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1.
N Engl J Med ; 369(19): 1783-96, 2013 Nov 07.
Article in English | MEDLINE | ID: mdl-24180494

ABSTRACT

BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).


Subject(s)
Imidazoles/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridazines/therapeutic use , Thrombosis/chemically induced , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Imidazoles/adverse effects , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Pyridazines/adverse effects , Thrombocytopenia/chemically induced , Young Adult
2.
J Clin Pharm Ther ; 38(6): 440-4, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23888935

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Ponatinib is a potent oral tyrosine kinase inhibitor with activity against BCR-ABL, the primary driver of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. This single-centre, single-dose, randomized, open-label, three-period crossover study evaluated the pharmacokinetics and bioavailability of a single oral dose of ponatinib (45-mg tablet) under fasting conditions and following consumption of high- and low-fat meals by healthy subjects. METHODS: Subjects were randomly assigned to one of the six possible treatment sequences, each evaluating three ponatinib 45-mg treatments: administered under fasting conditions; administered after a high-fat meal; or administered after a standardized low-fat meal. The high-fat meal derived approximately 50% of its total caloric content from fat, with approximately 150, 250 and 500-600 calories derived from protein, carbohydrates and fat, respectively (total of approximately 900-1000 calories). The standardized low-fat meal derived no more than 20% of total caloric content from fat, with approximately 56, 428 and 63 calories derived from protein, carbohydrates and fat, respectively (total of approximately 547 calories). During each of the three treatment periods, blood samples were collected predose and at 13 time points over the 96-h post-dose interval. Plasma concentrations of ponatinib were measured by liquid chromatography/tandem mass spectrometry. Mixed-model analyses of variance (anova) were performed on natural log-transformed PK parameters Cmax and AUC0-∞. RESULTS AND DISCUSSION: Geometric mean maximum plasma concentration (Cmax) values for the fasted, low-fat and high-fat regimens were 54·7, 51·6 and 51·5 ng/mL, respectively. Geometric mean area under the concentration-time curve from time zero to infinity (AUC0-∞) values for the fasted, low-fat and high-fat regimens were 1273, 1244 and 1392 h × ng/mL, respectively. All limits of the 90% CIs of the estimated geometric mean ratios for Cmax and all AUC comparisons fell within the 80%-125% margins. These results indicate that consumption of a high- or low-fat meal within 30 min prior to administration of ponatinib had no effect on the single-dose pharmacokinetics of ponatinib. WHAT IS NEW AND CONCLUSION: Food does not affect the single-dose pharmacokinetics of ponatinib. These data demonstrate that ponatinib may be administered with or without food.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Food-Drug Interactions , Imidazoles/pharmacokinetics , Pyridazines/pharmacokinetics , Adult , Analysis of Variance , Area Under Curve , Biological Availability , Body Mass Index , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Cross-Over Studies , Dietary Fats/pharmacology , Ethnicity , Fasting/metabolism , Female , Healthy Volunteers , Humans , Male , Middle Aged , Sex Characteristics , Tandem Mass Spectrometry , Young Adult
3.
Br J Cancer ; 108(5): 1021-6, 2013 Mar 19.
Article in English | MEDLINE | ID: mdl-23403817

ABSTRACT

BACKGROUND: This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer. METHODS: Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more. RESULTS: In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%). CONCLUSION: Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted.


Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Endometrial Neoplasms/drug therapy , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/adverse effects , Disease-Free Survival , Drug Administration Schedule , Endometrial Neoplasms/pathology , Female , Humans , Middle Aged , Retreatment , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/therapeutic use
4.
Ann Oncol ; 24(4): 1104-11, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23211938

ABSTRACT

BACKGROUND: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. RESULTS: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. CONCLUSION: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.


Subject(s)
Neoplasms/drug therapy , Sarcoma/drug therapy , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/metabolism , Adult , Aged , Aged, 80 and over , Animals , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Neoplasms/pathology , Sarcoma/pathology , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/antagonists & inhibitors , Sirolimus/pharmacokinetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , Treatment Outcome
5.
Ann Oncol ; 21(6): 1315-1322, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19901013

ABSTRACT

BACKGROUND: The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus) administered i.v. combined with paclitaxel (PTX; Taxol). MATERIALS AND METHODS: Patients with taxane-sensitive solid tumors were eligible. The main dose escalation foresaw 50% ridaforolimus increments from 25 mg with a fixed PTX dose of 80 mg/m(2), both given weekly 3 weeks in a 4-week cycle. Collateral levels with a lower dose of either drug were planned upon achievement of the maximum tolerated dose in the main escalation. Pharmacodynamic studies in plasma, peripheral blood mononuclear cells (PBMCs) and skin biopsies and pharmacokinetic (PK) interaction studies at cycles 1 and 2 were carried out. RESULTS: Two recommended doses were determined: 37.5 mg ridaforolimus/60 mg/m(2) PTX and 12.5 mg/80 mg/m(2). Most frequent toxic effects were mouth sores (79%), anemia (79%), fatigue (59%), neutropenia (55%) and dermatitis (48%). Two partial responses were observed in pharyngeal squamous cell and pancreatic carcinoma. Eight patients achieved stable disease > or =4 months. No drug interaction emerged from PK studies. Decrease of eukaryotic initiation factor 4E-binding protein1 (4E-BP1) phosphorylation was shown in PBMCs. Similar inhibition of phosphorylation of 4E-BP1 and mitogen-activated protein kinase was present in reparative epidermis and vascular tissues, respectively. CONCLUSION: Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms/drug therapy , Paclitaxel/administration & dosage , Sirolimus/analogs & derivatives , Adult , Aged , Algorithms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Disease-Free Survival , Drug Administration Schedule , Drug Interactions , Female , Humans , Injections, Intravenous , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/blood , Neoplasms/metabolism , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/pharmacokinetics , TOR Serine-Threonine Kinases , Treatment Outcome
6.
Oncogene ; 28(23): 2289-98, 2009 Jun 11.
Article in English | MEDLINE | ID: mdl-19398955

ABSTRACT

BRAF, a cellular oncogene and effector of RAS-mediated signaling, is activated by mutation in approximately 60% of melanomas. Most of these mutations consist of a V600E substitution resulting in constitutive kinase activation. Mutant BRAF thus represents an important therapeutic target in melanoma. In an effort to produce a pre-clinical model of mutant BRAF function in melanoma, we have generated a mouse expressing BRAF V600E targeted to melanocytes. We show that in these transgenic mice, widespread benign melanocytic hyperplasia with histological features of nevi occurs, with biochemical evidence of senescence. Melanocytic hyperplasia progresses to overt melanoma with an incidence dependent on BRAF expression levels. Melanomas show CDKN2A loss, and genetic disruption of the CDKN2A locus greatly enhances melanoma formation, consistent with collaboration between BRAF activation and CDKN2A loss suggested from studies of human melanoma. The development of melanoma also involves activation of the Mapk and Akt signaling pathways and loss of senescence, findings that faithfully recapitulate those seen in human melanomas. This murine model of mutant BRAF-induced melanoma formation thus provides an important tool for identifying further genetic alterations that cooperates with BRAF and that may be useful in enhancing susceptibility to BRAF-targeted therapeutics in melanoma.


Subject(s)
Melanocytes/pathology , Melanoma/pathology , Nevus/pathology , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/pathology , Amino Acid Substitution , Animals , Animals, Newborn , Blotting, Southern , Cell Line, Tumor , Cells, Cultured , Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression Profiling , Humans , Melanocytes/metabolism , Melanoma/genetics , Melanoma/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Mutation , Nevus/genetics , Nevus/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Schwann Cells/metabolism , Schwann Cells/pathology , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
7.
J Clin Oncol ; 19(3): 812-23, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11157035

ABSTRACT

PURPOSE: Although trials of adjuvant interferon alfa-2b (IFN alpha-2b) in high-risk melanoma patients suggest improvement in disease-free survival, it is unclear whether treatment offers improvement in overall survival. Widespread use of adjuvant IFN alpha-2b has been tempered by its significant toxicity. To quantify the trade-offs between IFN alpha-2b toxicity and survival, we assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a particular health state on a scale of 0 (death) to 1 (perfect health). PATIENTS AND METHODS: We assessed utilities for health states associated with adjuvant IFN among 107 low-risk melanoma patients using the standard gamble technique. Health states described four IFN alpha-2b toxicity scenarios and the following three posttreatment outcomes: disease-free health and melanoma recurrence (with or without IFN alpha-2b) leading to cancer death. We also asked patients the improvement in 5-year disease-free survival they would require to tolerate IFN. RESULTS: Utilities for melanoma recurrence with or without IFN alpha-2b were significantly lower than utilities for all IFN alpha-2b toxicities but were not significantly different from each other. At least half of the patients were willing to tolerate mild-moderate and severe IFN alpha-2b toxicity for 4% and 10% improvements, respectively, in 5-year disease-free survival. CONCLUSION: On average, patients rate quality of life with melanoma recurrence much lower than even severe IFN alpha-2b toxicity. These results suggest that recurrence-free survival is highly valued by patients. The utilities measured in our study can be applied directly to quality-of-life determinations in clinical trials of adjuvant IFN alpha-2b to measure the net benefit of therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Interferon-alpha/therapeutic use , Melanoma/drug therapy , Patient Satisfaction , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Attitude to Health , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Quality of Life , Recombinant Proteins , Risk Factors , Surveys and Questionnaires , Survival Rate
8.
Oncologist ; 6(1): 34-55, 2001.
Article in English | MEDLINE | ID: mdl-11161227

ABSTRACT

UNLABELLED: For the past 40 years, various forms of interferon (IFN) have been evaluated as therapy in a number of malignant and non-malignant diseases. With the advent of gene cloning, large quantities of pure IFN became available for clinical study. This paper reviews the biology, pharmacology, and clinical applications of IFN formulations most commonly used in oncology. It then reviews the most common side effects seen in patients treated with IFN, and makes recommendations for the management of IFN-induced toxicity. The major oncological indications for IFN include melanoma, renal cell carcinoma, AIDS-related Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, and chronic myelogenous leukemia. Unfortunately, IFN therapy is associated with significant toxicity, which can be divided into constitutional, neuropsychiatric, hematologic, and hepatic effects. These toxicities have a major impact on the patient's quality of life, and on the physician's ability to optimally treat the patient. Careful attention to all aspects of patient care can result in improved tolerability of this difficult but promising therapy. CONCLUSION: a better understanding of IFN biology, indications, side effect profiles, and toxicity management will aid in optimizing its use in the treatment of patients with cancer.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Interferons , Kidney Neoplasms/drug therapy , Leukemia, Hairy Cell/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Lymphoma, Follicular/drug therapy , Melanoma/drug therapy , Sarcoma, Kaposi/drug therapy , Skin Neoplasms/drug therapy , Bone Marrow Transplantation , Chemotherapy, Adjuvant , Combined Modality Therapy , Humans , Interferons/adverse effects , Interferons/pharmacokinetics , Interferons/pharmacology , Medical Oncology/trends , Quality of Life
9.
Arch Dermatol ; 136(9): 1118-22, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10987867

ABSTRACT

BACKGROUND: In patients with cutaneous melanoma, early age at disease onset is characteristic in familial cases and in individuals with multiple primary melanomas. Both subsets of patients with melanoma are at risk for harboring germline CDKN2A or CDK4 mutations. OBJECTIVE: We set out to prospectively determine the prevalence of CDKN2A and CDK4 mutations in a group of young patients with melanoma. DESIGN: We prospectively screened 913 patients over a 6-month period and identified 519 patients with invasive melanomas. We invited 172 patients with melanoma who were younger than 40 years to participate in the study, and 49 patients consented and donated peripheral blood samples. Forty-nine percent (n = 24) of our patients developed cutaneous melanoma before the age of 30 years. SETTING: A melanoma clinic in the Boston, Mass, area. MAIN OUTCOME MEASURE: We used a combination of single-strand conformation analysis and direct sequencing of samples of peripheral blood leukocyte DNA to search for mutations in exons 1alpha, 1beta, 2, and 3 of CDKN2A and in exon 2 of CDK4. RESULTS: The mean and median ages at diagnosis in our group were 30 and 32 years, respectively. Among a group of 49 patients, we detected 1 (2%; 95% confidence interval, 0.07%-10.8%) Met 53 Ile CDKN2A mutation, which was found in a patient with a strong family history of melanoma. This alteration has been previously shown to impair p16 function. One patient had an Ala 148 Thr change in CDKN2A, which has also been shown to be a polymorphism. We also detected a sequence polymorphism (in the 3' untranslated region [3'UTR] of CDKN2A) in 27% of our patients. A similar incidence of this 3'UTR polymorphism was observed in a control population. We found no CDK4 mutations. CONCLUSIONS: Germline CDKN2A and CDK4 mutations are not common in patients who develop melanoma at an early age. This finding contrasts with other cancer-predisposition syndromes, in which there is an increased incidence of germline mutations among young patients. Selection of patients with melanoma for genetic testing based solely on age at onset may not be warranted at the current time.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinases/genetics , Germ-Line Mutation/genetics , Melanoma/genetics , Proto-Oncogene Proteins , Skin Neoplasms/genetics , Adolescent , Adult , Cyclin-Dependent Kinase 4 , Female , Genetic Predisposition to Disease/genetics , Genetic Testing , Humans , Male , Melanoma/diagnosis , Melanoma/pathology , Prospective Studies , Sensitivity and Specificity , Skin Neoplasms/diagnosis , Skin Neoplasms/pathology
10.
Cell Immunol ; 204(1): 29-37, 2000 Aug 25.
Article in English | MEDLINE | ID: mdl-11006015

ABSTRACT

HLA-A2.1/K(b) transgenic mice (A2.1/K(b) mice) were used to investigate the processing of human gp100 melanoma antigen by murine antigen presenting cells (APC). Bone marrow-derived dendritic cells (DC) from A2.1/K(b) mice were transduced with adenovirus encoding human gp100 (Ad2/hugp100v2). The Ad2/hugp100v2-transduced DC express human gp100, as documented by immunoperoxidase staining. Flow cytometric analysis demonstrates that Ad vector transduction does not downregulate expression of several markers, including MHC class I. We show that Ad2/hugp100v2-transduced DC are recognized by peptide-specific, A2.1-restricted CTL, suggesting correct processing and presentation of the hugp100 antigen by murine DC. To assess dominance among the various A2.1-restricted epitopes encoded by hugp100, A2.1/K(b) transgenic mice were immunized with Ad2/hugp100v2-transduced DC. Resulting effector cytotoxic T lymphocytes (CTL) were assayed for peptide specificity using a panel of six synthetic peptides known to encode A2.1-restricted epitopes of human gp100 (denoted G154, G177, G209, G280, G457, G476). CTL obtained from Ad2/hugp100v2-transduced DC immunized A2.1/K(b) mouse lysed target cells presenting five of the six epitopes, supporting the observation that murine cells correctly process the hugp100 antigen. The immunogenicity of individual gp100 epitopes correlates with their binding affinity to A2.1. CTL generated from A2.1/K(b) mice immunized with Ad2/hugp100v2-transduced DC also specifically recognize A2.1(+)/gp100(+) human melanoma cells. These data suggest that murine APC process and present the same set of HLA-restricted peptides, similar to human APC. HLA transgenic mice serve as a useful model system to study class I-restricted epitopes of human tumor-associated antigens.


Subject(s)
Antigen Presentation , Antigens, Neoplasm/immunology , Dendritic Cells/immunology , HLA-A2 Antigen/immunology , Membrane Glycoproteins/immunology , Neoplasm Proteins/immunology , Adenoviridae/genetics , Animals , Cytotoxicity, Immunologic , Epitopes , Genes, MHC Class I , H-2 Antigens/genetics , H-2 Antigens/immunology , HLA-A2 Antigen/genetics , Humans , Melanoma/immunology , Membrane Glycoproteins/genetics , Mice , Mice, Transgenic , Neoplasm Proteins/genetics , Oligopeptides/immunology , Recombinant Fusion Proteins/immunology , Species Specificity , T-Lymphocytes, Cytotoxic , Transformation, Genetic , gp100 Melanoma Antigen
11.
Cancer ; 89(2): 356-62, 2000 Jul 15.
Article in English | MEDLINE | ID: mdl-10918166

ABSTRACT

BACKGROUND: The use of a high dose regimen of interferon-alpha-2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects. METHODS: The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN. RESULTS: The authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases. CONCLUSIONS: Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective mood-stabilizing agent for these patients.


Subject(s)
Acetates/therapeutic use , Amines , Anti-Anxiety Agents/therapeutic use , Antimanic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Bipolar Disorder/chemically induced , Bipolar Disorder/drug therapy , Cyclohexanecarboxylic Acids , Interferon-alpha/adverse effects , Melanoma/drug therapy , gamma-Aminobutyric Acid , Adult , Antineoplastic Agents/therapeutic use , Bipolar Disorder/prevention & control , Chemotherapy, Adjuvant , Depression/chemically induced , Depression/drug therapy , Female , Gabapentin , Humans , Interferon alpha-2 , Interferon-alpha/therapeutic use , Male , Middle Aged , Mood Disorders/chemically induced , Mood Disorders/drug therapy , Prospective Studies , Recombinant Proteins
12.
Cancer J ; 6(3): 139-45, 2000.
Article in English | MEDLINE | ID: mdl-10882328

ABSTRACT

We performed an analysis of toxicity and survival in stage III melanoma patients receiving adjuvant interferon alfa-2b (IFN). This was a retrospective single-arm analysis of 40 patients with stage III melanoma who received (IFN) administered at maximum tolerated doses of 20 mU/m2/day intravenously (i.v.) for 1 month and 10 mU/m2 three times per week subcutaneously (s.c.) for 48 weeks. Toxicity in our series is comparable to that experienced in the Eastern Cooperative Oncology Group (ECOG) 1684 trial, except for higher rates of dose-limiting myelosuppression and hepatotoxicity. All 40 patients experienced constitutional symptoms, but only 14/40 (35%) experienced grade 3 to 4 symptoms. Of the 40 patients, 36 (90%) experienced neurologic symptoms, but only seven (17.5%) experienced grade 3 to 4 neurotoxicity. Two patients stopped treatment because of severe psychiatric symptoms; one patient attempted suicide, and a psychosis developed in another. Thirty-nine (97.5%) patients experienced myelosuppression; 31 (77.5%) developing grade 3 to 4 myelosuppression. Hepatotoxicity was evident in 39 (97.5%) patients, and 26 (65%) experienced grade 3 to 4 hepatotoxicity. Three patients (7.5%) experienced mild renal toxicity. At a median follow-up of 27 months from initiation of therapy, there have been 19 relapses (47.5% disease-free survival [DFS]) and 10 deaths (75% OS) resulting from progression of disease. The DFS compares with the treatment arm in ECOG 1684 at 27 months, but overall survival is higher in our series of patients at the same time point. In a single program setting, IFN can be administered with similar side effects and outcome profiles seen in multi-institutional studies. Modifications in the induction regimen resulted in notably higher hematologic and hepatic toxicities but did not preclude administering further therapy and did not result in increased attrition rate among patients: only nine patients (22.5%) had their treatment stopped as a result of IFN-related toxicity. In comparison, 26% of patients had to have their treatment discontinued because of toxicity in ECOG 1684.


Subject(s)
Antineoplastic Agents/therapeutic use , Chemotherapy, Adjuvant , Interferon-alpha/therapeutic use , Melanoma/drug therapy , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , Clinical Trials as Topic , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/mortality , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Interferon-alpha/toxicity , Lymphatic Metastasis , Male , Melanoma/mortality , Middle Aged , Recombinant Proteins , Retrospective Studies , Risk Factors , Skin Neoplasms/drug therapy , Skin Neoplasms/mortality , Time Factors
13.
Cancer Res ; 60(7): 1800-4, 2000 Apr 01.
Article in English | MEDLINE | ID: mdl-10766161

ABSTRACT

Both inactivation of the tumor suppressor gene, PTEN/MMAC1, and oncogenic activation of RAS have been described in human cutaneous melanoma. In mice, activation of a RAS-containing pathway is a necessary step in the pathogenesis of murine melanomas. Because PTEN negatively regulates on the downstream effects of phosphatidylinositol-3-kinase (PI3-K), we hypothesized that the loss of PTEN/MMAC1 and the activation of RAS may be largely equivalent because RAS is a known positive upstream regulator of PI3-K. We expanded our previous survey of PTEN/MMAC1 mutations and analyzed the RAS status of 53 cutaneous melanoma cell lines, 18 glioma cell lines, and 17 uncultured cutaneous melanoma metastasis. Overall, 51% of the cell lines had alterations in either PTEN/MMAC1 or RAS. We found 16 cell lines (30%) with alterations in PTEN/MMAC1 and 11 cell lines (21%) with activating NRAS mutations; only 1 cell line had concurrent alterations in both genes. Moreover, glioma cell lines with a high frequency of PTEN/MMAC1 inactivation had no identifiable RAS alterations. Ectopic expression of PTEN in several cutaneous melanoma cell lines suppressed colony formation irrespective of PTEN/MMAC1 status; furthermore, PTEN expression in cell lines carrying activated RAS also suppressed colony formation. The relative reciprocity of PTEN/MMAC1 abrogation and NRAS activation suggests that the two genetic changes, in a subset of cutaneous melanomas, are functionally overlapping.


Subject(s)
Genes, Tumor Suppressor , Genes, ras , Melanoma/genetics , Mutation , Phosphoric Monoester Hydrolases/genetics , Skin Neoplasms/genetics , Tumor Suppressor Proteins , Alternative Splicing , Amino Acid Sequence , Animals , Base Sequence , Brain Neoplasms/genetics , Exons , Frameshift Mutation , Gene Deletion , Glioma/genetics , Humans , Melanoma, Experimental/genetics , Mice , PTEN Phosphohydrolase , Point Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Sequence Deletion , Tumor Cells, Cultured
14.
J Immunol ; 164(6): 3402-12, 2000 Mar 15.
Article in English | MEDLINE | ID: mdl-10706736

ABSTRACT

Replication-deficient recombinant adenovirus (Ad) encoding human gp100 or MART-1 melanoma Ag was used to transduce human dendritic cells (DC) ex vivo as a model system for cancer vaccine therapy. A second generation E1/E4 region deleted Ad which harbors the CMV immediate-early promoter/enhancer and a unique E4-ORF6/pIX chimeric gene was employed as the backbone vector. We demonstrate that human monocyte-derived DC are permissive to Ad infection at multiplicity of infection between 100 and 500 and occurs independent of the coxsackie Ad receptor. Fluorescent-labeled Ad was used to assess the kinetics and distribution of viral vector within DC. Ad-transduced DC show peak transgene expression at 24-48 h and expression remains detectable for at least 7 days. DC transduced with replication-deficient Ad do not exhibit any unusual phenotypic characteristics or cytopathic effects. DC transduced with Ad2/gp100v2 can elicit tumor-specific CTL in vitro from patients bearing gp100+ metastatic melanoma. Using a panel of gp100-derived synthetic peptides, we show that Ad2/gp100v2-transduced DC elicit Ag-specific CTL that recognize only the G209 and G280 epitopes, both of which display relatively short half-lives ( approximately 7-8 h) on the surface of HLA-A*0201+ cells. Thus, patients with metastatic melanoma are not tolerant to gp100 Ag based on the detection of CD8+ T cells specific for multiple HLA-A*0201-restricted, gp100-derived epitopes.


Subject(s)
Adenoviruses, Human/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Epitopes, T-Lymphocyte/immunology , HLA-A2 Antigen/immunology , Melanoma/immunology , Membrane Glycoproteins/immunology , Neoplasm Proteins/immunology , Adenoviruses, Human/genetics , Antigens, Neoplasm , Cells, Cultured , Dendritic Cells/metabolism , Enterovirus B, Human/genetics , Epitopes, T-Lymphocyte/genetics , Fluorescent Dyes/metabolism , Genetic Vectors/immunology , HLA-A2 Antigen/genetics , Half-Life , Humans , Immunodominant Epitopes/genetics , Immunodominant Epitopes/immunology , Immunophenotyping , MART-1 Antigen , Melanoma/genetics , Membrane Glycoproteins/genetics , Neoplasm Proteins/genetics , Peptide Fragments/genetics , Peptide Fragments/metabolism , Receptors, Virus/genetics , T-Lymphocytes, Cytotoxic/immunology , Virion/genetics , Virion/metabolism , Virus Replication/genetics , gp100 Melanoma Antigen
15.
Arch Surg ; 134(4): 381-7, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10199310

ABSTRACT

HYPOTHESIS: Patients with melanoma and histologically negative sentinel lymph nodes identified by lymphatic mapping have a very good prognosis. DESIGN: Cohort study with follow-up information obtained from medical records and telephone interviews. SETTING AND PATIENTS: Of all patients with cutaneous melanoma who underwent intraoperative sentinel lymph node mapping between November 15, 1993, and April 18, 1997, at the Massachusetts General Hospital, Boston, 89 were found to have no evidence of melanoma in their sentinel nodes. Forty-six lesions (51%) were on an extremity and 44 (49%) were of axial location. The median tumor thickness was 1.8 mm (range, 0.36-12.0 mm) and 11 tumors (12%) were ulcerated. INTERVENTIONS: Patients underwent intraoperative sentinel lymph node mapping with lymphazurin and radiolabeled sulfur colloid. Sentinel lymph nodes were analyzed by standard hematoxylin-eosin staining. Only 2 patients received adjuvant therapy following wide excision of the primary lesion. MAIN OUTCOME MEASURES: Site of initial recurrence and time to initial recurrence. RESULTS: The median follow-up for all patients was 23 months (range, 2-54 months). Eleven patients (12%) developed melanoma recurrences, and 78 (88%) patients remain disease free. Regional lymph nodes were the initial site of recurrence in 7 (8%) of 89 patients, and 7 (7%) of 106 mapped basins. Four patients had recurrence without involvement of regional lymph nodes: 2 with distant metastases and 2 with in transit metastases. The median time to recurrence was 12 months (range, 2-35 months). Sentinel lymph nodes were reanalyzed using serial sections and immunoperoxidase stains in 7 patients with recurrence and metastatic melanoma was identified in 3 (43%). CONCLUSIONS: The risk for melanoma recurrence is relatively low in patients with histologically negative sentinel nodes identified by lymphatic mapping. Longer follow-up will improve our understanding of the prognostic value of this procedure.


Subject(s)
Lymph Nodes/pathology , Melanoma/pathology , Skin Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Follow-Up Studies , Humans , Immunohistochemistry , Intraoperative Care , Lymphatic Metastasis , Male , Melanoma/mortality , Melanoma/secondary , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Skin Neoplasms/mortality , Survival Rate
16.
Biochem Biophys Res Commun ; 255(1): 59-63, 1999 Feb 05.
Article in English | MEDLINE | ID: mdl-10082655

ABSTRACT

The tumor suppressor gene MEN1 and several oncogenes including CCND1/cyclin D1/PRAD1 map to chromosome 11q13. However, molecular and cytogenetic analysis suggests the presence of a second tumor suppressor locus at this chromosome region. We have identified a novel gene from chromosome 11q13, which encodes a protein of 126 amino acids sharing an overall 57% identity with the p12(DOC-1) protein encoded by the DOC-1 gene, the human homolog of hamster putative tumor suppressor doc-1 (deleted in oral cancer-1). We therefore designated the novel gene as DOC-1R for DOC-1-related. The cytogenetic location was confirmed by chromosome fluorescent in situ hybridization. Northern blot analysis indicated that it was expressed in all the tissues examined. DOC-1R protein showed heterogeneous subcellular localization. RT-PCR-SSCP analysis failed to detect deleterious mutations of the DOC-1R transcript in four premalignant oral keratinocyte lines and 20 different cancer cell lines from tumor types which frequently harbor LOH at chromosome 11q13.


Subject(s)
Chromosomes, Human, Pair 11 , Genes, Tumor Suppressor , Oncogene Proteins/genetics , Proteins/genetics , Tumor Suppressor Proteins , Amino Acid Sequence , Animals , Cell Line , Chromosome Mapping , Cricetinae , DNA Mutational Analysis , Humans , Molecular Sequence Data , Sequence Alignment
17.
Cancer Res ; 59(1): 172-4, 1999 Jan 01.
Article in English | MEDLINE | ID: mdl-9892203

ABSTRACT

A novel p53-related gene, p73, was recently isolated and cytogenetically mapped to chromosome region 1p36. Functionally, p73 expression induces p21waf and suppresses tumor cell growth. We mapped p73 using radiation hybrids and localized the gene to an interval that putatively harbors a melanoma tumor suppressor locus. We then analyzed p73 transcripts from 24 melanoma cell lines using reverse transcription-PCR/single strand conformation polymorphism and identified nine polymorphic sequence changes (three novel and six previously published polymorphisms); furthermore, we found evidence of biallelic transcription in our cell lines. However, we did not detect any deleterious mutations. These data suggest that the p73 gene is unlikely to be essential in melanoma tumorigenesis.


Subject(s)
DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Melanoma/genetics , Nuclear Proteins/genetics , Chromosome Mapping , DNA Mutational Analysis , Humans , Transcription, Genetic , Tumor Cells, Cultured , Tumor Protein p73 , Tumor Suppressor Proteins
18.
Article in English | MEDLINE | ID: mdl-10800498

ABSTRACT

In melanoma, conventional therapies, especially cytotoxic chemotherapies, have proven unsatisfactory. Although a variety of agents have been tested singly and in combination, recent randomized studies have demonstrated that the response rates observed in single institution phase II trials are not generalizable to multi-institution settings. Studies of cytokine therapy, especially interferon-alpha in the adjuvant situation, and interleukin-2 for advanced disease, have demonstrated some utility to these agents. However, their toxicities remain formidable, and studies refining their use are under way. The limited successes of such immunomodulatory strategies have provided a rationale for continued pursuit of immunotherapy approaches. It is likely that in the near future such active immunization protocols will continue to be actively investigated.


Subject(s)
Melanoma/therapy , Chemotherapy, Adjuvant , Humans , Immunotherapy , Interferons/therapeutic use , Interleukin-12/therapeutic use , Interleukin-2/therapeutic use , Neoplasm Staging
20.
Oncogene ; 16(26): 3397-402, 1998 Jul 02.
Article in English | MEDLINE | ID: mdl-9692547

ABSTRACT

A novel tumor suppressor gene, PTEN/MMAC1, has been recently shown to be mutated in gliomas, breast, prostate, kidney cancers and melanomas. Loss-of-heterozygosity studies in melanoma have suggested the presence of at least one chromosome 10q locus lost early in tumor progression. In this study, we screened 45 melanoma cell lines and 17 paired uncultured metastatic melanoma and peripheral blood specimens for PTEN/ MMAC1 alterations using PCR-SSCP and direct sequencing. We found nine melanoma cell lines with homozygous deletions (five with intragenic loss) and four cell lines with mutations (one nonsense and one frameshift; two intronic); from among our uncultured melanoma specimens, we found one tumor with a somatic 17 bp duplication in exon 7 leading to a premature stop codon and one tumor with a possible homozygous deletion. Furthermore, we have identified a novel intragenic polymorphism within intron 4 of PTEN/MMAC1. Taken together, these data suggest that PTEN/MMAC1 may be a chromosome 10q tumor suppressor important in melanoma tumor formation or progression.


Subject(s)
Genes, Tumor Suppressor , Melanoma/genetics , Phosphoric Monoester Hydrolases , Protein Tyrosine Phosphatases/genetics , Tumor Suppressor Proteins , Chromosomes, Human, Pair 10 , Exons , Humans , Loss of Heterozygosity , Melanoma/etiology , Multigene Family , PTEN Phosphohydrolase , Polymorphism, Genetic , Polymorphism, Single-Stranded Conformational , Tumor Cells, Cultured
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