Emmett V. Schmidt

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors. Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method. Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders. Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR. See related commentary by Pérez-Ruiz et al., p. 5326

High Levels of Expression of P-glycoprotein/Multidrug Resistance Protein Result in Resistance to Vintafolide

Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared with DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, vintafolide has achieved favorable responses in phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR, as in vintafolide, fails to overcome P-gp–mediated efflux of DAVLBH in both in vitro and in vivo preclinical models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate. Mol Cancer Ther; 15(8); 1998–2008. ©2016 AACR.

Abstract CT115: Phase 1b KEYNOTE 200 (STORM study): A study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients

Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody that has yielded significant solid tumor responses via reversal of tumor induced T-cell suppression. Tumor infection by CVA21 can increase levels of immune-checkpoint molecules, immune-cell infiltration and enhancement of systemic antitumor immune response. Preclinical studies in immune-competent mouse models of NSCLC and melanoma confirmed that combinations of IV CVA21 + anti-PD-1 mAbs mediated significantly greater antitumor activity compared to use of either agent alone. The combination of CVA21+pembrolizumab may translate to a potential benefit in the clinic. Interim data are presented on the Phase Ib study assessing safety and efficacy of IV CVA21 alone (Part A) and in combination with pembrolizumab (Part B) in advanced cancer pts. Methods: The Phase I STORM: Systemic Treatment Of Resistant Malignancies: NCT02043665 (KEYNOTE-200): Primary objectives are to assess dose-limiting toxicities (DLT) of CVA21 alone and in combination with pembrolizumab. Secondary objectives are to assess ORR by irRECIST 1.1 criteria, PFS, and OS. Treatment:Part A: Pts were infused with CVA21 in 100 mL saline in Cohort 1 (n = 3), at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = 10) at a dose of 1 x 109 TCID50 on study days 1,3,5,22 and Q3W for 6 additional infusions. Part B: Pts are infused with CVA21 in 100 mL saline + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = ~80) at a dose of 1 x 109 TCID50 on study days 1,3,5,8,29,and Q3W for 6 additional infusions. Pembrolizumab is given in all cohorts at 200 mg IV Q3W from Day 8 for up to 2 years. Treatment with CVA21 + pembrolizumab will continue until confirmed CR or PD (whichever comes first) per irRECIST 1.1 or DLT. Results: Part A: Enrolment is complete. IV delivery of CVA21 to all patients in Part A was generally well tolerated, with no Grade 3 or 4 product-related AE’s with a median of 6 CVA21 infusions per patient. CVA21 tumor targeting in patients with melanoma, NSCLC and bladder cancer patients in Cohort 3 was confirmed by detection of CVA21 viral RNA in tumor biopsies at study Day 8 and viral replication by IHC in melanoma tumor biopsies. Of the 13 patients from Cohorts 1-3 eligible for investigator best overall response assessment, 1 PR, 8 SD and 4 PD were observed. Part B: The combination of intravenous CVA21 and pembrolizumab has been generally well-tolerated. At present one gr 3 CVA21-related hyponatremia with no DLT for the combination of CVA21 and pembrolizumab being observed. Enrolment in Cohorts 1 and 2 is complete with that of Cohort 3 currently underway. All patients in Part B have displayed active host-antiviral immune responses by developing detectable anti-CVA21 neutralizing antibodies by study Day 22. Conclusions: Intravenous delivery of CVA21 is able to target metastatic tumor deposits with the potential to up-regulate PD-L1 expression during the viral replication process. Systemic administration of CVA21 alone or in combination with pembrolizumab has been generally well-tolerated with at present no DLT’s. Citation Format: Hardev Pandha, Kevin Harrington, Cristy Ralph, Alan Melcher, Sumati Gupta, Wallace Akerley, Rachael E. Sandborn, Charles Rudin, Jonathan Rosenberg, David Kaufman, Emmett Schmidt, Mark Grose, Darren R. Shafren. Phase 1b KEYNOTE 200 (STORM study): A study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT115. doi:10.1158/1538-7445.AM2017-CT115

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Purpose Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. Patients and Methods Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks. Results Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. Conclusion Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Abstract B65: High levels of expression of P-glycoprotein/multidrug resistance protein result in resistance to vintafolide

Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared to DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, vintafolide has achieved favorable responses in Phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm in both in vitro and in vivo preclinical models that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR as in vintafolide fails to overcome P-gp mediated efflux of DAVLBH as seen in FR-expressing engineered cell lines and in vivo models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate. Citation Format: Amy D. Guertin, Jennifer O9Neil, Alexander Stoeck, Joseph A. Reddy, Razvan Cristescu, Brian B. Haines, Marlene C. Hinton, Ryan Dorton, Alicia Bloomfield, Melissa Nelson, Marilynn Vetzel, Serguei Lejnine, Michael Nebozhyn, Theresa Zhang, Andrey Loboda, Kristen L. Picard, Emmett V. Schmidt, Isabelle Dussault, Christopher P. Leamon. High levels of expression of P-glycoprotein/multidrug resistance protein result in resistance to vintafolide. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B65.

Abstract 1677: Preclinical activity of Vintafolide/MK-8109 monotherapy and in combination with standard of care therapy in triple-negative breast cancer models

Vintafolide (also known as EC145 or MK-8109), is a small molecule drug conjugate for the treatment of cancers expressing high affinity folate receptor (FR). Vintafolide consists of the anti-mitotic vinca alkaloid desacetylvinblastine monohydrazide (DAVLBH) chemically linked to folic acid. Binding of vintafolide to FR located on the cell surface delivers the chemotherapy payload directly to the tumor cell. Clinical investigations of vintafolide are underway in ovarian and lung cancer, indications with a high prevalence of FR expression. Triple negative breast cancer (TNBC) may represent an additional indication for vintafolide due to the prevalence of FR expression (∼30%), sensitivity to vinca alkaloids, and unmet medical need. Vintafolide and/or DAVLBH were evaluated in preclinical models of TNBC as monotherapies and in combination with taxanes (paclitaxel or docetaxel). Taxanes represent a commonly used standard of care therapy for TNBC. A panel of TNBC cell lines was generally sensitive to DAVLBH, with IC50s ranging from 4-67 nM. In the majority of cell lines tested, DAVLBH in combination with paclitaxel provided combination benefit and induced more cell death than either single agent. Vintafolide and DAVLBH were further evaluated in vivo in the FR-high MDA-MB-231 and FR-low CAL51 TNBC xenograft models. Vintafolide was dosed at its MTD of 9.6 mg/kg three times per week (TIW), and at 1.5 mg/kg TIW. DAVLBH was dosed at its MTD of 0.77 mg/kg TIW. Mice were dosed for 3 weeks followed by a 6 week follow-up. Both vintafolide doses resulted in marked MDA-MB-231 tumor regressions of 56-78% at the end of therapy (Day 21) and 75% cures (6 of 8 mice) over the 6 week follow-up period. In the CAL51 model, vintafolide produced 8% and 76% tumor growth inhibition (TGI), respectively, at the 1.5 and 9.6 mg/kg doses, and no cures. DAVLBH was less efficacious compared to vintafolide, giving 96% TGI in the MDA-MB-231 model and 46% TGI in the CAL51 model. In mechanism of action studies in the MDA-MB-231 xenograft model, a dose of vintafolide that gave tumor regressions/cures was associated with increased phospho-histone H3 staining, indicative of a mitotic block of tumor cells, and consistent with the mechanism of action of vinca alkaloids. In combination therapy experiments in vivo, docetaxel (20 mg/kg weekly) monotherapy achieved near tumor stasis (98% TGI) of MDA-MB-231 tumors over 3 weeks of therapy, but all tumors re-grew upon cessation of treatment. Since vintafolide monotherapy at 1.5 mg/kg TIW gave significant regressions and cures, a combination benefit with docetaxel could not be determined. However, DAVLBH and docetaxel combination therapy delayed tumor re-growth over single agents upon follow-up, suggesting benefit of a vinca alkaloid / taxane combination. Taken together, these preclinical data support further investigation of vintafolide monotherapy and in combination with taxane therapy in TNBC. Citation Format: Brian B. Haines, Jennifer O9Neil, Marlene C. Hinton, Christopher Ware, Tammie C. Yeh, Tianxiao Sun, Kristen L. Picard, Theresa Zhang, Emmett V. Schmidt, Isabelle Dussault. Preclinical activity of Vintafolide/MK-8109 monotherapy and in combination with standard of care therapy in triple-negative breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1677. doi:10.1158/1538-7445.AM2014-1677

Abstract OT2-6-15: Efficacy and safety of vintafolide alone and vintafolide plus paclitaxel vs paclitaxel alone in advanced triple negative breast cancer subjects using etarfolatide subject selection

Background: Vintafolide (V) is a folic acid-vinca alkaloid small molecule drug conjugate that targets tumors that over-express the folate receptor (FR). 99mTc-etarfolatide (EC20) is a folate-targeted molecular imaging agent being developed to identify FR-positive tumors. Data suggest that triple negative breast cancers (TNBCs) expressing high levels of FR are likely to benefit from treatment with vintafolide. Trial design/Patient eligibility: This is a multicenter, randomized, open-label, Phase IIa trial in subjects with advanced TNBC. Patients will be evaluated for tumor specific expression of the FR using a EC20 SPECT/CT scan and classified as FR(100%) if 100% of RECIST 1.1 target lesions are FR-positive. Only FR(100%) patients are eligible for treatment and will be randomized in a 1:1:1 ratio to V alone, V + paclitaxel (P) or P alone. V will be administered at 2.5 mg IV 3x/week for 2 weeks on Days 1, 3, 5, 15, 17 and 19 of a 28-day cycle. P will be administered at 80 mg/m2 IV on Days 1, 8, 15, and 22. Specific aims: The primary endpoint for the trial is centrally assessed progression free survival (PFS). Secondary objectives include: assess the frequency of target tumors expressing FR(100%) vs FR(20-80%) vs FR(0%) in subjects with TNBC using EC20 SPECT scans; compare the clinical activity in subjects with advanced TNBC of V alone vs P and V + P vs P alone as measured by objective response rate (ORR), (complete response [CR] + partial response [PR]), clinical benefit rate (CBR; CR + PR + stable disease for ≥6 months), and overall survival; and assess the safety and tolerability of V alone vs P alone and V + P vs P alone in subjects with advanced TNBC. Statistical methods and target accrual: PFS and overall survival will be assessed in the intention to treat population using a stratified Cox model with Efron9s tie handling method, and Kaplan-Meier method for PFS and OS curve estimation, respectively, in each treatment group. Inferential comparisons between the arms will be tested using the stratified log-rank test at one sided alpha level of 5%. This study will randomize 34 subjects into each treatment group with total study duration of ∼16-17 months. The study has 80% power to demonstrate that either patients treated with V or patients treated with V + P combination have a higher median time to an event of PFS than subjects treated with P at an unadjusted one-sided, 5% alpha-level, if the underlying constant hazard ratio between treatment groups is 0.5 and median survival time of 2.6 months. First patient enrollment is targeted for October. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-15.