalampoudis P1, Gogas H2, Kouraklis G1.

Abstract

melanoma (stage M1c) confer a very poor prognosis, as documented on the most recent revised version of the TNM/AJCC staging system. Emergency surgery for intra-abdominal complications from the disease is rare. We report on our 5-year single institution experience with surgical management of metastatic melanoma to the viscera in the emergent setting.

From 2009 to 2013, 14 patients with metastatic melanoma were admitted emergently due to an acute abdomen. Clinical manifestations encompassed intestinal obstruction and bleeding. Surgical procedures involved multiple enterectomies with primary anastomoses in 8 patients, and one patient underwent splenectomy, one adrenalectomy, one right colectomy, one gastric wedge resection, one gastrojejunal anastomosis, and one transanal debulking, respectively. The 30-day mortality was 7 percent. Median follow-up was 14 months. Median overall survival was 14 months. Median disease free survival was 7.5 months. One-year overall survival was 64.2 percent and 2-year overall survival was 14.2 percent. Emergency surgery for metastatic melanoma to the viscera is rare. Elective curative surgery combined with novel cytotoxic systemic therapies is under investigation in an attempt to grant survival benefit in melanoma patients with visceral disease.

2.Cancer Med. 2014 Jun;3(3):565-71. doi: 10.1002/cam4.206. Epub 2014 Feb 10.

Gamma Knife radiosurgery to four or more brain metastases in patients without prior intracranial radiation or surgery.

Ojerholm E1, Lee JY, Kolker J, Lustig R, Dorsey JF, Alonso-Basanta M.

Abstract

surgery who received Gamma Knife (GK) as sole treatment to ≥4 brain metastases in a single session. Twenty-eight cases with follow-up imaging were analyzed for intracranial progression. Prognostic factors were examined by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. Common primary tumors were non-small cell lung (45%), melanoma (37%), and breast (8%). Cases were recursive partitioning analysis class II (94%) or III (6%). Patients harbored a median five tumors (range 4-12) with median total tumor volume of 1.2 cc. A median dose of 21 Gy was prescribed to the 50% isodose line. Patients survived a median 6.7 months from GK. Local treatment failure occurred in one case (4%) and distant failure in 22 (79%). On multivariate analysis, total tumor volume ≥3 cc was significantly associated with distant failure and worsened overall survival (P = 0.042 and 0.040). Fourteen patients (37%) underwent salvage WBRT at a median 10.3 months from GK and seven patients received repeat GK. GK as sole initial treatment for four or more simultaneous metastases spares some patients WBRT and delays it for others. Increased total tumor volume (≥3 cc) is significantly associated with worsened overall survival.

3.Eur J Med Res. 2013 Nov 4;18:39. doi: 10.1186/2047-783X-18-39.

Malignant melanoma of the ileo-anal pouch anastomosis after restorative proctocolectomy for ulcerative colitis: report of a case.

Lingohr P1, Galetin T, Matthaei H, Straub E, Jafari A, Bölke E, Kalff JC, Vestweber KH.

Abstract

melanoma (MM) was found after repeated biopsies of the pouch. Complete staging revealed no evidence for distant metastases and the patient underwent abdominoperineal pouch resection. Six weeks later, the patient was readmitted because of severe general deterioration and diffuse metastatic spread to the liver was found. The patient died of hepatorenal syndrome shortly thereafter.Patients with inflammatory bowel disease are at increased risk of developing cancer, including rarities such as MM. Our experience stresses the importance of repeated biopsies in therapy-refractory pouchitis.

Artículo completo.

Cancer Chemotherapy and Pharmacology

Cancer Chemother Pharmacol. 2014; 74(4): 691–697. Published online 2014 Jul 26. doi:  10.1007/s00280-014-2501-1PMCID: PMC4175037

Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide)

Chang Xia, Roberto Leon-Ferre, Douglas Laux, Jeremy Deutsch, Brian J. Smith, Melanie Frees, and Mohammed Milhem

Abstract

Purpose

To explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy.

Methods

A Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8),

and oral temozolomide 150 mg/m2/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m2/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent.

Results

Twenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65 %) were male, and 6 (35 %) were female. Eleven (64.7 %) had cutaneous melanoma, 4 (23.5 %) had ocular melanoma, and 2 (11.8 %) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1–6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24 %), anemia (12 %), neutropenia (12 %), and fatigue (12 %), as well as grade 2 leukopenia (30 %), neutropenia (23 %), nausea (23 %), and lymphopenia (18 %). The most common reason for study discontinuation was disease progression.

Conclusions

This triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.

Keywords: Melanoma, Epigenetics, Epigenetic priming, Resistance, Hypomethylation, Histone deacetylationGo to:

Introduction

Until the recent advances in immune and targeted therapeutic approaches, progress in the treatment of metastatic melanoma remained dormant for nearly two decades. The approval of the immune stimulant ipilimumab and the subsequent development of novel targeted agents against BRAF, MEK, and PD-1 have fundamentally changed the landscape of melanoma treatment. Despite the excitement generated by these novel agents, much remains to be understood and significant hurdles remain to be conquered. When individual oncogenic pathways are blocked pharmacologically, melanoma cells find ways to adapt and selectively activate alternative pathways that allow them to “escape” the effects of targeted agents. To prevent this, various trials are evaluating the combined use of drugs targeting multiple pathways simultaneously. While targeting multiple downstream effectors of these pathways might be beneficial, we believe that depriving the cells of the ability to adapt and selectively activate such pathways by targeting upstream epigenetic mechanisms might be a more effective approach.

Epigenetic manipulation is a novel approach to cancer therapy that has proven successful in the treatment of hematologic malignancies, but remains to be further explored in solid tumors. Epigenetic alterations contribute to melanomagenesis by down-regulating tumor suppressor genes, apoptotic mediators, and DNA repair enzymes [1]. They also appear to be an important driving force in resistance mechanisms to multiple therapies. There is evidence that epigenetic silencing may contribute to resistance to chemotherapeutics and that drugs targeting epigenetic mechanisms may enhance chemosensitivity [2, 3]. Epigenetic drugs also appear to enhance the endogenous anti-tumor immune response via several mechanisms including, but not limited to, increased expression of cancer-testis antigens [4–14]. Furthermore, epigenetic drugs have shown the ability of reconstituting the functionality of apoptotic processes that, when deregulated, appear to play a crucial role in the resistance to chemotherapeutics [15], immune responses [11, 16], and targeted agents such as BRAF and MEK inhibitors [17, 18]. These, along with many other potential mechanisms, support the notion that epigenetic modifications represent a global mechanism for treatment resistance in melanoma.

In this Phase I trial, we explore the safety and tolerability of combining two epigenetic drugs: decitabine [a DNA methyltransferase (DNMT) inhibitor] and panobinostat [a histone deacetylase (HDAC) inhibitor], with traditional chemotherapy with temozolomide (an alkylating agent), setting the stage of epigenetic interruption of melanoma cell resistance. This trial started enrolling patients when temozolomide was a standard treatment for metastatic melanoma, prior to the approval of ipilimumab and subsequent targeted therapies. The primary objective of this trial was to evaluate the safety and tolerability of this triple agent regimen at previously defined doses. Since the use of decitabine in this trial was aimed at achieving epigenetic modification and not cytotoxicity, decitabine was administered at low doses known to cause hypomethylation. Panobinostat was dose-escalated as shown in Table 1. Temozolomide was administered at standard doses. While our model tested epigenetic drugs in combination with chemotherapy, we believe that a similar approach could be used with the newer immune and targeted therapies.

Table   1 Doses of decitabine and panobinostata Go to:

Materials and methods

Patients and eligibility criteria

Eligible participants included male or female patients that were 18 years of age or older, with recurrent or unresectable stage III or IV melanoma of any site. Since we sought to

evaluate enhancement of chemosensitivity by epigenetic drugs, this trial enrolled patients with inherently aggressive and resistant disease, including noncutaneous melanoma like ocular and mucosal; patients with brain metastases, after the brain disease was adequately addressed either by whole brain radiation, radiosurgery, or resection; and patients that had progressed during or after their most recent treatment. Eligibility criteria also included adequate liver, renal, cardiac and bone marrow function; normal electrolytes; normal thyroid function (or on adequate replacement doses); normal LVEF by MUGA or echocardiogram; measurable disease per RECIST 1.0 criteria; and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Previously treated or treatment-naïve patients were both eligible, except those who had previously received valproic acid, HSP90 inhibitors, hypomethylating agents, or HDAC inhibitors. Female patients of childbearing potential were required to not be pregnant, breast-feeding, and to use double contraception during and 3 months after study completion.

Exclusion criteria included: uncontrolled hypertension; history of ventricular fibrillation, torsades de pointes, or sustained ventricular tachycardia; heart rate <50 beats/min; congestive heart failure NYHA class III or IV; acute coronary syndrome within 6 months of study enrollment; ECG abnormalities of QTc prolongation (>450 ms), right bundle branch block or left anterior hemiblock; known HIV or hepatitis C positivity; unresolved diarrhea or significant gastrointestinal impairment potentially interfering with panobinostat or temozolomide absorption; and concomitant use of CYP3A4 inhibitors or drugs known to increase risk of torsades de pointes.

This trial was conducted with full Institutional Review Board approval. All participants provided written consent before participating. This study was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Novartis provided panobinostat and financial support for this trial.

Study treatment and dose escalation

Patients were treated with subcutaneous decitabine at a dose of 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat at a dose of 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide at a dose of 150 mg/m2/day on days 9 through 13 (Fig. 1; Table 1). In cycle 2, temozolomide dose was increased to 200 mg/m2/day if neutropenia or thrombocytopenia had not occurred. Prophylactic trimethoprim–sulfamethoxazole was not used. Each treatment cycle lasted 6 weeks, and patients could receive up to six cycles of combination treatment. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent. Maximum tolerated dose (MTD) was defined as the highest dose cohort where ≤1/6 patients experienced a dose-limiting toxicity (DLT). If a DLT was observed in the first three patients, the cohort was expanded to six patients, and all six patients needed to complete the first cycle of therapy without an additional DLT before dose escalation could proceed. Intrapatient dose escalation was not allowed. DLT was defined as grade 4 hematologic toxicity, grade ≥3 nonhematologic toxicity, or grade 2 nonhematologic or grade 3 hematologic toxicity requiring a dose

reduction or treatment interruption for more than 7 days during the first cycle. Grade 3 or 4 nausea, vomiting, or diarrhea were only considered DLTs if they occurred despite optimal medical management. Grade 3 electrolyte, uric acid, or phosphorus abnormalities were not considered DLTs if they were correctable within 1 week.

Fig.   1 Treatment schema. Cycle duration: 42 days. Decitabine: days 1, 3, 5, 8, 10, 12. Panobinostat: days 8, 12, 16, 20, 24, 28, 32, 36, 40. Temozolomide: days 9–13

In cycle 2, dose was increased to 200 mg/m2/day if there was no neutropenia or thrombocytopenia.

Safety and response assessments

Patients were assessed for safety every 2 weeks during the first two cycles and then once every cycle. CBC with differential and serum chemistries were obtained once a week during the first two cycles and every 2 weeks thereafter. ECGs were performed prior to and following the first dose of panobinostat during cycle 1, and then on day 8 of every subsequent cycle. Toxicity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Tumor response was assessed using whole body FDG PET–CT or CT scan after two cycles of treatment. Response was determined based on the response evaluation criteria in solid tumors (RECIST).

Go to:

Results

Patient characteristics

Twenty patients were enrolled in the Phase I portion of this study. One patient had rapid progression of disease and was not treated with the protocol. One patient did not meet eligibility criteria due to untreated brain metastases. One patient withdrew consent. A total of seventeen patients received treatment. Characteristics are listed in Table 2. The median age was 56 years. Eleven (65 %) were male, and 6 (35 %) were female. Eleven (64.7 %) had cutaneous melanoma, 4 (23.5 %) had ocular melanoma, and 2 (11.8 %) had mucosal melanoma.

Table   2 Patient characteristics (n = 17)

Exposure to treatment and clinical toxicities

All seventeen patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1–6). The dose escalation schema and number of patients enrolled in each cohort are described in Table 1. None of the patients experienced DLT. One patient in cohort 3 had grade 4 neutropenia that resolved within 3 days and did not meet criteria to be categorized as DLT. MTD was not achieved. Adverse events in each cohort are summarized in Table 3. These included grade 3 lymphopenia (24 %), anemia (12 %), neutropenia (12 %), and fatigue (12 %), as well as grade 2 leukopenia (30 %), neutropenia (23 %), nausea (23 %), and lymphopenia (18 %). The most common reason for study discontinuation was disease progression.

Table   3 Summary of adverse events

The majority of the adverse events occurred in cohort 3. Of the 10 adverse events observed, only 8 were deemed to be treatment related (hypokalemia and back pain were not treatment related). Subjects’ characteristics and underlying disease might have contributed to the relatively high occurrence of adverse events in Cohort 3. Two out of the four subjects in cohort 3 were withdrawn from the study due to rapid disease progression and died shortly after.

Treatment efficacy

Of the 17 patients treated, 9 were considered nonevaluable for efficacy given that they did not complete two cycles of therapy due to early disease progression. Among eight patients evaluable for radiographic response, 6 (75 %) had either stable disease (5, 62.5 %) or complete response (1, 12.5 %). The patient with the complete response had mucosal

melanoma and had the best response after two cycles of therapy. Response lasted for 8 months. Of the five patients with stable disease, two were from Cohort 1, two from Cohort 3, and one from Cohort 4. The two remaining patients (25 %) had progressive disease after two cycles of therapy (Table 4).

Table   4 Response assessment (by RECIST criteria)Go to:

Discussion

The field of epigenetics might offer a novel approach to the treatment of melanoma that could potentially add to the recent progress in immune and targeted therapies. Though significantly explored in hematologic malignancies, epigenetic therapeutic approaches have lagged behind in solid tumors. It has been well established that epigenetic processes, specifically DNA promoter methylation and histone acetylation/deacetylation, are key cellular events during tumorigenesis [19]. Moreover, melanoma cells appear to use the epigenetic apparatus to “adapt” and acquire resistance to external offenders such as chemotherapeutics [15], the immune system [11, 16], and even the newer targeted agents [17, 18]. In this Phase I trial, we explored the safety and tolerability of traditional chemotherapy combined with dual epigenetic therapy with sequential DNMT and HDAC inhibition. We used temozolomide, a known standard agent for metastatic melanoma prior to 2011, combined with decitabine and panobinostat.

During DNA methylation, a methyl group is added to cytosine in CpG islands located predominantly in promoter regions, resulting in the silencing of genes regulated by the affected promoter. Abnormal genetic silencing by DNA methylation appears to modulate cancer biology and development of drug resistance [20]. Decitabine is a powerful DNMT inhibitor that has shown the ability to impair the methylation process in numerous cancer cell lines (including melanoma), allowing the re-expression of genes that malignant cells are trying to turn off [5]. There is evidence that the doses required to achieve hypomethylation are much lower than the usual cytotoxic doses [21–23]. In addition, given that active cell cycling is required to achieve methylation reversal, prolonged courses achieve more hypomethylation than shorter courses [24]. In myeloid neoplasms, extended administration of low doses of hypomethylating agents may result in increased or sustained response rates [25]. When the goal is to achieve and maintain methylation reversal, keeping decitabine toxicity to a minimum might be key, as this allows for repeated doses and longer courses. This approach might be more effective than trying to push decitabine doses until

DLT or MTD are reached [20]. Most trials using decitabine in solid tumors have used high, toxic doses, with short administration periods [26–29]. These factors, at least partly, may account for the disappointing responses to decitabine in solid tumors, as compared to responses in hematopoietic malignancies. For these reasons, in this trial, we used low doses of decitabine in an extended dosing regimen. DLT or MTD were not reached, allowing for repeated dose administration.

In addition to promoter methylation patterns, gene expression is also highly influenced by DNA–histone interactions that regulate the ability of the transcription apparatus to access the DNA. The opposing activities of histone acetyltransferase and HDAC maintain histone acetylation patterns that lead to cell-specific gene expression profiles. Aberrant HDAC recruitment appears to play a critical role in gene expression changes seen in malignant transformed cells that allow them to block apoptotic mechanisms. HDAC inhibitors appear to reestablish apoptosis in melanoma cells [30], induce cell differentiation, and inhibit tumor growth in animal models by down-regulating positive cell cycle regulators such as cyclin D1, c-Myc, C-RAF, and AKT [31–37], while inducing the expression of a number of anti-proliferative genes [38–40]. Melanoma cells exposed to HDAC inhibitors also exhibit decreased levels of activated MEK1/2 and ERK1/2 [41], key melanomagenic kinases blocked by novel targeted agents. HDAC inhibitors may also interfere with the appropriate folding of HSP90-client proteins (including AKT and RAF) that are critical to cancer cell growth [36, 37]. HDAC inhibitors, however, are unable to reactivate the expression of genes that have been previously silenced by methylation of their promoters. This provides a rationale for the sequential use of DNMT inhibitors followed by HDAC inhibitors to provide “epigenetic synergy,” which has shown to enhance gene re-expression and drug sensitivity [42]. In this trial, we administered Panobinostat, a novel and potent HDAC inhibitor, a week after decitabine initiation. In animal studies, panobinostat has been shown to have affinity to melanin, judged by measurable drug-related radioactivity in the uveal and pigmented skin at 96 h port-dose administration (data from Novartis Investigator’s Brochure). In our study, panobinostat was administered every 96 h.

This triple agent regimen of decitabine, panobinostat, and temozolomide was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached. As discussed before, when the goal is to achieve epigenetic modulation, administration of higher doses of DNMT inhibitors might hinder the ability of patients to tolerate the frequent dosing intervals required to maintain hypomethylation throughout the treatment cycle. Maintaining hypomethylation also appears to be more important than deepening the nadir of methylation in each cycle. Given that the doses used in all cohorts proved safe, cohort 3 dose level was the recommended dose for the Phase II portion of this trial, as this is the subcutaneous dose of decitabine that has been shown to achieve successful hypomethylation [43]. This is supported by the observation of a gradual increase of hemoglobin F concentration 2 weeks after the initiation of therapy (preliminary data from Phase II, not shown) that appears to persist through the course of treatment. Patient responses in this cohort as shown in Table 4 are intriguing, especially given the inclusion of patients with ocular and mucosal melanoma, two highly chemoresistant variants of melanoma. The complete response observed in one subject with mucosal melanoma is very intriguing. This subject achieved this best response (complete response) after two cycles. Mucosal melanomas tend to have c-kit mutations and are

generally negative for B-RAF. They metastasize quite frequently, behaving differently from cutaneous melanoma. The effect of epigenetic therapy in this patient population might provide clues to the disease biology and warrants more investigation. However, the rarity of these tumors will likely make studying this subpopulation more difficult. We hypothesize that DNMT inhibition followed by HDAC inhibition target key epigenetic events that melanoma cells use to selectively turn on or off specific pathways that confer resistance to chemotherapy and apoptosis. This study started enrolling patients prior to the approval of ipilimumab and the new targeted agents that are revolutionizing the treatment of melanoma. We believe that epigenetic alterations might represent a global resistance mechanism in melanoma and other cancers. Clinical trials using a similar approach, but this time combining epigenetic agents with immune therapies and novel targeted agents such as BRAF, MEK, or PD-1 inhibitors, are warranted. This approach of crippling “upstream” epigenetic mechanisms that allow melanoma cells to adapt and acquire resistance to novel agents could prove to be an alternative to blocking multiple “downstream” effectors using multiple targeted agents.

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