scholarly journals 470 A phase 1/2, open-label, dose escalation and expansion study of GI-101 as a single agent and in combination with a pembrolizumab, lenvatinib or local RT in advanced solid tumors (KEYNOTE-B59)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A499-A499
Author(s):  
Byoung Chul Cho ◽  
Sang Joon Shin ◽  
Jae-Lyun Lee ◽  
Byoung Yong Shim ◽  
Hyung Soon Park ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Interleukin 2 ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Part D ◽  
Anti Tumor Activity

BackgroundGI-101 is a novel bispecific fusion protein containing CD80 and interleukin-2 (IL-2) variant, designed to exhibit high affinity to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and preferential binding to IL-2Rβ subunit. In various animal models, GI-101 exerted strong anti-tumor efficacy, accompanied by robust stimulation of CD8+ T and NK cell proliferation without a significant increase in regulatory T cells. GI-101 also elicited synergistic anti-tumor efficacy when used in combination with pembrolizumab (anti-PD1 agents), lenvatinib (tyrosine kinase inhibitor) and radiation in in vivo.1 Given the complementary mechanisms of action of GI-101 via blocking CTLA4 with IL-2 activity to enhance the proliferation and activation of effector T and NK cells, it was hypothesized that GI-101 as a single agent or in combination with other immunotherapies, VEGF inhibitors or RT may exert anti-tumor activity in cancers with high unmet needs.MethodsKEYNOTE-B59 (NCT04977453) is an ongoing phase 1/2 study composed of 4 parts. This study is planned to enroll approximately 374 patients across the indications. Patients assigned to Part A and B receive either GI-101 monotherapy (Part A) or GI-101 + 200 mg of pembrolizumab (Part B) via IV infusion on every 3 weeks (q3w). In Part C, patients will receive GI-101 q3w in combination with lenvatinib (oral, once daily). In Part D, patients will be given GI-101 q3w in combination with local tumor irradiation. Each part is initiated with dose-escalation/optimization phases which will enroll patients with advanced solid tumors, except Part D that enrolls advanced melanoma and sarcoma only. This phase utilizes conventional 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of GI-101 as a monotherapy and in combination. Once RP2D is determined, patients will be enrolled in dose-expansion phases of each part that includes specific tumor types, such as solid cancers failed on standard of care, treatment-naïve unselected or CPI-treated solid tumors. Patients with advanced solid tumors and recovered from prior therapy will be enrolled. This study will assess safety, tolerability, dose-limiting toxicities, MTD, RP2D, preliminary anti-tumor activity, and pharmacokinetics/pharmacodynamics of GI-101 as a single agent and in combination.ResultsThis study is currently enrolling patients with advanced or metastatic solid tumors.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by GI Innovation, Inc.Trial RegistrationNCT04977453ReferencePyo KH, Synn CB, Koh YJ, et al. Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeuticantibody candidate with bispecific immuno-oncology target. Cancer Res 2021;81(13_Suppl).Ethics ApprovalThis study was approved by Severance hospital institutions’ Ethics Review Board (IRB); approval number 4-2021-0185, Asan Medical center‘s IRB; approval number 2021-0669.

Phase I study of volasertib (BI 6727) combined with afatinib (BIBW 2992) in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Marc Peeters ◽  
Jean-Pascal H. Machiels ◽  
Korinna Pilz ◽  
Marina De Smet ◽  
Natalja Strelkowa ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Ecog Ps ◽  
Anti Tumor Activity

2521 Background: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases (Plk). Volasertib and afatinib, an irreversible ErbB family blocker, have shown single agent anti-tumor activity and manageable safety profiles in patients (pts) with advanced solid tumors. This dose escalation study was designed to determine the maximum tolerated dose (MTD) of two combination schedules of volasertib and afatinib in pts with advanced solid tumors refractory to or not amenable to standard therapy. Methods: In a 3 + 3 design, cohorts of 3–6 pts received volasertib 150–300 mg IV d1 Q3W + afatinib 30–50 mg PO QD d2–21 Q3W (Schedule A) or afatinib 50–90 mg d2–6 Q3W (Schedule B). Up to 12 additional pts were enrolled at the MTD. Primary endpoint was the MTD per schedule. Secondary endpoints included pharmacokinetics (PK), safety and efficacy (RECIST). Results: 57 pts (median 58 yr; ECOG PS 0/1/2: 35%/60%/5%) were treated (n=29, Schedule A; n=28, Schedule B). MTD was volasertib 300 mg/afatinib 30 mg (Schedule A) and volasertib 300 mg/afatinib 70 mg (Schedule B). Cycle 1 dose limiting toxicities (DLTs) were experienced by 5 (Schedule A) and 7 (Schedule B) pts. Most common DLTs were diarrhea (n=5), neutropenia (n=3), fatigue (n=2) and decreased ejection fraction (n=2) in Schedule A, and thrombocytopenia (n=6), neutropenia (n=5), diarrhea (n=4) and febrile neutropenia (n=3) in Schedule B. Most common grade 3/4 adverse events were neutropenia (n=8), thrombocytopenia (n=6), diarrhea (n=3) and febrile neutropenia (n=3). Volasertib exhibited multi-exponential PK behavior with a long half-life (130 hr), moderate clearance (900 mL/min) and large volume of distribution (Vss >6000 L). Co-administration of volasertib and afatinib had no effect on the PK profile of either drug. Two pts in Schedule A (volasertib 300 mg/afatinib 30 mg) achieved partial responses (tumor types: NSCLC, head and neck). Conclusions: MTD of volasertib was 300 mg Q3W combined with afatinib 30 mg d2-21 (Schedule A) or afatinib 70 mg d2-6 (Schedule B). Both agents could be combined at previously shown active single agent doses. At the MTD, treatment was manageable and showed preliminary anti-tumor activity. Clinical trial information: NCT01206816.

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

scholarly journals Phase 1 dose‐escalation study of single‐agent veliparib in Japanese patients with advanced solid tumors

2017 ◽  
Vol 108 (9) ◽  
pp. 1834-1842 ◽  
Author(s):  
Tadaaki Nishikawa ◽  
Koji Matsumoto ◽  
Kenji Tamura ◽  
Hiroyuki Yoshida ◽  
Yuichi Imai ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

A phase 1/2 trial of ORIN1001, a first-in-class IRE1 inhibitor, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3080-3080
Author(s):  
Nashat Y. Gabrail ◽  
Erika P. Hamilton ◽  
Anthony D. Elias ◽  
Mothaffar F. Rimawi ◽  
Chao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Pharmacokinetic Analysis ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Duration Of Treatment ◽  
Open Label

3080 Background: ORIN1001 is a first-in-class small molecule with a novel, unique enzyme and mode of inhibition that selectively inhibits Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum (ER). IRE1α/XBP1 has been implicated in a host of pathologies, and molecules that modulate it are under intense investigation for the treatment of oncologic, metabolic, neurodegenerative and other diseases. ORIN1001 has demonstrated preclinical anti-tumor activity alone and in combination with standard of care across multiple animal models including breast, prostate, lung, liver, pancreatic, brain, colon, ovarian, esophageal, and hematologic cancers and is now undergoing first-in-human testing. Methods: A phase 1, open label, 3+3 dose escalation trial is testing ORIN1001 administered PO daily to patients (pts) with advanced solid tumors (single agent) or relapsed refractory breast cancer (in combination with Abraxane). The phase 1 dose escalation part of the trial evaluates the safety, tolerability, pharmacokinetics and preliminary efficacy of ORIN1001. After identification of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) for the single agent, the dose expansion part of the trial will test ORIN1001 in combination with Abraxane. Results: As of Jan 25, 2021, 22 patients with advanced cancer have received ORIN1001 dosed at 100mg, 200mg or 300mg per day in 21-day continuous cycles with a median age of 61 (range 42-77). The pts had received a median of 4 prior line of treatments. Two DLTs were observed at 200 mg with thrombocytopenia and rash. MTD has not been reached. Common (>15%) treatment-emergent adverse events (TEAEs) included nausea, vomiting, rash, fatigue, and hypokalaemia. The vast majority of these events were Grade 1-2 in severity. Seven (32%) pts had at least 1 TRAE grade≥ 3, the most frequent of which were thrombocytopenia (N=3) and rash (N=3). Preliminary pharmacokinetic analysis showed ORIN1001 exposure to increase in a dose proportional manner. Mean t1/2 at steady state was 18 hrs. Thirteen pts were evaluated for preliminary efficacy. Best response, per RECIST 1.1, was stable disease (SD) in 8 pts while 5 pts had progressive disease (PD). For 2 ongoing patients with advanced liver or colorectal cancer, duration of treatment has exceeded 300 days and 570 days, respectively. Conclusions: To date, the phase 1 part of the first-in-human trial has demonstrated a reasonable safety and pharmacokinetic profile for ORIN1001 at 100mg and 200mg dose levels. While efficacy data have yet to mature, chronic dosing achieved in pts with heavily treated advanced solid tumors, suggests clinical potential for in the setting of advanced solid cancers. The phase 2 part of the trial testing ORIN1001 in combination with Abraxane is currently enrolling pts with advanced breast cancer. Clinical trial information: NCT03950570.

Phase 1 and phase 2a, first-in-human (FIH) study, of DRP-104, a broad glutamine antagonist, in adult patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3149-TPS3149
Author(s):  
Melissa Lynne Johnson ◽  
Deborah Blythe Doroshow ◽  
Tanguy Y. Seiwert ◽  
Michael K. Gibson ◽  
Vamsidhar Velcheti ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Adult Patients ◽  
Glutamine Metabolism ◽  
Advanced Solid Tumors

TPS3149 Background: Dependence of cancer cells on glutamine has made glutaminolysis an attractive therapeutic target in cancer. Prior clinical trials evaluating glutamine analogues for the treatment of cancer were abandoned due to lack of efficacy and/or tolerability. DON (6-Diazo-5-oxo-L-norleucine) is an irreversible inhibitor of several enzymes that utilize glutamine as a metabolic substrate. In addition to direct anti-tumor efficacy, inhibition of glutamine metabolism in the tumor microenvironment has been shown to improve T-cell activation and tumor infiltration, increasing anti-tumor immune responses. As such, combining DON with an immune checkpoint inhibitor (ICI), has strong preclinical rationale. The investigational product DRP-104 (sirpiglenastat) is an inactive prodrug of DON designed to limit systemic DON exposure while targeting glutamine dependence in tumor cells. Methods: A phase 1/2a, FIH, multi-center, non-randomized, multi-cohort, open-label study of DRP-104 is currently open to accrual for patients with advanced solid tumors. This study will be conducted in 4 parts: A) Dose Escalation of IV and subQ DRP-104 (Run-In phase followed by modified Continual Reassessment Method) to define MTD/RP2D. Primary objective of dose escalation is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of DRP-104 as a single agent; B) Dose Expansion of IV and subQ DRP-104 for safety assessment while primary objective is to select and recommend phase 2 DRP-104 route of administration; C) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in 2 patient cohorts: patients with locally advanced/metastatic NSCLC with KEAP1, NFE2L2 and/or STK11 mutation and patients with unresectable or metastatic SCCHN, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 as a single agent; D) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in combination with atezolizumab in adult patients with advanced solid tumors previously treated with an ICI, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 in combination with atezolizumab; DRP-104 IV is infused TIW over 1 hour infusion for 2 consecutive weeks followed by 1 week off. DRP-104 subQ is administered BIW weekly. Study is currently open with 6 IV patients (Run-In Phase completed and at Dose Level 4) and 3 subQ patients at Dose Level 1 at time of submission. Clinical trial information: NCT04471415.

A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2566-2566 ◽  
Author(s):  
Patricia LoRusso ◽  
Geoffrey Shapiro ◽  
Shuchi Sumant Pandya ◽  
Eunice Lee Kwak ◽  
Cheryl Jones ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Fdg Pet ◽  
Metabolic Response ◽  
Phase 1 ◽  
Single Agent ◽  
Pi3k Inhibitor ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Phase Ib

2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.

A phase 1 dose-escalation study of BBI503, a first-in-class cancer stemness kinase inhibitor in adult patients with advanced solid tumors.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2527-2527 ◽  
Author(s):  
Scott Andrew Laurie ◽  
Derek J. Jonker ◽  
William Jeffery Edenfield ◽  
Joe Stephenson ◽  
Deborah Keller ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Adult Patients ◽  
Advanced Solid Tumors ◽  
Cancer Stemness ◽  
Dose Escalation Study
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