Pharmacokinetic/pharmacodynamic (PK/PD) profile of AG-120 in patients with IDH1-mutant cholangiocarcinoma from a phase 1 study of advanced solid tumors.

4082 Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) produce the oncometabolite D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class selective inhibitor of mutant IDH1 (mIDH1) under evaluation in an ongoing phase 1 study in patients with mIDH1 advanced solid tumors, including cholangiocarcinoma (CC) (NCT02073994). Objectives for this abstract were to 1) characterize the PK profile of AG-120 and the relationship between AG-120 exposure and 2-HG suppression, and 2) evaluate the influence of intrinsic patient factors on AG-120 clearance, in patients with mIDH1 CC. Methods: AG-120 was administered orally once daily (QD) or twice daily (BID) in continuous 28-day cycles. As of Dec 5, 2016, 60 of 73 patients enrolled with mIDH1 CC had PK/PD samples available for analysis at 100 mg BID, 300 mg QD, 400 mg QD, 500 mg QD, 800 mg QD, and 1200 mg QD in dose escalation (n = 24) and 500 mg QD (n = 36) in dose expansion. Blood (n = 60) and fresh tumor biopsy samples (n = 14) were collected to assess AG-120 and 2-HG using qualified liquid chromatography-tandem mass spectrometry methods. Results: Following both single and multiple doses, AG-120 plasma exposure increased less than dose proportionally from 100 to 1200 mg. Mean terminal half-life was 38.4–85.8 h, supporting a QD dosing regimen. Following multiple doses, steady state was reached within 15 days, with approximately 2-fold accumulation in plasma AG-120 exposure. No patient-specific factors were identified as clinically significant covariates affecting AG-120 plasma clearance. After multiple doses, plasma 2-HG levels were reduced (up to 98.4% inhibition, achieving levels similar to those in healthy volunteers) and tumor biopsy 2-HG levels were also substantially reduced (by up to 99.9%) at all dose levels tested. The 500 mg QD dose resulted in the largest magnitude of 2-HG inhibition vs. other dose levels. Conclusions: AG-120 demonstrated a long half-life in patients with mIDH1 CC and robustly inhibited 2-HG in plasma and tumor samples. These PK/PD data, along with emerging safety and clinical activity data, support the selection of 500 mg QD for future clinical investigation. Clinical trial information: NCT02073994.

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A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-016-3010-1 ◽

2016 ◽

Vol 77 (5) ◽

pp. 997-1003 ◽

Cited By ~ 35

Author(s):

Toshio Shimizu ◽

Kazuya Fukuoka ◽

Masayuki Takeda ◽

Tutomu Iwasa ◽

Takeshi Yoshida ◽

...

Keyword(s):

Focal Adhesion Kinase ◽

Solid Tumors ◽

Focal Adhesion ◽

Phase 1 ◽

Japanese Patients ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Phase 1 Study

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Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4074 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4074-4074 ◽

Cited By ~ 10

Author(s):

Jean-Charles Soria ◽

John H. Strickler ◽

Ramaswamy Govindan ◽

Seungjean Chai ◽

Nancy Chan ◽

...

Keyword(s):

Solid Tumors ◽

Kinase Inhibitor ◽

Phase 1 ◽

Performance Status ◽

Objective Response ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Ecog Performance Status ◽

Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

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Phase 1 Study of FS-1502 in Patients With HER2 Expressed Advanced Solid Tumors and Local Advanced or Metastatic, HER2 Positive Breast Cancer.

Case Medical Research ◽

10.31525/ct1-nct03944499 ◽

2019 ◽

Author(s):

Keyword(s):

Breast Cancer ◽

Solid Tumors ◽

Phase 1 ◽

Advanced Solid Tumors ◽

Her2 Positive ◽

Phase 1 Study ◽

Her2 Positive Breast Cancer ◽

Local Advanced ◽

Positive Breast Cancer

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Phase 1 Study of TPX-0022, a MET/CSF1R/SRC Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in MET

Case Medical Research ◽

10.31525/ct1-nct03993873 ◽

2019 ◽

Author(s):

Keyword(s):

Solid Tumors ◽

Phase 1 ◽

Genetic Alterations ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Src Inhibitor

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0417 ◽

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.

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Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001095 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001095 ◽

Cited By ~ 1

Author(s):

Lillian Siu ◽

Joshua Brody ◽

Shilpa Gupta ◽

Aurélien Marabelle ◽

Antonio Jimeno ◽

...

Keyword(s):

Radiation Therapy ◽

Solid Tumors ◽

Phase 1 ◽

Objective Response ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Palliative Radiation ◽

Cell Counts ◽

Palliative Radiation Therapy ◽

Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

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Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-010-1243-y ◽

2010 ◽

Vol 66 (5) ◽

pp. 935-943 ◽

Cited By ~ 14

Author(s):

Yasuhito Fujisaka ◽

Yasuhide Yamada ◽

Noboru Yamamoto ◽

Toshio Shimizu ◽

Yutaka Fujiwara ◽

...

Keyword(s):

Solid Tumors ◽

Phase 1 ◽

Angiogenesis Inhibitor ◽

Japanese Patients ◽

Advanced Solid Tumors ◽

Phase 1 Study

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0412 ◽

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.

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