Showing papers by "Richard D. Carvajal published in 2017"
TL;DR: The biology of uveal melanoma is explored and how this relates to ongoing trials of targeted therapies in the metastatic disease setting is considered and the options to optimise patient management and care are considered.
Abstract: Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care.
260 citations
Harvard University1, Sarah Cannon Research Institute2, University of Texas MD Anderson Cancer Center3, University of California, Los Angeles4, Vanderbilt University Medical Center5, Beth Israel Deaconess Medical Center6, Washington University in St. Louis7, Yale University8, Memorial Sloan Kettering Cancer Center9
TL;DR: The first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors is described, which has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600-mutant solid-tumor malignancies.
Abstract: Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF-mutant solid tumors.Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600-mutant solid-tumor malignancies. Cancer Discov; 8(2); 184-95. ©2017 AACR.See related commentary by Smalley and Smalley, p. 140This article is highlighted in the In This Issue feature, p. 127.
257 citations
TL;DR: The diagnosis, management, and surveillance of primary UM and the adjuvant therapy trials under way are reviewed and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease.
Abstract: Uveal melanoma (UM) is the most common intraocular malignancy and arises from melanocytes in the iris, ciliary body, or choroid. Early diagnosis and local treatment is crucial, as survival correlates with primary tumor size. However, approximately 50% of patients will develop metastatic disease with 6-12 months' survival from metastatic diagnosis. Genomic analyses have led to the development of gene-expression profiles that effectively predict metastatic progression; unfortunately, no adjuvant therapy has been shown to prolong survival to date. New insights into the molecular biology of UM have found frequent activating mutations in genes encoding for the G-protein α-subunit, GNAQ and GNA11, and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease. Studies are under way with rationally developed regimens targeting these pathways, and novel agents are under development. We review the diagnosis, management, and surveillance of primary UM and the adjuvant therapy trials under way.
210 citations
Peking University1, Columbia University Medical Center2, University of Kiel3, University of California, San Francisco4, Mayo Clinic5, University of Barcelona6, Ludwig Maximilian University of Munich7, Cancer Institute8, Sunnybrook Health Sciences Centre9, Johns Hopkins University10, European Institute of Oncology11, Novartis12, Harvard University13
TL;DR: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients, and nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting thatnilotinib may be an effective treatment option for patients with specific KIT mutations.
109 citations
TL;DR: Dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination, but this limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST.
Abstract: Purpose: A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic.Experimental Design: A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC).Results: A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively.Conclusions: Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy. Clin Cancer Res; 23(12); 2972-80. ©2016 AACR.
102 citations
TL;DR: Although immunotherapy with anti-CTLA-4 and anti-PD-1 agents has dramatically changed the treatment approach to cutaneous melanoma, its success in uveal melanoma has been much more limited.
Abstract: Uveal melanoma is a distinct subset of melanoma with a biology and treatment approach that is unique from that of cutaneous melanoma Here we will review the current data evaluating immunotherapies in both the adjuvant and metastatic settings in uveal melanoma In the adjuvant setting, interferon demonstrated no survival benefit in uveal melanoma, and studies evaluating immune-based strategies such as vaccine therapy are ongoing Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in uveal melanoma have been evaluated in several small prospective and/or retrospective studies with rare responses and no overall survival benefit demonstrated Ongoing studies evaluating combination checkpoint inhibition and other antibody-based therapies are ongoing Although immunotherapy with anti-CTLA-4 and anti-PD-1 agents has dramatically changed the treatment approach to cutaneous melanoma, its success in uveal melanoma has been much more limited Clinical trial participation should be prioritized in patients with uveal melanoma
68 citations
TL;DR: Responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred, and select agents and combinations currently in development are highlighted.
Abstract: Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P < 0.001). Notably, responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred. Studies evaluating combination treatments involving oncolytic viruses and immunologic agents are ongoing. This review focuses on the mechanisms of action for oncolytic viruses and highlights select agents and combinations currently in development.
56 citations
Journal Article•
TL;DR: The features of mucosal melanoma that distinguish it from melanomas arising at other sites, and recent biological discoveries and emerging treatment options for this aggressive disease are reviewed.
Abstract: Mucosal melanoma is a rare disease that is distinct from melanomas arising at other sites in the body. While melanocytes are most abundant in the skin, they can be found in smaller numbers in the mucous membranes, as well as in the eye. There are epidemiologic, genetic, and other physiologic differences between melanomas arising from melanocytes at these various sites, and these differences have important implications for both disease prognosis and treatment. Here, we review the features of mucosal melanoma that distinguish it from melanomas arising at other sites, and we highlight recent biological discoveries and emerging treatment options for this aggressive disease.
46 citations
TL;DR: Cytotoxic systemic therapy has modest activity in advanced/unresectable MM, belying its adjuvant benefit and brain imaging should be considered in routine surveillance.
Abstract: There are very few data available regarding the pattern of first metastases in resected mucosal melanomas (MMs) as well as the response of advanced MM to cytotoxic therapy A retrospective, single-institution cohort was assembled of all patients with advanced/unresectable MM between 1995 and 2012 who had received systemic therapy with available imaging (N=81) Responses to first-line and second-line systemic therapy were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 11 The relationship between response, overall survival, and clinical covariates was investigated using Cox proportional hazards regression Primary sites included anorectal (N=31, 38%), vulvovaginal (N=28, 35%), head and neck (N=21, 26%), and gallbladder (N=1, 1%) mucosa Seven percent of patients had their first relapse in the brain Cytotoxic therapy represented 82 and 51% of first-line and second-line regimens The best response achieved in the first-line setting was similar for single-agent [10%; 95% confidence interval (CI): 1-32%] and combination alkylator therapy (8%; 95% CI: 2-21%) Median overall survival from first-line treatment was 103 months (95% CI: 87-139 months) Patients with elevated lactic dehydrogenase [hazard ratio (HR): 187, 95% CI: 110-319, P=0020] and Eastern Cooperative Oncology Group performance status 1-2 (HR: 169, 95% CI: 105-272, P=0030) had a higher risk of death, whereas patients with 12-week objective responses had a lower risk of death (HR: 012, 95% CI: 004-041, P<0001) Cytotoxic systemic therapy has modest activity in advanced/unresectable MM, belying its adjuvant benefit Patients whose tumors have an objective response to therapy have a lower probability of death Brain imaging should be considered in routine surveillance
32 citations
TL;DR: A bispecific biologic capable of redirecting T cells against the melanocyte-associated antigen gp100 and preliminary efficacy in the first-in-human (FIH) clinical trial is reported.
Abstract: 9531Background: IMCgp100 is a bispecific biologic capable of redirecting T cells against the melanocyte-associated antigen gp100. In the first-in-human (FIH) clinical trial,preliminary efficacy of ...
17 citations
TL;DR: VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial, and veliparib clearance was slightly lower than previously reported.
Abstract: Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas.Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20-400 mg twice a day, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort.Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2 Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response.Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702 Clin Cancer Res; 23(15); 4119-26. ©2017 AACR.
TL;DR: Patients generally regarded ipilimumab positively despite the risk of unique toxicities and potential for delayed therapeutic responses; however, those with progression expressed uncertainty regarding whether taking ipILimumab was worthwhile.
Abstract: Ipilimumab was the first FDA-approved agent for advanced melanoma to improve survival and represents a paradigm shift in melanoma and cancer treatment. Its unique toxicity profile and kinetics of treatment response raise novel patient education challenges. We assessed patient perceptions of ipilimumab therapy across the treatment trajectory. Four patient cohorts were assessed at different time points relative to treatment initiation: (1) prior to initiation of ipilimumab (n = 10), (2) at weeks 10–12 before restaging studies (n = 11), (3) at week 12 following restaging studies indicating progression of disease (n = 10), and (4) at week 12 following restaging studies indicating either a radiographic response or disease stability (n = 10). Patients participated in a semistructured qualitative interview to assess their experiences with ipilimumab. Quality of life was assessed via the Functional Assessment of Cancer Therapy-General and its Melanoma-specific module. Perceived quality of life was comparable across cohorts, and a majority of the sample understood side effects from ipilimumab and the potential for a delayed treatment response. Patients without progression of disease following restaging studies at week 12 held more positive views regarding ipilimumab compared to patients who had progressed. Patients generally regarded ipilimumab positively despite the risk of unique toxicities and potential for delayed therapeutic responses; however, those with progression expressed uncertainty regarding whether taking ipilimumab was worthwhile. Physician communication practices and patient education regarding realistic expectations for therapeutic benefit as well as unique toxicities associated with ipilimumab should be developed so that patients can better understand the possible outcomes from treatment.
TL;DR: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells.
Abstract: 2521Background: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells. Dose escalation of this ...
Memorial Sloan Kettering Cancer Center1, Montefiore Medical Center2, Emory University3, National Institutes of Health4, Northwestern University5, Mayo Clinic6, Roy J. and Lucille A. Carver College of Medicine7, University Health Network8, University of Pennsylvania9, University of Chicago10, Mount Sinai Hospital11, University of Michigan12, Thomas Jefferson University13, University of Colorado Denver14, Columbia University Medical Center15
TL;DR: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment and patients may be willing to tolerate select AEs without dose modification (if medically appropriate).
Abstract: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE.
Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.
TL;DR: Intratumoral infiltration with macrophages correlation with CSF-1 receptor binding results in proliferation, differentiation, and migration of monocytes/macrophages in mice.
Abstract: 2523Background: Binding of CSF-1 to the CSF-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. Intratumoral infiltration with macrophages correla...
Huntsman Cancer Institute1, Harvard University2, Columbia University Medical Center3, Washington University in St. Louis4, University of Michigan5, University of Texas MD Anderson Cancer Center6, University of California, San Diego7, University of Alabama at Birmingham8, University of Wisconsin-Madison9, University of California, San Francisco10, University of Washington11, University of New Mexico12, Ford Motor Company13, Sarah Cannon Research Institute14
TL;DR: The Pac-CB combination has been well tolerated and has demonstrated clinical activity in heavily pre-treated pts with TNBC, and the best overall response rate (BORR) has been PR in 20% (3 pts), SD in 47% (7 pts) and PD in 33% (5 pts) with 5 patients remaining on study.
Abstract: Background: CB-839 is a first-in-class highly selective inhibitor of GLS, a key enzyme in the utilization of glutamine by cancer cells. TNBC has high GLS expression and is very dependent upon GLS-mediated conversion of glutamine to glutamate for tumor cell growth. CB-839 has antitumor activity in vitro and in vivo in preclinical models of TNBC. Recent studies demonstrate that glutamine utilization can contribute to resistance to paclitaxel, a therapy frequently used to treat TNBC patients. Paclitaxel sensitivity is dependent on down-regulation of the glutamine transporter, SLC1A5, and over-expression of SLC1A5 causes paclitaxel resistance. Consistent with these observations, inhibition of glutamine metabolism with CB-839 has demonstrated strong antitumor activity in combination with paclitaxel. CX-839-001 is an ongoing Phase 1 trial of CB-839 as monotherapy and in combination with approved agents. We previously reported pharmacodynamic studies demonstrating robust inhibition of GLS in pt blood and tumors and excellent tolerability of CB-839 monotherapy in a variety of tumor types including TNBC. In light of the preclinical rationale and monotherapy tolerability a combination arm was opened testing CB-839 with paclitaxel (Pac-CB) in patients with advanced TNBC. We report here updated results on the Pac-CB dose escalation and expansion cohorts. Methods: Patients with refractory advanced/metastatic TNBC (prior taxane therapy allowed) received escalating doses of CB-839 (400-800 mg BID) in combination with a fixed weekly Pac dose of 80 mg/m2 Days 1, 8, 15 of a 28 day cycle. Upon demonstration of safety and tolerability, an expansion cohort of TNBC pts was opened. Results: To date, 15 pts have received Pac-CB at three dose levels of CB-839: 7 pts at 400 mg BID, 5 at 600 mg BID and 3 at 800 mg BID with the latter dose level not completed. 40% of enrolled patients have received >5 prior lines of systemic therapy for adv/met disease, and 10 pts have received prior taxane therapy including 5 in the adv/met setting. The Pac-CB combination has been well tolerated with one DLT during dose escalation (G4 neutropenia at 400 mg BID) and a low rate of dose reductions (2 for Pac and 1 for CB-839). Of 15 pts, the best overall response rate (BORR, see Table) has been PR in 20% (3 pts), SD in 47% (7 pts) and PD in 33% (5 pts) with 5 patients remaining on study. At doses ≥600 mg BID (n=8) the BORR is 38% (3 pts), and disease control rate (CR + PR + SD) is 88% (7 pts). All 3 pts with PRs have received prior Pac, including 2 pts with disease that was refractory to Pac in the advanced/metastatic setting. Conclusions: The Pac-CB combination has been well tolerated and has demonstrated clinical activity in heavily pre-treated pts with TNBC. At doses ≥600 mg BID, BORR has been 38% and DCR 88%. Notably, PRs have occurred in pts with prior Pac therapy, including 2 pts with Pac-refractory disease in the adv/met setting. Updated data on the escalation and expansion cohorts will be presented. Citation Format: DeMichele AM, Harding JJ, Telli ML, Munster P, McKay RR, Iliopoulos O, Whiting S, Orford KW, Bennett MK, Mier JW, Owonikoko TK, Patel MR, Kalinsky K, Carvajal RD, Infante JR, Merit-Bernstam F. Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), in combination with paclitaxel (Pac) in patients (its) with triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-05.
TL;DR: Uveal melanoma is a rare subtype of melanoma with no effective therapy for advanced disease and characterized by mutations in GNAQ and GNA11 leading to constitutive activation in patients with advanced disease.
Abstract: TPS9597Background: Uveal melanoma (UM) is a rare subtype of melanoma with no effective therapy for advanced disease. UM is characterized by mutations in GNAQ and GNA11 leading to constitutive activ...
TL;DR: Evidence supports a synergistic effect between immunotherapy and radiotherapy and a single-institution study compared outcomes of patients with melanoma brain metasta...
Abstract: e21026Background: Evidence supports a synergistic effect between immunotherapy and radiotherapy In this single-institution study, we compared outcomes of patients (pts) with melanoma brain metasta
TL;DR: Front-line treatment with the combination of nivolumab and ipilimumab, even in the presence of an actionable mutation, is recommended for patients with advanced disease and adequate performance status, and anti-PD-1 monotherapy or targeted therapy is also a reasonable option in appropriate cases.
Abstract: Introduction: Mucosal melanoma (MM) is a rare, aggressive subtype of melanoma arising from melanocytes in mucosal surfaces. Patients with MM have poorer stage-matched prognosis than those with cutaneous melanoma (CM). Immune checkpoint inhibition has improved outcomes for patients with advanced CM, but data on the efficacy of immunotherapy in MM is limited.Areas covered: This article reviews the epidemiology and biology of MM, the general approach to management, the role of targeted therapy, and recent advances in immunotherapy for the treatment of MM.Expert opinion: Immune checkpoint inhibition demonstrates significant clinical activity in MM, though the effects are more modest than those seen in CM. Clinical trial enrollment is encouraged whenever possible. All patients should have their tumors evaluated for BRAF and KIT alterations. If a trial is not available, we recommend front-line treatment with the combination of nivolumab and ipilimumab, even in the presence of an actionable mutation, for...