Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600–mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

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An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps2671 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS2671-TPS2671

Author(s):

Mark R. Middleton ◽

Joseph J. Sacco ◽

Jaime R. Merchan ◽

Brendan D. Curti ◽

Ari M. Vanderwalde ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Single Agent ◽

Objective Response ◽

Phase 2 ◽

Biomarker Analysis ◽

Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

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Phase I trial of Seneca Valley Virus (NTX-010), a newly discovered systemically deliverable oncolytic picornavirus, in patients with solid tumors with neuroendocrine features

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18014 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18014-18014

Author(s):

C. M. Rudin ◽

D. Lansey ◽

K. D. Burroughs ◽

L. M. Hales ◽

J. R. Neefe ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Metastatic Cancer ◽

Cell Cancer ◽

Safety Data ◽

Small Cell ◽

Low Grade ◽

Viral Kinetics ◽

Xenograft Models

18014 Background: NTX-010 is a replication-competent cytolytic picornavirus with selective tropism for cancers with neuroendocrine features. NTX-010 mediates high selective cytotoxicity for tumor cells with neuroendocrine properties and has no cytotoxicity on any human adult cell type tested. Antitumor efficacy has been demonstrated in 11/11 xenograft models, including metastatic, orthotopic, and syngeneic models. Intravenous (IV) administration of doses as low as 107 vp/kg are effective in xenograft models of small cell lung cancer. No significant toxicity in animals is seen at doses up to 1013 vp/kg. Methods: We initiated a single dose administration phase I dose-escalation study in patients with advanced solid tumors with neuroendocrine markers (CD56+, synaptophysin+, or chromogranin A+), starting at 107 vp/kg IV over 1h. Planned dose escalation is in log increments. Results: The first dose cohort has been completed, with no dose-limiting toxicities observed. Low grade fever, chills, arthralgias and myalgias starting 3 - 4 days after virus administration and lasting less than a week have been noted. The first study subject, with a widely metastatic small cell cancer with bladder invasion, demonstrated viral replication in vivo peaking d4 with >10,000-fold amplification of the input dose. This subject had complete clearance of infectious virus by day 17, but persistence of viral RNA detectable by RT-PCR in blood and urine until the time of her death from metastatic cancer on day 28. Autopsy demonstrated extensive intratumoral necrosis, and immunohistochemistry confirmed the presence of NTX-010 capsid protein in liver metastases but not adjacent normal liver. Conclusions: NTX-010 is a novel first-in-class anticancer virus with selective tropism for tumors with neuroendocrine features. This is the first anticancer virus given intravenously with documented selective intratumoral infection and replication. Administration was well tolerated. Safety data and viral kinetics will be presented. No significant financial relationships to disclose.

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Phase I experience with first in class TnMUC1 targeted chimeric antigen receptor T-cells in patients with advanced TnMUC1 positive solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14513 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14513-e14513

Author(s):

Rodolfo Gutierrez ◽

Payal D Shah ◽

Omid Hamid ◽

Alfred L. Garfall ◽

Avery Posey ◽

...

Keyword(s):

T Cells ◽

Phase I ◽

Solid Tumors ◽

Chimeric Antigen Receptor ◽

Dose Escalation ◽

Intracellular Signaling ◽

Antigen Receptor ◽

Low Grade ◽

Gi Symptoms ◽

Dose Levels

e14513 Background: MUC1 is a glycoprotein that is expressed in healthy tissues on the luminal surface of simple and glandular epithelium. In tumors that arise from these cells, an alternate form with aberrant glycosylation is frequently over expressed and distinguishes tumor associated TnMUC1 from normal MUC1. We have generated a novel chimeric antigen receptor (CAR) targeting the TnMUC antigen comprised of a mouse anti-human scFv derived from the monoclonal antibody 5E5 which recognizes the epitope comprising Tn glycan of MUC1, a CD8a transmembrane region and dual CD2 and CD3z intracellular signaling domains. CD2 signaling in T-cells has been demonstrated to result in delayed exhaustion. The novel incorporation of this co-stimulatory domain may lead to enhanced persistence of the CART cells which is believed to be critical for efficacy in solid-tumors. Methods: This is a multi-center first in human Phase I study to evaluate the safety and preliminary efficacy of CART-TnMUC1-Cells for the treatment of solid-tumors. Solid-tumors included in the dose-escalation phase include metastatic treatment-resistant ovarian cancer (OC), pancreatic adenocarcinoma (PC), triple-negative breast cancer (TNBC) or non-small lung cancer (NSCLC). All patients must have TnMUC1 expression as determined by immunohistochemistry. Results: As of January 2021, a total of six patients were treated. Three in Cohort 1 (no lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 OC, 1 TNBC and 1 PC) and 3 in Cohort 2 (flu/cy lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 NSCLC and 2 OC). None of the patients treated experienced DLT’s. The trial is currently enrolling to Cohort 3 (flu/cy lymphodepletion, 5-6 x 107 TDN). No CRS, neurotoxicity, serious adverse reactions and no on-target/off-tumor toxicity was observed at these dose levels. The most common AE’s were low-grade GI symptoms (e.g., nausea, abdominal pain) in 5/6 patients (83.3%), generalized disorders (e.g., chills, fatigue) in 5/6 (83.3%) and hematologic disorders (e.g., anemia, neutropenia) in 3/6 (50%) of patients. CAR expansion was demonstrated in all patients and was improved in Cohort 2 following LD chemotherapy. Preliminary efficacy assessed by RECIST v1.1 at Day +28 demonstrate SD in all patients in Cohort 2. Conclusions: This is the first report of a novel CART-TnMUC1 construct containing a CD2 co-stimulatory domain that has been used in clinical trials for the treatment of refractory solid-tumor malignancies. While the study is still early in dose-escalation having completed only 2 of 6 planned dose levels there is no evidence of safety concerns or on-target/off-tumor toxicity. Additional safety, efficacy and biomarker data is currently being reviewed and will be presented. Clinical trial information: NCT04025216.

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A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3016 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3016-3016

Author(s):

Patricia LoRusso ◽

Mrinal M. Gounder ◽

Manish R. Patel ◽

Noboru Yamamoto ◽

Todd Michael Bauer ◽

...

Keyword(s):

Antitumor Activity ◽

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Geometric Mean ◽

Dose Range ◽

Low Grade ◽

Advanced Solid Tumors ◽

Dose Escalation Study

3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

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DIPG-11. A PHASE I DOSE ESCALATION STUDY OF BXQ-350 IN CHILDREN AND YOUNG ADULTS WITH RELAPSED SOLID TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.061 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii289-iii289

Author(s):

Bhuvana Setty ◽

Timothy Cripe ◽

Mariko DeWire- Schottmiller ◽

Richard Curry ◽

Mohamed AdelBaki

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Trial ◽

Objective Response ◽

Antitumor Effects ◽

Serious Adverse Events ◽

Dose Escalation Study ◽

Pediatric Dose

Abstract BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS). BXQ-350 demonstrated antitumor effects in vitro and in vivo. Many tumors, including diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed PS-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. An adult Phase I trial with BXQ-350 completed enrollment in 2019 having dosed 86 recurrent solid tumor patients, including glioblastoma, with only one serious infusion-related reaction. The highest planned dose of 2.4 mg/kg was achieved and seven patients remain on study with multiple cases demonstrating an objective response. A Phase I pediatric dose escalation trial in recurrent solid tumors, including central nervous system (CNS) tumors, also completed enrollment in 2019. The highest planned dose of 3.2 mg/kg was achieved and there have been no BXQ-350 related serious adverse events. Eight patients (7 CNS and 1 non-CNS) completed at least one cycle with one DIPG patient completing cycle five. A pediatric Phase I trial in newly diagnosed DIPG and diffuse midline glioma (DMG) is planned for 2nd quarter 2020.

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An open-label, phase I trial of BI 754091 alone and in combination with BI 754111 in Asian patients (pts) with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3054 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3054-3054

Author(s):

Yoon-Koo Kang ◽

Kensei Yamaguchi ◽

Do-Youn Oh ◽

Shunsuke Kondo ◽

Yasutoshi Kuboki ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Primary Endpoint ◽

Dose Escalation ◽

Phase I Trial ◽

Objective Response ◽

Hepatocellular Cancer ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Open Label

3054 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, may enhance the anti-tumor response versus PD-1 blockade alone. This Phase I trial investigated BI 754091, an anti-PD-1 antibody, as monotherapy and in combination with BI 754111, an anti-LAG-3 antibody, in Asian pts with advanced solid tumors. Methods: This trial comprised 3 parts. Parts 1 and 2 (dose escalation) were in pts with unresectable/metastatic solid tumors. In Part 1, pts received BI 754091 240 mg intravenously (iv), every 3 weeks (q3w); in Part 2, pts received BI 754091 240 mg in combination with BI 754111 (400 mg, 600 mg or 800 mg iv, q3w). Dose escalation was guided by a Bayesian logistic regression model, with overdose control. The primary endpoint in Parts 1 and 2 was maximum tolerated dose (MTD) of BI 754091 alone or in combination with BI 754111, based on dose-limiting toxicities (DLTs) in Cycle 1. In Part 3, BI 754091 240 mg plus BI 754111 600 mg q3w was assessed in 4 expansion cohorts. Cohorts A–C included pts with: A) gastric/esophagogastric junction cancer; B) esophageal cancer; C) hepatocellular cancer; all had received ≥1 line of prior systemic therapy and no prior anti-PD-(L)1 therapy. Cohort D included pts who had received prior anti-PD-(L)1 therapy for the tumor types in Cohorts A–C. The primary endpoint in Part 3 was objective response (confirmed complete response or partial response [PR] per RECIST 1.1). Results: In Part 1, 6 pts received BI 754091 240 mg. In Part 2, 9 pts received BI 754091 240 mg plus BI 754111 (400 mg/600 mg/800 mg; n = 3 per cohort). No DLTs were reported in Parts 1 and 2. In Part 3, 121 pts were treated (97 [80%] male, median age 61 years [range 23–80]); Cohorts A/B/C/D included 33/33/20/35 pts. All-grade adverse events (AEs) and treatment-related AEs (TRAEs) were experienced by 96 (79%) and 47 (39%) pts, respectively. The most commonly reported AEs (all/≥G3) were pyrexia (21%/0%), decreased appetite (17%/2%), anemia (11%/6%), and nausea (9%/0%). 36 (30%) pts reported immune-related AEs, most commonly hypothyroidism, in 7 (6%) pts. Confirmed PR was observed in 6 pts (5%; Cohort A/B, n = 4/2) and 35 (29%) pts had stable disease (Cohort A/B/C/D, n = 9/11/10/5). Conclusions: MTD was not reached for BI 754091 monotherapy or for BI 754091 in combination with BI 754111. The recommended dose for the combination was determined as BI 754091 240 mg plus BI 754111 600 mg q3w. Treatment was well tolerated and consistent with that observed in the global trial. Preliminary anti-tumor activity was seen. Clinical trial information: NCT03433898 .

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Phase I study of LBL-007, a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2523 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2523-2523

Author(s):

Yuankai Shi ◽

Suxia Luo ◽

Huan Zhou ◽

Shengyu Zhou ◽

Shan An ◽

...

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Objective Response ◽

Human Study ◽

Human Antibody ◽

Advanced Solid Tumors ◽

Tumor Immune Escape

2523 Background: LAG-3 is an immune checkpoint receptor expressed on activated T cells to negatively regulate these cells, resulted in tumor immune escape. LBL-007, a novel anti-LAG-3 antibody, was developed by screening of a human antibody phage display library and demonstrated specific binding to human LAG-3, stimulation of IL-2 release and blockage of LAG-3 binding to its ligands including MHC II. It has shown that LBL-007 significantly inhibited tumor growth in a mouse MC38 tumor model in hLAG-3 knock-in mice with more pronounced tumor inhibition when combined with an anti-PD-1 antibody. Methods: A phase I, multicenter, open-label and first-in-human study was conducted to evaluate the safety, tolerability, and PK in patients with advanced solid tumors. The dose escalation phase was designed with 6 dose cohorts of LBL-007 at 0.05, 0.25, 1, 3, 6 and 10 mg/kg (iv every 2 weeks), using a modified 3+3 design. Key inclusion criteria included: age≥18 years, histologically/cytologically confirmed advanced solid tumors, failed ≥2 lines of prior standard therapies, ECOG of 0-1, and adequate hematologic, renal, hepatic, and cardiac function. Patients who received anticancer or immunotherapy 4 weeks from first dose of LBL-007 were excluded. The primary endpoints were tolerability and safety. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Any potential efficacy was assessed by objective response rate (ORR) evaluated by CT/MRI per RECIST 1.1. Results: From March 12th, 2020 to Feb 9th, 2021, 17 patients were evaluated in this study. There were no dose limiting toxicities (DLTs) at any dose cohorts, and patients were tolerated very well. Overall, there were 129 adverse events (AEs), and 8 events were serious adverse event (SAE), of which 5 were defined as suspected unexpected serious adverse reaction (SUSAR), but most unlikely treatment related AEs (TRAEs). All AEs regardless of attribution included anemia, hypocalcemia, and flu related respiratory infection, etc. The most common AEs were anemia (14, 10.9%), hypocalcemia (6, 4.7%) and thrombocytopenia (4, 3.1%). Totally, there were 8 patients without disease progression, defined as SD at the first evaluation and sustained for 3.5-9 months. The target lesions in 2 of these 8 patients were reduced by 18.9% and 23.2% (both in esophagus cancer). The progression-free survival of these 2 patients was 4.4 and 9.0 months, respectively. Patients are also being enrolled into the indication exploratory phase (3 and 6 mg/kg), testing the combination therapy with an anti-PD-1 antibody in patients with melanoma and other solid tumors. Conclusions: The dose escalation part of the study revealed tolerability of LBL-007 with an impressive safety profile, and potentially some encouraging signs of anti-tumor activities. Clinical trial: Chinaclinicaltrials.org.cn (1900025904). Clinical trial information: CTR20210196.

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RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.810 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii194-ii194

Author(s):

Ingo Mellinghoff ◽

Martin van den Bent ◽

Jennifer Clarke ◽

Elizabeth Maher ◽

Katherine Peters ◽

...

Keyword(s):

High Risk ◽

Dose Escalation ◽

Objective Response ◽

Data Monitoring Committee ◽

Progression Free Survival ◽

High Risk Population ◽

Low Grade ◽

Who Grade ◽

Free Survival ◽

Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

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