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First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors
Davis, Elizabeth J; Martin-Liberal, Juan; Kristeleit, Rebecca; Cho, Daniel C; Blagden, Sarah P; Berthold, Dominik; Cardin, Dana B; Vieito, Maria; Miller, Rowan E; Hari Dass, Prashanth; Orcurto, Angela; Spencer, Kristen; Janik, John E; Clark, Jason; Condamine, Thomas; Pulini, Jennifer; Chen, Xuejun; Mehnert, Janice M
BACKGROUND:OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. METHODS:Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. RESULTS:Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. CONCLUSION:No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER:NCT02923349.
PMCID:9628691
PMID: 36316061
ISSN: 2051-1426
CID: 5358222
Risk and tropism of central nervous system (CNS) metastases in patients with stage II and III cutaneous melanoma
Johannet, Paul; Simons, Morgan; Qian, Yingzhi; Azmy, Nadine; Mehnert, Janice M; Weber, Jeffrey S; Zhong, Judy; Osman, Iman
BACKGROUND:Recent data suggest that patients with stage III melanoma are at high risk for developing central nervous system (CNS) metastases. Because a subset of patients with stage II melanoma experiences worse survival outcomes than some patients with stage III disease, the authors investigated the risk of CNS metastasis in stage II melanoma to inform surveillance guidelines for this population. METHODS:test, the cumulative incidence, and Cox multivariable regression analyses were performed to evaluate the association between baseline characteristics and the development of CNS metastases. RESULTS:Patients with stage III melanoma had a higher rate of developing brain metastases than those with stage II melanoma (100 of 468 patients [21.4%] vs. 82 of 586 patients [14.0%], respectively; p = .002). However, patients who had stage IIC melanoma had a significantly higher rate of isolated first recurrences in the CNS compared with those who had stage III disease (12.1% vs. 3.6%; p = .002). The risk of ever developing brain metastases was similarly elevated for patients who had stage IIC disease (hazard ratio [HR], 3.16; 95% CI, 1.77-5.66), stage IIIB disease (HR, 2.83; 95% CI, 1.63-4.91), and stage IIIC disease (HR, 2.93; 95% CI, 1.81-4.74), and the risk was highest in patients who had stage IIID disease (HR, 8.59; 95% CI: 4.11-17.97). CONCLUSIONS:Patients with stage IIC melanoma are at elevated risk for first recurrence in the CNS. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals until more accurate predictive markers can be identified.
PMID: 36006879
ISSN: 1097-0142
CID: 5331732
Baseline Serum Autoantibody Signatures Predict Recurrence and Toxicity in Melanoma Patients Receiving Adjuvant Immune Checkpoint Blockade
Johannet, Paul; Liu, Wenke; Fenyo, David; Wind-Rotolo, Megan; Krogsgaard, Michelle; Mehnert, Janice M; Weber, Jeffrey S; Zhong, Judy; Osman, Iman
PURPOSE:Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab. EXPERIMENTAL DESIGN:This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915. RESULTS:In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98-6.55], and outperformed a model composed of clinical variables including PD-L1 expression (P < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59-86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38-7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84-37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48-28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10-212.50). CONCLUSIONS:Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility. See related commentary by Hassel and Luke, p. 3914.
PMID: 36106402
ISSN: 1557-3265
CID: 5335062
A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors
Silk, Ann W; Saraiya, Biren; Groisberg, Roman; Chan, Nancy; Spencer, Kristen; Girda, Eugenia; Shih, Weichung; Palmeri, Marisa; Saunders, Tracie; Berman, Robert M; Coric, Vlad; Chen, Suzie; Zloza, Andrew; Vieth, Joshua; Mehnert, Janice M; Malhotra, Jyoti
BACKGROUND:Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors. METHODS:Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy. RESULTS:We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested. CONCLUSION/CONCLUSIONS:The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.
PMCID:9250196
PMID: 35780243
ISSN: 2047-783x
CID: 5278302
Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era?
Berger, Assaf; Bernstein, Kenneth; Alzate, Juan Diego; Mullen, Reed; Silverman, Joshua S; Sulman, Erik P; Donahue, Bernadine R; Pavlick, Anna C; Gurewitz, Jason; Mureb, Monica; Mehnert, Janice; Madden, Kathleen; Palermo, Amy; Weber, Jeffrey S; Golfinos, John G; Kondziolka, Douglas
PURPOSE/OBJECTIVE:New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS:We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS:SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION/CONCLUSIONS:Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.
PMID: 35665462
ISSN: 1573-7373
CID: 5248172
The "Great Debate" at Melanoma Bridge 2021, December 2nd-4th, 2021
Ascierto, Paolo A; Warner, Allison Betof; Blank, Christian; Caracò, Corrado; Demaria, Sandra; Gershenwald, Jeffrey E; Khushalani, Nikhil I; Long, Georgina V; Luke, Jason J; Mehnert, Janice M; Robert, Caroline; Rutkowski, Piotr; Tawbi, Hussein A; Osman, Iman; Puzanov, Igor
The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.
PMCID:9087170
PMID: 35538491
ISSN: 1479-5876
CID: 5214372
Double Trouble: Immunotherapy Doublets in Melanoma-Approved and Novel Combinations to Optimize Treatment in Advanced Melanoma
Dimitriou, Florentia; Hauschild, Axel; Mehnert, Janice M; Long, Georgina V
Immune checkpoint inhibitors, particularly anti-PD-1-based immune checkpoint inhibitors, have dramatically improved outcomes for patients with advanced melanoma and are currently deemed a standard of care. Ipilimumab/nivolumab is the first combination of immune checkpoint inhibitors to improve progression-free survival and overall survival in the first-line setting, with durable responses and the longest median overall survival, 72.1 months, of any drug therapy approved for advanced melanoma. However, its use is limited by the high rate of severe (grade 3-4) treatment-related adverse events. More recently, the novel immune checkpoint inhibitor combination of nivolumab/relatlimab (anti-PD-1/anti-LAG3) showed improved progression-free survival compared with nivolumab alone in the first-line setting and was well tolerated; thus, it is likely this combination will be added to the armamentarium as a first-line treatment for advanced melanoma. These changes in the treatment landscape have several treatment implications for decision-making. The choice of first-line systemic drug therapy, and the decision between immune checkpoint inhibitor monotherapy or combination therapy, requires a comprehensive assessment of disease-related factors and patient characteristics. Despite this striking progress, many patients' disease still progresses. Several new agents and therapeutic approaches are under investigation in clinical trials. Intralesional treatments hold promise for accessible metastases, although their broad application in the clinic will be limited. Prognostic and predictive biomarkers, as well as strategies to reduce treatment-related toxicities and overcome resistance, are required and are now the focus of clinical and translational research.
PMID: 35658500
ISSN: 1548-8756
CID: 5283022
BAMM (BRAF Autophagy and MEK inhibition in Melanoma): A phase I/II trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600-mutant melanoma
Mehnert, Janice M; Mitchell, Tara; Huang, Alexander C; Aleman, Tomas S; Kim, Benjamin J; Schuchter, Lynn M; Linette, Gerald P; Karakousis, Giorgos; Mitnick, Sheryl; Giles, Lydia; Carberry, Mary; Frey, Noelle; Kossenkov, Andrew; Groisberg, Roman; Hernandez-Aya, Leonel F; Ansstas, George; Silk, Ann W; Chandra, Sunandana; Sosman, Jeffrey A; Gimotty, Phyllis A; Mick, Rosemarie; Amaravadi, Ravi
PURPOSE/OBJECTIVE:Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg bid and trametenib 2 mg qd (D+T). PATIENTS AND METHODS/METHODS:melanoma patients. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%. RESULTS:34 were evaluable for one-year PFS rate. Patient demographics: elevated LDH: 47%; Stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose limiting toxicity. HCQ 600 mg po bid with D+T was the RP2D. The one-year PFS rate was 48.2% (95% CI = 31.0-65.5%), median PFS was 11.2 months (95% CI = 5.4-16.9 months), and response rate (RR) was 85% (95% CI=64-95%). The complete response rate was 41% and median overall survival (OS) was 26.5 months. In patient with elevated LDH (n=16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively. CONCLUSION/CONCLUSIONS:melanoma patients with elevated LDH and previous immunotherapy is being conducted.
PMID: 35022320
ISSN: 1557-3265
CID: 5118852
A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies
Tan, Antoinette R; Chan, Nancy; Kiesel, Brian F; Stein, Mark N; Moss, Rebecca A; Malhotra, Jyoti; Aisner, Joseph; Shah, Mansi; Gounder, Murugesan; Lin, Hongxia; Kane, Michael P; Lin, Yong; Ji, Jiuping; Chen, Alice; Beumer, Jan H; Mehnert, Janice M
PURPOSE/OBJECTIVE:Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS:) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS:Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION/CONCLUSIONS:V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.
PMID: 34669023
ISSN: 1432-0843
CID: 5043302
Examination of speakership gender disparity at an international oncology conference. [Meeting Abstract]
Caro, Jessica; Boatwright, Christina; Li, Xiaochun; Fiocco, Constance; Stempel, Jessica M.; Stoeckle, James Hart; Smithy, James W.; Warner, Allison Betof; Shum, Elaine; Sabari, Joshua K.; Malhotra, Jyoti; Chan, Nancy; Spencer, Kristen Renee; Kunz, Pamela L.; Goldberg, Judith D.; Mehnert, Janice M.
ISI:000863680300277
ISSN: 0732-183x
CID: 5754732