scholarly journals P856 AVID200, first-in-class TGF-beta1 and beta3 selective inhibitor: results of a phase 1 monotherapy dose escalation study in solid tumors and evidence of target engagement in patients

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A6.2-A7 ◽  
Author(s):  
Timothy Yap ◽  
Daniel Araujo ◽  
Debra Wood ◽  
Jean-François Denis ◽  
Tina Gruosso ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Evasion ◽  
Phase 1 ◽  
Locally Advanced ◽  
List Type ◽  
Functional Evaluation ◽  
Tgf Beta ◽  
Link Type ◽  
Skin Biopsies ◽  
Dose Levels

BackgroundAVID200 is a rationally designed first-in-class receptor ectodomain trap that inhibits transforming growth factor-beta (TGF-beta) isoforms -beta1 and -beta3 with pM potency. TGF-beta signaling is highly immunosuppressive in the tumor microenvironment and has been associated with immune checkpoint inhibitor resistance.1-4 TGF-beta1 and -beta3 are most closely associated with cancer progression whereas TGF-beta2 is required for normal cardiac function and hematopoiesis. Accordingly, selective targeting of TGF-beta1 and -beta3 by AVID200 may improve the efficacy of immunotherapy while avoiding toxicities associated with earlier generations of non-selective TGF-beta inhibitors.MethodsThis open-label, multicenter Phase 1 study (NCT03834662) evaluated safety, tolerability and dose-limiting toxicities (DLTs) of sequential escalating doses of AVID200 (Q3W IV) to establish the recommended Phase 2 dose. Patients with documented, locally advanced or metastatic solid tumors without other treatment options were eligible. The primary objective was safety and tolerability; secondary objectives included preliminary anti-tumor activity, pharmacokinetics (PK), and assessment of pharmacodynamic biomarkers indicative of target modulation. PK was assessed by enzyme immunoassay. Ability of AVID200 to selectively sequester and neutralize its target was assessed by TGF-beta quantification per ELISA, as well as cell-based IL-11 release functional evaluation of TGF-beta signal inhibition. In addition, phosphorylation of SMAD2, a downstream target of TGF-beta, was assessed by immunohistochemistry in skin biopsies at screening and Cycle 1, Day 4 (C1D4).ResultsEnrollment to all planned cohorts is complete: A total of 13 patients with ECOG 0-1 received AVID200 across the three planned dose levels of 180 (N=7), 550 (N=3), and 1100 mg/m2 (N=3) (~5, 15, and 30 mg/kg). The MTD was not reached. Grade 3 study drug-related AEs were reported in two patients (diarrhea, lipase elevation); no related Grade 4 or 5 AEs were observed. Serum exposure was dose-proportional. AVID200 sequestered circulating endogenous active TGF-beta at all dose levels. Moreover, AVID200 in patient plasma potently neutralized TGF-beta1- and -3 – but not -beta2 – mediated signaling. SMAD2 phosphorylation in skin biopsies was detectably reduced at C1D4 across all dose levels. Three of nine patients evaluated for response had a best response of stable disease (SD), including one prolonged SD which was ongoing at six months at time of writing.ConclusionsAVID200 has been well tolerated as monotherapy and engaged its target in patients providing proof-of-principle that selective and potent inhibition of TGF-beta1 and -beta3 is feasible in the clinic. The results warrant evaluation of AVID200 in combination with anti-PD(L)1 and other anti-cancer therapies.AcknowledgementsWe would like to thank all participating patients, their families and caretakers as well as staff members at the clinical sites.Trial RegistrationClinicaltrials.gov NCT03834662Ethics ApprovalThe study was approved by START-Midwest‘s IRB (approval number STMW2018.19), University Health Network‘s Research Ethics Board (approval number 18-6104), and The University of Texas MD Anderson Cancer Center‘s IRB (approval number 2018-1079).ReferencesMariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554:544–548.Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 2018; 9:4692.Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018; 554:538–543.Zhao F, Evans K, Xiao C, et al. Stromal Fibroblasts Mediate Anti–PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma. Cancer Immunol Res 2018; 6:1459–1471.

scholarly journals 861 Reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A902-A902
Author(s):  
Peter Keller ◽  
Irina Mazo ◽  
Yun Gao ◽  
Vijayapal Reddy ◽  
Francisco Caballero ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Phase 1 ◽  
Treg Cells ◽  
Cell Killing ◽  
Therapeutic Window ◽  
List Type ◽  
Link Type

BackgroundMALT1 protease is a promising target in aggressive lymphomas1, and two phase 1 clinical trials in hematological cancers are ongoing (NCT03900598, NCT04876092). More recently, MALT1 protease inhibition was also shown to reprogram regulatory T cells (Treg) in solid tumors, causing them to lose their immunosuppressive function and secrete interferon-gamma (IFN).2 Changes in Treg metabolism in the tumor microenvironment (TME) may account for their destabilization and selective susceptibility to reprogramming in tumor tissue.3 4 5 While strong MALT1 inhibition can cause Treg depletion in blood and induce autoimmune toxicity,6 a therapeutic window for a differentiated MALT1 inhibitor that reprograms destabilized Treg in the TME before affecting Treg in healthy tissue may exist.2 MPT-0118 is an orally dosed MALT1 inhibitor developed to reprogram destabilized Treg in the TME without causing autoimmune symptoms. A Phase 1/1b dose-escalation and cohort-expansion clinical trial evaluating MPT-0118 is underway (NCT04859777).MethodsHuman xenograft models of lymphoma were used to assess the direct activity of MPT-0118 on MALT1-dependent (but not not MALT1-independent) hematologic tumors. Effects of MPT-0118 on solid tumors were determined in syngeneic cancer models. Human and mouse tumor tissues were evaluated for Treg reprogramming by in situ hybridization or flow cytometry. Patient-derived organotypic tumor spheroids were assessed for immune-mediated cell killing. Studies in rodents and dogs assessed pharmacokinetics (PK) and safety.ResultsMPT-0118 was selective and effective in preventing growth of aggressive MALT1 protease-dependent lymphomas. Beyond direct activity on hematologic malignancies, MPT-0118 also increased anti-tumor immune responses as single-agent or in combination with anti-PD-1 in syngeneic tumor models that are otherwise unresponsive to immune checkpoint blockade (ICB). MPT-0118-treated syngeneic tumors showed an increase in IFN-secreting Treg, associated with decelerated tumor growth. PK studies reveal that MPT-0118 has a high volume of distribution, and effective inhibitor concentrations are reached in the murine tumors upon oral dosing. The drug candidate caused tumor-associated Treg to produce IFN without changing the frequency of Treg circulating in the blood. Ex vivo, MPT-0118 induced Treg reprogramming in tumors resected from patients with colorectal and endometrial cancers and cell killing in spheroids derived from patients with colorectal cancer.ConclusionsThe MALT1 inhibitor MPT-0118 is a clinical candidate for treating MALT1-expressing lymphomas and Treg-infiltrated solid tumors. MPT-0118 exploits the therapeutic opportunity presented by destabilized Treg in the TME. Treg reprogramming represents a novel strategy with the potential to improve responses to ICB therapy in a broad range of solid tumors.ReferencesNagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, Hlahla D, Neuenschwander M, Peter von Kries J, Hadian K, Dörken B, Lenz P, Lenz G, Schendel DJ, Krappmann D. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 2012 December 11;22(6):825–37.Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, Usmani SM, Misale S, Zappulli V, Carrizosa E, Mani V, Ligorio M, Warner RD, Medoff BD, Marangoni F, Villani AC, Mempel TR. Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy. Nature 2019 June;570(7759):112–116.Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, Dhungana Y, Chapman NM, Long L, Saravia J, Vogel P, Chi H. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 2021 March;591(7849):306–311.Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, Watson MJ, Leftin A, Maniyar R, Verma S, Lubin M, Ko M, Mane MM, Zhong H, Liu C, Ghosh A, Abu-Akeel M, Ackerstaff E, Koutcher JA, Ho PC, Delgoffe GM, Blasberg R, Wolchok JD, Merghoub T. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 2021 March;591(7851):652–658.Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood JM, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 2017 June 1;169(6):1130–1141.e11.Martin K, Junker U, Tritto E, Sutter E, Rubic-Schneider T, Morgan H, Niwa S, Li J, Schlapbach A, Walker D, Bigaud M, Beerli C, Littlewood-Evans A, Rudolph B, Laisney M, Ledieu D, Beltz K, Quancard J, Bornancin F, Zamurovic Ribrioux N, Calzascia T. Pharmacological inhibition of MALT1 protease leads to a progressive IPEX-Like pathology. Front Immunol 2020 April 30;11:745.

scholarly journals 501 Survival and immune response data from intratumoral INT230–6 alone (IT-01) and with pembrolizumab [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A533-A533
Author(s):  
Jacob Thomas ◽  
Anthony El-Khoueiry ◽  
Anthony Olszanski ◽  
Nilofer Azad ◽  
Giles Whalen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Prognostic Factors ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Phase 1 ◽  
Prognostic Score ◽  
Locally Advanced ◽  
Cancer Center ◽  
List Type

BackgroundBackground: Study IT-01 (KEYNOTE-A10) evaluates INT230-6, a novel formulation of cisplatin (CIS) and vinblastine (VIN) with an amphiphilic cell penetration enhancer designed for intratumoral (IT) administration, as monotherapy and in combination with pembrolizumab (PEM). In preclinical studies, INT230-6 increases drug dispersion throughout the tumor, allows drug diffusion into cancer cells and recruits dendritic, CD4 and CD8 T cells. The addition of PEM improves these responses in mouse models.MethodsIT-01 is an open-label phase 1/2 study, currently enrolling adult subjects with solid tumors in phase 2. The study assesses the safety and efficacy of INT230-6 IT Q2W up to 5 doses as monotherapy or with PEM 200mg Q3W. Biopsies from injected tumor are taken pretreatment and Day 28 for immunohistochemistry (IHC) analysis.ResultsFifty-seven INT230-6, two INT230-6 then PEM combination, and thirteen INT230-6 + PEM combination subjects were enrolled having a median of 4 prior therapies (0, 10). Median age was 62. 20+ cancer types were accrued; breast cancer and sarcoma were the most frequent. Over 500 image guided INT230-6 IT injections were given (253 to deep tumors) at doses of 0.3 to 172mL (86 mg CIS, 17.2 mg VIN) in a single session (contains higher amounts than typical IV chemo doses). PK shows that 95% of INT230-6 active agents remain in the tumor.1 The most common (>25%) related adverse events (AEs) for INT230-6 alone were localized pain (59%), nausea (37%), and fatigue (29%). Safety profile of the PEM combination was similar. There were no related grade 4 or 5 AEs in either arm. The median overall survival (mOS) estimated with removal of <2cm3 and >700cm3 tumor burdens was 433 days for monotherapy (n=51) and 513 days for PEM combination (n=12), which compares favorably to results seen in basket studies of patients having similar prognostic factors (ECOG, LDH, # of metastatic sites).2 IHC results indicate influx of CD4 and CD8 T-cells in injected lesions. No meaningful changes were observed in circulating inflammatory cytokines. Abscopal effects in the monotherapy arm were observed in 15 visceral/deep lesions in 11 patients, primarily who received an INT230-6 dose >50% of their total tumor burden (TTB).ConclusionsINT230-6 is well tolerated when administered IT as monotherapy and combined with PEM. Data suggests that INT230-6 prolongs survival compared to published basket studies in patients with similar prognostic factors. IHC and abscopal results indicate dosing INT230-6 may also activate a T-cell mediated immune response.AcknowledgementsN/ATrial RegistrationNCT# 03058289ReferencesOwelien. Historical PK data from IV administration. J Cancer Res 1977; 8.Abstract. Wagner M, et al. Validation of the Royal Marsden Hospital (RMH) prognostic score in 100 patients with advanced sarcoma enrolled in early phase clinical trials at a major cancer center. JCO 2015. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.10558Ethics ApprovalThe protocol was approved by an institutional review board, independent ethics committee, or research ethics board at each institution. All subjects or their legally acceptable representative provided written informed consent before screening. The study was designed, undertaken, and reported in accordance with the Declaration of Helsinki, and is registered with clinicaltrial.gov with registration no NCT03058289.

scholarly journals 417 Design and rationale of a phase 1 study evaluating AMG 256, a novel, targeted, IL-21 receptor agonist and anti-PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A443-A443
Author(s):  
Gregory Durm ◽  
Sophia Frentzas ◽  
Erik Rasmussen ◽  
Saltanat Najmi ◽  
Nooshin Sadraei
Keyword(s):  
Solid Tumors ◽  
Tumor Immunity ◽  
Renal Cell ◽  
Phase 1 ◽  
List Type ◽  
Solid Organ ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Drug Study ◽  
Interleukin 21

BackgroundCheckpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance.1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer.2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.3 4 AMG 256 is a mutated IL-21 cytokine fused to an anti-PD-1 antibody to combine IL-21 pathway stimulation with checkpoint inhibition—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors.MethodsThis is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies.ResultsN/AConclusionsN/AAcknowledgements• The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.).Trial RegistrationNCT04362748Ethics ApprovalThe study was approved by all institutional ethics boards.ReferencesKluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398.Thompson JA, Curti BD, Redman BG, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034–2039.Lewis KE, Selby MJ, Masters G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology. 2017;7:e1377873.Shen S, Sckisel G, Sahoo A, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol 2020;11:832.

347 Clinical outcomes of ovarian cancer patients treated with ALKS 4230, a novel engineered cytokine, in combination with pembrolizumab: ARTISTRY-1 trial

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A372-A373
Author(s):  
Ira Winer ◽  
Lucy Gilbert ◽  
Ulka Vaishampayan ◽  
Seth Rosen ◽  
Christopher Hoimes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Marker ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Comprehensive Cancer Center ◽  
List Type ◽  
Link Type ◽  
Heavily Pretreated

BackgroundALKS 4230 is a novel engineered cytokine that selectively targets the intermediate-affinity interleukin-2 receptor complex to activate CD8+ T cells and natural killer cells.1 The ARTISTRY-1 trial (NCT02799095) has shown encouraging efficacy and acceptable tolerability of ALKS 4230 among patients with advanced solid tumors.2 We report a detailed analysis of ovarian cancer (OC) patients who received combination therapy in ARTISTRY-1.MethodsARTISTRY-1 is an ongoing multicohort phase 1/2 trial exploring intravenous ALKS 4230 as monotherapy and combined with pembrolizumab. OC patients were enrolled into a cohort with mixed anti PD 1/L1 unapproved tumor types who had progressed on prior chemotherapy. OC patients received ALKS 4230 (3 µg/kg) on days 1–5 and pembrolizumab (200 mg) on day 1 of a 21 day cycle. Outcomes presented include antitumor activity (RECIST v1.1) and safety as of 7/24/2020. To evaluate changes in tumor microenvironment (TME), baseline and on-treatment biopsies were collected.ResultsFourteen heavily pretreated patients with OC were enrolled. Patients received a median of 5 (range, 2 11) prior regimens and all were previously treated with platinum based therapy. Among 13 evaluable patients with ≥1 assessment, 9 experienced disease control and 4 experienced disease progression; median treatment duration was approximately 7 weeks. Three patients experienced an objective response, including 1 complete response, 1 partial response (PR), and 1 unconfirmed PR; all were platinum resistant and negative for BRCA mutations. Five patients experienced tumor burden reductions (table 1). Treatment-related adverse events at the doses tested have generally been transient and manageable, with the majority being grade 1 and 2 in severity. Overall, based on preliminary data, the combination with ALKS 4230 did not demonstrate any additive toxicity to that already established with pembrolizumab alone. Additional safety and efficacy data are being collected in ongoing cohorts. In the monotherapy dose escalation portion of the study, ALKS 4230 alone increased markers of lymphocyte infiltration in 1 paired melanoma biopsy (1 of 1; on treatment at cycle 2); CD8+ T cell density and PD-L1 tumor proportion score increased 5.2- and 11 fold, respectively, supporting evidence that ALKS 4230 has immunostimulatory impact on the TME and providing rationale for combining ALKS 4230 with pembrolizumab (figure 1).Abstract 347 Table 1Summary of response observations among patients with ovarian cancerAbstract 347 Figure 1Increased markers of lymphocyte tumor infiltrationAn increase in CD3+CD8+ T cells (A, red = CD3; blue = CD8; purple = CD3+CD8+; teal = tumor marker), GranzymeB (B, red = CD8; green = granzymeB; yellow = granzymeB+CD8+; teal = tumor marker), and PD-L1 (C, red = PD-L1; blue = tumor marker) in the tumor microenvironment of a single patient was observed after the patient received monotherapy ALKS 4230ConclusionsThe combination of ALKS 4230, an investigational agent, and pembrolizumab demonstrates an acceptable safety profile and provides some evidence of tumor shrinkage and disease stabilization in some patients with heavily pretreated OC. This regimen could represent a new therapeutic option for these patients.AcknowledgementsThe authors would like to thank all of the patients who are participating in this trial and their families. The trial is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel and funded by Alkermes, Inc.Trial RegistrationClinicalTrials. gov NCT02799095Ethics ApprovalThis trial was approved by Ethics and Institutional Review Boards (IRBs) at all trial sites; IRB reference numbers 16–229 (Dana-Farber Cancer Institute), MOD00003422/PH285316 (Roswell Park Comprehensive Cancer Center), 20160175 (Western IRB), i15-01394_MOD23 (New York University School of Medicine), TRIAL20190090 (Cleveland Clinic), and 0000097 (ADVARRA).ReferencesLopes JE, Fisher JL, Flick HL, Wang C, Sun L, Ernstoff MS, et al. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. J Immunother Cancer 2020;8:e000673. doi: 10.1136/jitc-2020-000673.Vaishampayan UN, Muzaffar J, Velcheti V, Winer I, Hoimes CJ, Rosen SD, et al. ALKS 4230 monotherapy and in combination with pembrolizumab (pembro) in patients (pts) with refractory solid tumors (ARTISTRY-1). Oral presentation at: European Society for Medical Oncology Annual Meeting; September 2020; virtual.

scholarly journals 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A437-A437
Author(s):  
Elena Garralda ◽  
Ravit Geva ◽  
Eytan Ben-Ami ◽  
Corinne Maurice-Dror ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Dose Levels

BackgroundAgonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L)1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBody-PD­-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381).MethodsDuring dose escalation, patients with metastatic or unresectable solid tumors not eligible for standard therapy received flat-dose DuoBody-PD-L1×4-1BB (25–1200 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included pharmacokinetic parameters and antitumor activity (RECIST 1.1). Pharmacodynamic biomarkers and antitumor activity (iRECIST) were assessed as exploratory endpoints.ResultsAs of June 22, 2020, 61 patients were enrolled (median age: 59 years). The most common cancer types were colorectal (19.7%), ovarian (14.8%), pancreatic (9.8%), and NSCLC (9.8%). Patients had previously received a median (range) of 3 (1–11) treatments; 44.2% had prior anti-PD-(L)1 immunotherapy. Patients received a median (range) of 4 (1–15) treatment cycles; Cmax was observed shortly after the end of infusion (mean T½: 2.3–10.3 days). Maximum tolerated dose was not reached; 6 patients experienced DLTs. The most common (=10%) treatment-related AEs (all grades; grades 3–4) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%). Treatment-related grade-3 transaminase elevations decreased upon corticosteroid administration; no treatment-related bilirubin increases or grade-4 transaminase elevations occurred. Disease control, including stable disease at first assessment and partial responses in triple-negative breast cancer, ovarian cancer, and immune checkpoint inhibitor (ICI)–pretreated NSCLC, occurred in 40/61 patients (65.6%). Pharmacologic activity, as measured by modulation of adaptive immunity mediators, was observed across a broad range of dose levels. Peripheral proliferating (Ki67+) CD8+ effector memory T cells and serum interferon-gamma levels showed maximum induction relative to baseline (p=0.01) 8 days following treatment.ConclusionsDuoBody-PD-L1×4-1BB demonstrated biologic activity and a manageable safety profile. Encouraging early clinical activity across different dose levels was observed in a heavily pretreated population with advanced solid tumors, including those resistant to prior immunotherapy or typically less sensitive to ICIs. Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.AcknowledgementsThe authors thank Manish Gupta, Lei Pang, and Thomas Breuer at Genmab A/S; Alice Bexon, Alexander Muik, and Friederike Gieseke at BioNTech SE; and Zuzana Jirakova (formerly at BioNTech SE) for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE.Trial RegistrationClinicalTrials. gov; trial number: NCT03917381Ethics ApprovalThis trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.ConsentWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5600-TPS5600
Author(s):  
Ramaswamy Govindan ◽  
Amanda Rose Townsend ◽  
Kathy D. Miller ◽  
Inderjit Mehmi ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Solid Tumors ◽  
Triple Negative ◽  
Phase 1 ◽  
Locally Advanced ◽  
Maximum Plasma ◽  
High Grade ◽  
Serous Ovarian Cancer

TPS5600 Background: KIF18A is a mitotic kinesin motor protein that regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. TP53 mutant unstable aneuploid cancer cells with chromosomal instability (CIN) features are dependent on KIF18A motor activity to prevent lethal multipolar cell division. Preclinical data demonstrate that treatment with AMG 650; an oral, first in class, selective small molecule inhibitor of KIF18A may be safe and tolerable. We are conducting a first-in-human phase 1 study with AMG 650 in adult subjects with locally advanced or metastatic solid tumors with TP53MUT, triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC) or serous like endometrial cancers and other solid tumors. Methods: In this phase 1, multicentric, dose escalation and dose expansion study we evaluate the safety and tolerability of AMG 650 monotherapy in patients with advanced/metastatic solid tumors (NCT04293094). The main objective is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) based on emerging safety, efficacy, and pharmacodynamics (PD) data prior to reaching the MTD. Key inclusion criteria include the presence of measurable disease and diagnosis of advanced/metastatic triple negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC), serous-like endometrial cancer or other solid tumors with documented TP53 mutations. In the dose expansion phase, participants with locally advanced or metastatic TNBC or HGSOC will be treated with the preliminary RP2D identified from the dose exploration part of the study. Primary endpoints include the incidence of Dose Limiting Toxicities (DLTs),Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment-related Adverse Events and the evaluation of the number of participants who experience a clinically significant change from baseline in vital signs, electrocardiogram and laboratory tests parameters. Secondary endpoints include Objective Response Rate, Duration of Response, Progression-free Survival, Clinical Benefit Rate, Time to Response, Time to Progression, Overall Survival (OS), Maximum Plasma Concentration (Cmax) of AMG 650, Time to Maximum Plasma Concentration (Tmax) of AMG 650 as well as Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval for AMG 650. Continuous monitoring of toxicity is conducted. The study began enrolling pts in March 2020 and is ongoing. For more information, please contact Amgen Medical Information: [email protected] Clinical trial information: NCT04293094.

A multicenter open-label phase 1 study evaluating the safety and tolerability of HMPL-306 in patients with locally advanced or metastatic solid tumors with IDH mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3159-TPS3159
Author(s):  
Filip Janku ◽  
John S. Kauh ◽  
Christopher Tucci ◽  
Zhao Yang ◽  
Marek K. Kania ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tricarboxylic Acid Cycle ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Low Grade Glioma ◽  
Statistical Hypothesis ◽  
Low Grade ◽  
Open Label ◽  
Idh Mutations

TPS3159 Background: Isocitrate dehydrogenase (IDH) is a rate-limiting tricarboxylic acid cycle enzyme with 3 isoforms. Mutations in IDH1 and IDH2 result in gain-of-function activity that can cause tumor formation and/or progression and have been associated with various tumor types. Therefore, selective, single mutant IDH (mIDH) isotype inhibitors (mIDH1 or mIDH2) can lead to insufficient efficacy and the potential for tumor resistance. HMPL-306 is an innovative, small-molecule, orally available, highly selective, potent inhibitor of both mIDH1 and mIDH2. Clinical development of a compound that concurrently targets, inhibits, and suppresses multiple mIDHs could lead to significant and durable clinical benefit for patients (pts) with solid tumors harboring IDH mutations. Methods: This is a phase 1, open-label, dose escalation (Part 1) and dose expansion (Part 2) study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-306 in pts ≥18 years with locally advanced or metastatic solid tumors with any IDH mutations. HMPL-306 will be administered orally, once daily in a 28-day continuous dosing treatment cycle. The HMPL-306 dose will be escalated in Part 1 according to the modified toxicity probability interval-2 (mTPI-2) design in 4 cohorts in approximately 15-20 pts: 50, 100, 150, and 200 mg. Eligible pts must have locally advanced or metastatic solid tumors with IDH1 or IDH2 mutations. The primary objectives are to evaluate safety, dose limiting toxicities (DLTs), tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and PK. Approximately 95 pts will be enrolled at the RP2D in Part 2 to further characterize the safety, tolerability, PK, PD, and preliminary anti-tumor activities of HMPL-306. Part 2 will include 5 dose expansion cohorts: cholangiocarcinoma (n = 20), skeletal chondrosarcoma (n = 20), low-grade glioma (n = 20), perioperative low-grade glioma (n = 15), any other solid tumor harboring an IDH1/2 mutation (n = 20). All pts will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or at the investigator’s discretion. Safety will be assessed based on reports of adverse events including clinical laboratory testing, vital signs, physical examinations, and electrocardiograms. All pts who receive any study treatment will be included in safety and efficacy analyses. Antitumor activity based on investigator-assessed overall response will be evaluated using descriptive analyses. Objective response rate will be calculated with 95% confidence interval using the Clopper-Pearson method. The Kaplan-Meier method will be used to summarize the time-to-event data such as progression-free survival and duration of response. No statistical hypothesis testing is planned. Enrollment started February 2021.

Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric patients with relapsed/refractory solid tumors or myelodysplastic syndrome (MDS): A Children's Oncology Group Phase I Consortium study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10023-10023
Author(s):  
S. L. Berg ◽  
H. Russell ◽  
M. Cairo ◽  
A. M. Ingle ◽  
P. C. Adamson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Fixed Dose ◽  
Ischemic Event ◽  
Thromboembolic Risk ◽  
Once Daily ◽  
Antiproliferative Effects ◽  
Dose Levels

10023 Background: LEN, which has immunomodulatory, antiangiogenic, and antiproliferative effects, is indicated for the treatment of adults with MDS and multiple myeloma. We report the final results of a phase 1 and PK study of LEN in children with recurrent or refractory solid tumors (ST) or MDS. Methods: LEN was administered by mouth once daily for 21 of 28 days. Cohorts of 3 to 12 children with ST were enrolled at 15, 25, 40, 55 and 70 mg/m2/d dose levels. Children with MDS received a fixed dose of 5 mg/m2/d. PK and correlative biology studies were performed in cycle 1. Results: 49 patients (23 female), median age 16 years (range, 1–21) were enrolled and received a median of 1 cycle (range 1–11). 39/46 ST patients and 3/3 MDS patients were fully evaluable for toxicity. 0/3 patients with MDS had DLT. At 15 mg/m2/d, 1/6 ST patients developed DLT (Gr 3 hypercalcemia). At 25 mg/m2/d 1 patient had a cerebrovascular ischemic event of uncertain relationship to LEN; future subjects were screened for thromboembolic risk factors prior to enrollment. At 40 mg/m2/d 3/12 patients developed DLTs (Gr 3 hypophosphatemia/hypokalemia; Gr 4 neutropenia delaying the start of the next cycle for > 7 days; Gr 3 somnolence); at 55 mg/m2/d 1/6 patients developed DLT (Gr 3 urticaria). At 70 mg/m2/d 0/6 patients had DLT. No further dose escalation was attempted. No objective responses were observed. LEN enhanced IL-2 and IL-15 concentrations; NK expansion and activation; and NK and LAK cytotoxicity (Ayello, ASH, 2008). The median apparent LEN clearance and half-life were 135 ± 45 ml/min/m2 and 2.3 ± 1.1 hr. Conclusions: LEN is well tolerated at doses up to 70 mg/m2/d x 21d of 28 days in children with recurrent or refractory ST. Enhancement of immune function is significant. PK parameters in children are similar to those in adults. No significant financial relationships to disclose.

FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3157-TPS3157 ◽  
Author(s):  
David Michael Hyman ◽  
Lipika Goyal ◽  
Petros Grivas ◽  
Funda Meric-Bernstam ◽  
Josep Tabernero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Tumor Type ◽  
Phase 2 ◽  
Alternative Treatment Option

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.

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