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

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2003 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2003-2003 ◽

Cited By ~ 5

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]

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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

Neuro-Oncology ◽

10.1093/neuonc/noz175.107 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi28-vi29 ◽

Cited By ~ 5

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.

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A Randomized Phase 1 Pharmacokinetic Study Comparing the Potential Biosimilar LRG201902 With Liraglutide (Victoza®) in Healthy Male Subjects

Frontiers in Pharmacology ◽

10.3389/fphar.2020.610880 ◽

2021 ◽

Vol 11 ◽

Author(s):

Gang Mai ◽

Lianlian Fan ◽

Mupeng Li ◽

Peiwen Zhang ◽

Chunyan Gan ◽

...

Keyword(s):

Phase 1 ◽

Geometric Mean ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Post Dose ◽

Time Profiles ◽

Healthy Adult Male ◽

To Receive ◽

Second Period ◽

Male Subjects

Objective: Pharmacokinetic (PK) similarity between biosimilar candidate LRG201902 and European Union-sourced liraglutide reference product (Victoza®) was evaluated. Safety and immunogenicity were also assessed.Methods: This single-dose, randomized, open-label, 2-period crossover study (CTR20192342) was conducted in thirty-eight healthy adult male subjects. Volunteers were randomized 1:1 at the beginning to receive a single 0.6 mg dose of Victoza® or LRG201902 by subcutaneous injection during the first period. Following 8 days washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 72 h after administration. The primary pharmacokinetic endpoints were AUC0–t, AUC0–∞, and Cmax. Pharmacokinetic similarity was achieved if 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUC0-t, AUC0–∞, and Cmax were within the range of 80–125%. Other pharmacokinetic parameters including Tmax, t½, and λz were also measured. Safety profile and immunogenicity data were collected from each subject.Results: Cmax, AUC0–t, and AUC0–∞ were similar between the two groups. GMRs of Cmax, AUC0–t, and AUC0–∞ were 113.50%, 107.21%, and 106.97% between LRG201902 and Victoza® respectively. The 90% CIs for the GMRs of Cmax, AUC0-t, and AUC0–∞ were all within the PK equivalence criteria. Mean serum concentration-time profiles, secondary pharmacokinetic parameters (Tmax, t½, and λz) were comparable between groups. Treatment-related adverse events were reported by 27.8% and 23.7% subjects in the LRG201902 and Victoza® arms, respectively. All post-dose samples were detected negative for anti-drug antibodies.Conclusion: This study demonstrates pharmacokinetic similarity of LRG201902 to Victoza® in healthy subjects. The safety and immunogenicity profiles were similar for the two products.

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A randomized study to evaluate safety and immunogenicity of the BNT162b2 COVID-19 vaccine in healthy Japanese adults

Nature Communications ◽

10.1038/s41467-021-27316-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Miwa Haranaka ◽

James Baber ◽

Yoichiro Ogama ◽

Masako Yamaji ◽

Masakazu Aizawa ◽

...

Keyword(s):

Adverse Events ◽

Phase 1 ◽

Geometric Mean ◽

Randomized Study ◽

Age Groups ◽

Serious Adverse Events ◽

Robust Immune Response ◽

Japanese Adults ◽

To Receive ◽

Ongoing Phase

AbstractWe report interim safety and immunogenicity findings from an ongoing phase 1/2 study of BNT162b2 in healthy Japanese adults. Participants were randomized 3:1 to receive 2 intramuscular injections of 30 μg BNT162b2 or placebo 21 days apart. Overall, 160 individuals were randomized: 119 received BNT162b2, and 41 received placebo. Participants were stratified by age: 20–64 years (n = 130) and 65–85 years (n = 30). More than 97% of BNT162b2 recipients received 2 doses. Local reactions and systemic events were generally transient and mild to moderate. Severe adverse events were uncommon; there were no serious adverse events. One month after dose 2, SARS-CoV-2 50% serum neutralizing geometric mean titers were 571 and 366, and geometric mean fold rises were 55.8 and 36.6, in the younger and older age groups, respectively. In summary, BNT162b2 has an acceptable safety profile and produces a robust immune response, regardless of age, in Japanese adults. (ClinicalTrials.gov, NCT04588480).

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A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-020-01055-5 ◽

2021 ◽

Author(s):

Noboru Yamamoto ◽

Toshio Shimizu ◽

Kan Yonemori ◽

Shigehisa Kitano ◽

Shunsuke Kondo ◽

...

Keyword(s):

Liver Function ◽

Solid Tumors ◽

Dose Escalation ◽

Enzyme Inhibitor ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Open Label ◽

Phase 1 Study ◽

Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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A phase 1, open-label, drug–drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04338-7 ◽

2021 ◽

Author(s):

Mingxiang Liao ◽

Krzysztof G. Jeziorski ◽

Monika Tomaszewska-Kiecana ◽

István Láng ◽

Marek Jasiówka ◽

...

Keyword(s):

Drug Interaction ◽

Solid Tumors ◽

Oral Contraceptives ◽

Interaction Analysis ◽

Phase 1 ◽

Geometric Mean ◽

Pharmacokinetic Analysis ◽

Advanced Solid Tumors ◽

Open Label ◽

Drug Drug Interaction

Abstract Purpose This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives. Methods Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis. Results Thirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug–drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration–time curve from time zero to last quantifiable measurement (AUC0–last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment. Conclusion Rucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib. ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.

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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

International Journal of Clinical Oncology ◽

10.1007/s10147-021-01902-2 ◽

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.

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Pharmacokinetic Interactions between Primaquine and Chloroquine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02794-13 ◽

2014 ◽

Vol 58 (6) ◽

pp. 3354-3359 ◽

Cited By ~ 50

Author(s):

Sasithon Pukrittayakamee ◽

Joel Tarning ◽

Podjanee Jittamala ◽

Prakaykaew Charunwatthana ◽

Saranath Lawpoolsri ◽

...

Keyword(s):

Oral Dose ◽

Hospital Admissions ◽

Geometric Mean ◽

Pharmacokinetic Interaction ◽

Plasmodium Ovale ◽

Open Label ◽

Content Type ◽

Reference Number ◽

Electrocardiographic Changes ◽

To Receive

ABSTRACTChloroquine combined with primaquine has been the standard radical curative regimen forPlasmodium vivaxandPlasmodium ovalemalaria for over half a century. In an open-label crossover pharmacokinetic study, 16 healthy volunteers (4 males and 12 females) aged 20 to 47 years were randomized into two groups of three sequential hospital admissions to receive a single oral dose of 30 mg (base) primaquine, 600 mg (base) chloroquine, and the two drugs together. The coadministration of the two drugs did not affect chloroquine or desethylchloroquine pharmacokinetics but increased plasma primaquine concentrations significantly (P≤ 0.005); the geometric mean (90% confidence interval [CI]) increases were 63% (47 to 81%) in maximum concentration and 24% (13 to 35%) in total exposure. There were also corresponding increases in plasma carboxyprimaquine concentrations (P≤ 0.020). There were no significant electrocardiographic changes following primaquine administration, but there was slight corrected QT (QTc) (Fridericia) interval lengthening following chloroquine administration (median [range] = 6.32 [−1.45 to 12.3] ms;P< 0.001), which was not affected by the addition of primaquine (5.58 [1.74 to 11.4] ms;P= 0.642). This pharmacokinetic interaction may explain previous observations of synergy in preventingP. vivaxrelapse. This trial was registered at ClinicalTrials.gov under reference number NCT01218932.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps3159 ◽

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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Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2564 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2564-2564

Author(s):

Dominique Berton ◽

Susana N. Banerjee ◽

Giuseppe Curigliano ◽

Sara Cresta ◽

Hendrik-Tobias Arkenau ◽

...

Keyword(s):

Antitumor Activity ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Solid Tumors ◽

Phase 1 ◽

Objective Response ◽

Low Grade ◽

Open Label ◽

Tumor Types

2564 Background: Dostarlimab is an investigational, humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1 and PD-L2. GARNET (NCT02715284) is a phase 1 study assessing the antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors. Methods: This multicenter, open-label, single-arm study is being conducted in 2 parts: dose escalation and expansion. Here we report on the 2 expansion cohorts that enrolled mismatch repairdeficient/microsatellite instabilityhigh (dMMR/MSI-H) patients. Cohort A1 enrolled patients with advanced or recurrent dMMR/MSI-H endometrial cancer (EC), and cohort F enrolled patients with advanced or recurrent dMMR/MSI-H or POLε-hypermutated non-EC solid tumors, mainly gastrointestinal (GI) tumors (99 [93.4%] had GI tumors, including 69 [65.1%] with colorectal cancer). Patients received 500 mg IV of dostarlimab every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks until disease progression or discontinuation. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by RECIST v1.1. Here we report ORR and DOR, by individual cohort and as an overall population, in patients with dMMR tumors identified by immunohistochemistry testing. Results: For this interim analysis, an efficacy analysis was performed for the patients who had baseline measurable disease and ≥6 months of follow-up in the study (N = 209). The ORR was 41.6% (95% CI, 34.9%48.6%) for the combined A1+F dMMR cohorts (Table). Responses were durable, and median DOR has not been reached in either cohort (median follow-up: cohort A1, 16.3 months; cohort F, 12.4 months). A total of 267 patients were included in the safety population (all patients who received ≥1 dose; cohort A1, N = 126; cohort F, N = 141). Treatment-related adverse events (TRAEs) were consistent across tumor types. Overall, the most frequently reported any-grade TRAEs were asthenia (13.9%), diarrhea (13.5%), and fatigue (11.2%). The most common grade ≥3 TRAEs were anemia (2.2%), lipase increased (1.9%), alanine aminotransferase increased (1.1%), and diarrhea (1.1%). No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in patients with dMMR solid tumors, with consistent antitumor activity seen across endometrial and nonendometrial tumor types. The safety profile was manageable, with no new safety signals detected. Most TRAEs were low grade and were similar across cohorts. Clinical trial information: NCT02715284. [Table: see text]

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