scholarly journals ACTR-66. A PHASE 1, OPEN-LABEL, PERIOPERATIVE STUDY OF IVOSIDENIB (AG-120) AND VORASIDENIB (AG-881) IN RECURRENT IDH1 MUTANT, LOW-GRADE GLIOMA: UPDATED RESULTS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi29 ◽  
Author(s):  
Ingo Mellinghoff ◽  
Timothy Cloughesy ◽  
Patrick Wen ◽  
Jennie Taylor ◽  
Elizabeth Maher ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Phase 1 ◽  
Low Grade ◽  
Wild Type ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1 ◽  
Drug Concentrations ◽  
Reference Samples ◽  
Ongoing Phase ◽  
Orthotopic Glioma

Abstract BACKGROUND Ivosidenib (AG-120, IVO) is a first-in-class oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), and vorasidenib (AG-881, VOR) is an oral, potent, brain-penetrant inhibitor of mIDH1/2. Both have been evaluated in glioma patients in ongoing phase 1 studies. In orthotopic glioma models, IVO and VOR reduced 2-hydroxyglutarate (2-HG) levels by 85% and 98%, respectively, despite different brain-to-plasma ratios (< 0.04 vs 1.33). METHODS Patients with recurrent, nonenhancing, WHO-2016 grade 2/3, mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500mg QD, VOR 50mg QD, or no treatment (cohort 1), or 1:1 to IVO 250mg BID or VOR 10mg QD (cohort 2), for 4 weeks preoperatively. Postoperatively, patients continued receiving IVO or VOR (control patients were randomized 1:1 to IVO or VOR). Tumors were assessed for mIDH1 status, cellularity, and 2-HG and drug concentrations. Treated subjects were compared with controls and mIDH1/wild-type banked reference samples. Primary endpoint: tumor 2-HG concentration following IVO or VOR. RESULTS As of March 1, 2019, 27 patients (18 men; 25/2 grade 2/3) were randomized preoperatively in cohort 1 (IVO 10, VOR 12, untreated 5): 27 received drug (IVO 13, VOR 14); 1 discontinued VOR postoperatively due to disease progression. Of 26 tumors analyzed, 22 were evaluable. Mean brain-to-plasma ratios: 0.13 IVO, 1.59 VOR. Relative to untreated samples, IVO and VOR reduced tumor 2-HG by 92.0% (95% CI 73.2, 97.4) and 92.5% (95% CI 78.1, 97.7), respectively. Common (≥ 4 patients) TEAEs (all cohort 1 patients, all grades): diarrhea (37.0%), constipation, hypocalcemia, and nausea (each 18.5%), anemia, hyperglycemia, pruritus, headache, and fatigue (each 14.8%). Cohort 2 has completed accrual, with analyses ongoing. CONCLUSIONS In cohort 1 of this phase 1 perioperative study, IVO and VOR demonstrated brain penetrance and lowered 2-HG compared with controls. Updated data from both cohorts will be presented.

A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: Results from cohort 1.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2003-2003 ◽  
Author(s):  
Ingo K. Mellinghoff ◽  
Timothy Francis Cloughesy ◽  
Patrick Y. Wen ◽  
Jennie Webster Taylor ◽  
Elizabeth A. Maher ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase 1 ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Open Label ◽  
Phase 1 Study ◽  
Isocitrate Dehydrogenase 1 ◽  
And Control ◽  
To Receive ◽  
Ongoing Phase

2003 Background: AG-120 (ivosidenib [IVO]) is a first-in-class oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) evaluated in 66 glioma patients (pts) in an ongoing phase 1 study. AG-881 (vorasidenib [VOR]) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 evaluated in 52 glioma pts in an ongoing phase 1 study. In an orthotopic glioma model, IVO and VOR reduced 2-hydroxyglutarate (2-HG) by 85% and 98%, respectively, despite different brain:plasma ratios (<0.04 vs 1.33). Methods: Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment in mIDH1 low-grade glioma. Pts with recurrent non-enhancing WHO-2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500mg QD, VOR 50mg QD, or no treatment for 4 wks preoperatively in Cohort 1. Post-operatively, pts continued to receive IVO or VOR and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared to control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Pts with non-evaluable tissue were replaced. Results: As of 29 Nov 2018, 26 pts (17M, 9F; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5), 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed with 16 evaluable. Common (>10%) TEAEs (all grade 1/2): diarrhea (36%), hypocalcemia and constipation (each 20%), anemia, hyperglycemia, pruritus, headache and nausea (each 16%), and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio: 0.16 for IVO, 2.4 for VOR. Tumor 2-HG results are shown in Table. Updated data from Cohort 1 will be presented. Conclusions: In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered 2-HG compared to untreated samples. Cohort 2 is open and will evaluate IVO 250mg BID and VOR 10mg QD. Brain tumor 2-HG concentration. Clinical trial information: NCT03343197. [Table: see text]

scholarly journals PL3.1 A phase 1, open-label, perioperative study of ivosidenib (AG-120) and vorasidenib (AG-881) in recurrent, IDH1-mutant, low-grade glioma: results from cohort 1

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii2-iii2
Author(s):  
I K Mellinghoff ◽  
P Y Wen ◽  
J W Taylor ◽  
E A Maher ◽  
I Arrillaga-Romany ◽  
...  
Keyword(s):  
Phase 1 ◽  
Geometric Mean ◽  
Low Grade ◽  
Wild Type ◽  
Treatment Control ◽  
Open Label ◽  
Phase 1 Study ◽  
And Control ◽  
To Receive ◽  
Ongoing Phase

Abstract BACKGROUND Mutant isocitrate dehydrogenase (mIDH) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO; AG-120) is a first-in-class oral inhibitor of mIDH1 being evaluated in 66 glioma patients (pts) in an ongoing phase 1 study (NCT02073994). Vorasidenib (VOR; AG-881) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 being evaluated in 52 glioma pts in an ongoing phase 1 study (NCT02481154). In an orthotopic glioma model, IVO and VOR reduced 2-HG levels by 85% and 98%, respectively, despite different brain:plasma ratios (<0.04 vs 1.33). MATERIAL AND METHODS This is a phase 1, multicenter, open-label, perioperative study (NCT03343197). Pts with recurrent, nonenhancing WHO 2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500 mg QD, VOR 50 mg QD, or no treatment (control) for 4 wk preoperatively in Cohort 1. Postoperatively, pts continued to receive IVO or VOR, and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared with control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment. Pts with nonevaluable tissue were replaced. RESULTS As of 29 Nov 2018, 26 pts (17 men, 9 women; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5) and 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed, with 16 evaluable. Treatment-emergent adverse events in >10% of patients (all Gr 1 or 2) were diarrhea (36%); hypocalcemia and constipation (each 20%); anemia, hyperglycemia, pruritus, headache, and nausea (each 16%); and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio was 0.16 for IVO and 2.4 for VOR. Geometric mean (range) tumor 2-HG levels (μg/mL) were: IVO (n=6), 10 (2.2-104); VOR (n=6), 6.8 (3.9-10); control mIDH1 (n=65 [4 pts, 61 ref]), 141 (4.8-909); and WT ref (n=15), 2.7 (0.46-12). Mean changes (95% CI) in 2-HG level vs control were IVO -93% (74%, 98%) and VOR -95% (82%, 99%). Updated data from Cohort 1 will be presented. CONCLUSION In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered tumor 2-HG levels compared with untreated samples. Cohort 2 is open and will evaluate IVO 250 mg BID and VOR 10 mg QD. FUNDING Agios Pharmaceuticals, Inc.

scholarly journals Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants

2018 ◽  
Vol 475 (20) ◽  
pp. 3221-3238 ◽  
Author(s):  
Diego Avellaneda Matteo ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
Adam J. Grunseth ◽  
Olga Zagnitko ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Resistance Mutation ◽  
Poor Response ◽  
Fold Increase ◽  
Structural Features ◽  
Low Grade ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Dynamics Simulations ◽  
Mutant Idh1

Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

Anatomical location differences between mutated and wild-type isocitrate dehydrogenase 1 in low-grade gliomas

2017 ◽  
Vol 127 (10) ◽  
pp. 873-880 ◽  
Author(s):  
Jinhua Yu ◽  
Zhifeng Shi ◽  
Chunhong Ji ◽  
Yuxi Lian ◽  
Yuanyuan Wang ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Anatomical Location ◽  
Low Grade ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Low Grade Gliomas

scholarly journals Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma

2020 ◽  
Vol 38 (29) ◽  
pp. 3398-3406 ◽  
Author(s):  
Ingo K. Mellinghoff ◽  
Benjamin M. Ellingson ◽  
Mehdi Touat ◽  
Elizabeth Maher ◽  
Macarena I. De La Fuente ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Isocitrate Dehydrogenase ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Adverse Event Rate ◽  
Low Grade ◽  
Lower Grade ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1

PURPOSE Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

scholarly journals ATIM-31. SAFETY OF TUMOR-SPECIFIC PEPTIDE VACCINE TARGETING ISOCITRATE DEHYDROGENASE 1 MUTATION IN RECURRENT RESECTABLE LOW GRADE GLIOMA PATIENTS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi8-vi8
Author(s):  
Katherine Peters ◽  
Kendra Congdon ◽  
Gary Archer ◽  
Sarah Woodring ◽  
Denise Jaggers ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Isocitrate Dehydrogenase ◽  
Phase 1 ◽  
Peptide Vaccine ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Grade Ii ◽  
Specific Peptide

Abstract BACKGROUND Low grade gliomas (LGGs) represent 10–15% of glial tumors in adults and while LGG patients have a better prognosis over high-grade gliomas, these cancers ultimately recur and transform to more aggressive tumors. Isocitrate dehydrogenase 1 (IDH1) is commonly mutated in LGG, and when mutated, it is the oncogenic driver by leading to the production of oncometabolite 2-hydroxyglutarate (2-HG). We developed a phase 1 study for recurrent resectable IDH1 mutant LGG utilizing a tumor-specific peptide vaccine targeting IDH1 mutant protein that spans the mutated region of IDHR132H (PEPIDH1M vaccine). METHODS We performed a phase 1, single-center, clinical trial in recurrent resectable IDH1 mutant WHO grade II glioma patients. Subjects received three PEPIDH1M vaccine q2wks and then proceeded to surgical resection. If subject’s tumor retained grade II status, then the subject proceeded with 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). If subject’s tumor transformed to grade III, then subject proceeded to radiation therapy (RT) with concurrent TMZ followed by 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). Primary endpoint was safety of PEPIDH1M vaccine in combination with adjuvant TMZ and/or XRT/TMZ and evaluable subjects needed to receive ≥6 PEPIDH1M vaccines. We assessed safety using CTCAE 4.03. RESULTS We enrolled 24 recurrent LGG subjects with mean age of 43.8 yrs (sd=11.4 yrs). Twenty subjects completed ≥6 PEPIDH1M vaccines. Most common related toxicity was grade 1 injection site reaction (N=20) and skin induration (n=17) with no grade 3–4 related toxicities. CONCLUSIONS PEPIDH1M vaccine in combination with surgical resection, daily TMZ and/or RT + TMZ with daily TMZ was safe and well tolerated in recurrent IDH1 mutant LGG. We are currently exploring secondary/correlative endpoints including immunogenicity of PEPIDH1M vaccine and magnetic resonance spectroscopy for 2-HG.

scholarly journals CBMT-10. MUTANT ISOCITRATE DEHYDROGENASE 1 INHIBITION INDUCES A UNIQUE MRS-DETECTABLE METABOLIC SIGNATURE IN LOW-GRADE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi34-vi35
Author(s):  
Abigail Molloy ◽  
Aliya Lakhani ◽  
Chloé Najac ◽  
Elavarasan Subramani ◽  
Anne Marie Gillespie ◽  
...  
Keyword(s):  
Cell Lines ◽  
Isocitrate Dehydrogenase ◽  
Phase 1 ◽  
Genetically Engineered ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
1H Mrs ◽  
Low Grade Gliomas ◽  
Non Invasive

Abstract Mutations in isocitrate dehydrogenase 1/2 (IDHmut) are reported in 70–90% of low-grade gliomas and secondary glioblastomas. IDHmut catalyzes the reduction of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that drives tumorigenesis. Inhibition of IDHmut is therefore a rapidly emerging therapeutic approach and IDHmut inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. The goal of this study was to identify early non-invasive metabolic biomarkers of IDHmut inhibition that can serve to moniter response to these therapies. We used 1H and 13C magnetic resonance spectroscopy (MRS) to investigate the response of two genetically-engineered IDHmut cell lines (U87-based and normal human astrocyte-based) to AG-120 and AG-881 treatment. As expected, in both cell lines, our 1H-MRS data indicated that AG-120 and AG-881 induced a significant decrease in 2-HG. Interestingly however, we also observed a significant increase in phosphocholine and glutamate, pointing to broader changes in the metabolism of treated cells and a unique MRS signature. To further investigate the increase in glutamate induced by AG-120 and AG-881 in our models, we used 13C-MRS and quantified the flux of [1-13C] glucose and [3-13C] glutamine to 13C-labeled glutamate. Our results indicate that both AG-120 and AG-881 significantly increase the flux of 13C-labeled glutamine to 13C glutamate, while the flux of 13C-labeled glucose to 13C glutamate remained unchanged. Further studies are currently underway to explore the utility of using hyperpolarized [1-13C]-glutamine and hyperpolarized [1-13C]-a-KG for monitoring flux to glutamate and 2-HG, and to validate these probes as additional biomarkers of response to IDHmut inhibition. Taken together, our studies indicate that IDHmut inhibition induces a unique MRS-detectable metabolic profile that can potentially be exploited for early non-invasive, clinically translatable detection of response to emerging IDHmut inhibitors.

scholarly journals Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study

2021 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yasutoshi Kuboki ◽  
Makio Gamoh ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Wild Type ◽  
Open Label ◽  
Safety And Efficacy ◽  
Multicentre Phase

Abstract Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

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.

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