Showing papers by "Richard D. Carvajal published in 2011"

KIT as a therapeutic target in metastatic melanoma

Abstract: Context Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease. Objective To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations. Design, Setting, and Patients A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites. Intervention Imatinib mesylate, 400 mg orally twice daily. Main Outcome Measures Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response. Results Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%-30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6-18 weeks; 95% CI, 11-18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P = .05), indicating positive selection for the mutated allele. Conclusions Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance. Trial Registration clinicaltrials.gov Identifier: NCT00470470

A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors

Abstract: Purpose: Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (l- threo -dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C). Experimental Design: A 3 + 3 dose escalation was used. For safety, S was given alone 1 week before the combination. S + C were then administered every 3 weeks. S was given over 60 to 120 minutes, depending on dose. Sixty minutes later, C was given over 60 minutes. The C dose of 75 mg/m 2 was reduced in cohort 4 to 60 mg/m 2 due to excessive fatigue. Results: Forty-three patients were treated, 41 were evaluable for toxicity, and 37 for response. The maximum tolerated dose (MTD) was S 840 mg/m 2 over 120 minutes C 60 mg/m 2 , every 3 weeks. Dose-limiting toxicity (DLT) attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of more than 20 μmol/L and maintained levels greater than and equal to 5 μmol/L for 4 hours. The best response was stable disease in 6 patients for on average 3.3 months (range 1.8–7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was associated with a dose-dependent reduction in S1P in plasma. Conclusions: Safingol, the first putative SphK inhibitor to enter clinical trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclinical data. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m 2 and C 60 mg/m 2 , every 3 weeks. Clin Cancer Res; 17(8); 2484–92. ©2011 AACR .

Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma

Abstract: Uveal melanoma represents the most common primary intraocular malignancy in adults. Although uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biologically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease, and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available; however, recent advances in our understanding of the biology of this rare and devastating disease, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic strategies derived from this emerging biology, and the next generation of recently initiated clinical trials for the treatment of advanced uveal melanoma.

Treatment implications of the emerging molecular classification system for melanoma.

Abstract: Summary Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF V600E ) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF V600E or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT , against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11 , rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.

A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors

Abstract: Purpose Vorinostat (V) at levels >2.5 µM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. Experimental Design One week before combination treatment, V alone was given daily for 3d (cycle -1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15–17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. Results 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m2 over 30 min and 30 mg/m2 over 4 h. V Cmax at the 800 mg dose was 4.8 µM (± 2.8). V Cmax ≥2.5 µM was achieved in 86% of patients at the MTD. F increased the Cmax of V by 27% (95% CI 11%–43%). F Cmax of ≥2 µM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6–13.2 m). Conclusions Intermittent high dose oral V in combination with F is feasible and achieves target serum levels >2.5 µM. V concentrations higher than previously reported with oral dosing were achieved.

Treatment of Locally Recurrent Mucosal Melanoma With Topical Imiquimod

Abstract: Case Report 1 A 75-year-old woman presented with a 6-month history of a periurethral burning sensation. Biopsy of a pigmented lesion on the left labia minora revealed a 3-mm mucosal melanoma. Modified radical vulvectomy with bilateral inguinofemoral lymphadenectomy confirmed multifocal invasive melanoma involving the vulva bilaterally. Surgical margins were negative, as were 12 bilateral resected lymph nodes. Five months postoperatively, a large multifocal local recurrence occurred in the vulvovaginal area; it was 2 mm thick and ulcerated on biopsy (Fig 1A, recurrent melanoma within the submucosa). Because of the large field involved, additional surgery was not possible. Topical imiquimod was commenced and led to almost complete clinical resolution of pigmentation in the vaginal area within 6 months of treatment initiation, with the exception of a small area of periurethral tissue that corresponded to the area from which the topical imiquimod was removed after urination. Sixteen months later, the patient developed a solitary right lower lobe lung nodule that was confirmed to be metastatic malignant melanoma. Concurrently, a melanotic plaque was detected at the left vulva and biopsied. Whereas biopsy of the periurethral area showed recurrent melanoma in situ and minimal postinflammatory change (Fig 1C), biopsy of the labia showed fibrosis, pigment incontinence, and abundant melanophages, which were indicative of an immune response similar to that seen in other regressed melanocytic proliferations (Fig 1B). The patient is currently receiving chemotherapy for her metastatic disease.

Characterization of Computed Tomography Scan Abnormalities in Patients With Biopsy-Proven Hepatic Metastases From Uveal Melanoma

Abstract: Objectives To describe the computed tomography (CT) features in patients with biopsy-proven hepatic metastases of uveal melanoma and correlate these findings with survival. Methods The medical records of patients with uveal melanoma evaluated at Memorial Sloan-Kettering Cancer Center from January 1998 to September 2009 were reviewed. Inclusion criteria were biopsy-proven liver metastasis and CT scan images available within 2 months of biopsy. Exclusion criteria were prior systemic or liver-directed therapy for uveal melanoma. Statistical analyses were carried out using the t test, χ2 test, and Kaplan-Meier log-rank analyses. Results Of 505 medical records reviewed, 76 were selected for study. Characteristic CT findings included multiple (68 patients [90%]), hypodense (100%), heterogeneous (100%), and enhancing (100%) hepatic lesions with a mean dominant lesion size of 46.8 cm2. Eighteen patients (24%) exhibited hepatomegaly. Predominant lesion size larger than 100 cm2, hepatomegaly, and ascites correlated with a lower survival rate (P = .008, P Conclusions Radiographic evidence of predominant lesion size larger than 100 cm2, hepatomegaly, and ascites—but not radiographic evidence of extrahepatic metastases—correlate with a lower survival rate in patients with biopsy-proven hepatic metastases of uveal melanoma.

Keratoacanthomas associated with imatinib mesylate.

Abstract: To the Editor,Imatinib mesylate, an orally available inhibitor of constitutively activated BCR-ABL tyrosine kinase, platelet-derived growth factor receptor (PDGFR) alpha and beta, and the c-kit rec...

A phase II trial of sorafenib (S) and dacarbazine (D) in leiomyosarcoma (LMS), synovial sarcoma (SS), and malignant peripheral nerve sheath tumor (MPNST).

Abstract: 10025 Background: Sorafenib has a low single agent RR in sarcoma. Other angiogenesis inhibitors are more effective when combined with standard chemotherapy. Sorafenib has been safely combined with dacarbazine for treatment of melanoma. As PRs, MRs and prolonged SD were seen in LMS, SS and MPNST in our single agent S study, we chose to investigate S+D in those histologies. Methods: Patients with LMS, SS or MPNST with up to 2 priors, and adequate hepatic, renal and marrow function receive S at 400 mg BID and D at 1000mg/m2 every 3 weeks. Pts are restaged every 2 cycles. The primary objective of this trial is to determine Clinical Benefit Response rate (CBR=CR+PR + SD x18 weeks) of S+D in these subtypes. A Simon two stage design to distinguish between a CBR rate of 20% and 40% required 4 CBRs out of the first 17 pts to expand to a second cohort, and 11/37 (29.7%) CBRs to be considered positive. Results: From 2/09-12/10, 31 pts have been enrolled: 17 F, 14 M; median age 55, range 27-80; ECOG PS 0 16, 1 14; 20...

A first-in-human phase I study of MORAb-004 (MOR4), a humanized monoclonal antibody recognizing TEM-1 (endosialin), in patients with solid tumors.

Abstract: 3086 Background: TEM-1 is a novel anticancer target expressed in many human malignancies and critical to tumor development. It is a transmembrane glycoprotein found on the cell surface of activated...