KRYSTAL-2: A phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS146-TPS146
Author(s):  
Joshua K. Sabari ◽  
Haeseong Park ◽  
Anthony W. Tolcher ◽  
Sai-Hong Ignatius Ou ◽  
Edward B. Garon ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Human Tumor ◽  
Mapk Signaling ◽  
Cellular Growth ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2

TPS146 Background: KRAS is the most frequently mutated oncogene in cancer and a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS G12C tumor mutations occur in approximately 14% of patients with lung adenocarcinoma and 3-4% of colorectal adenocarinoma. SHP2 is a phosphatase that acts as a key mediator of signaling from receptor tyrosine kinases (RTKs) to downstream RAS/MAPK pathways. Adagrasib (MRTX849) is a specific small-molecule investigational inhibitor of KRAS G12C that covalently binds to and locks mutant KRAS in its GDP-bound inactive form. Adagrasib has been optimized for a long half-life and extensive tissue distribution to enable inhibition throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of adagrasib demonstrated promising antitumor activity and tolerability across multiple KRAS G12C tumor types. TNO155 is a selective inhibitor of SHP2 with demonstrated inhibition of RTK signaling and significant antitumor activity in preclinical models. Preclinical studies have shown that resistance to KRAS G12C inhibition may be mediated by SHP2-dependent feedback loops. Because KRAS G12C retains some level of cycling between GTP- and GDP-bound states, KRAS G12C that is not bound by inhibitor can activate downstream signaling. Active SHP2 functions to increase the active state of RAS proteins (including mutant KRAS) and also increases ERK pathway activation. Therefore, the addition of TNO155 to adagrasib may augment antitumor activity and overcome resistance by inhibiting cycling to GTP-bound KRAS and/or through inhibition of feedback activation and more comprehensively inhibiting downstream ERK signaling. In KRAS G12C human tumor models, adagrasib combined with a SHP2 inhibitor demonstrated greater activity compared to each agent alone. These data provide support for clinical evaluation of this combination in KRAS G12C tumors. Methods: KRYSTAL-2 is a multicenter Phase 1/2 study evaluating adagrasib and TNO155 in patients with advanced solid tumors harboring a KRAS G12C mutation. Overall objectives of the trial include evaluating safety, tolerability, and PK. The Phase 1 portion will evaluate adagrasib and TNO155 utilizing a modified Toxicity Probability Interval dose escalation design to identify maximum tolerated dose and recommended Phase 2 dose. The Phase 2 portion utilizes a Simon's optimal two-stage design to evaluate the clinical activity of adagrasib with TNO155 in 2 cohorts of up to 108 patients—CRC (54 patients) and NSCLC (54 patients). Efficacy endpoints include Objective Response Rate (RECIST 1.1), Duration of Response (DOR), Progression-free Survival (PFS), and Overall Survival (OS). The study is currently enrolling and patients will receive study treatment until disease progression, unacceptable adverse events, patient withdrawal, or death. Clinical trial information: NCT04330664.

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

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
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.

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

scholarly journals Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study

2020 ◽  
Vol 8 (1) ◽  
pp. e000437
Author(s):  
Lin Shen ◽  
Jun Guo ◽  
Qingyuan Zhang ◽  
Hongming Pan ◽  
Ying Yuan ◽  
...  
Keyword(s):  
Cell Death ◽  
Antitumor Activity ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Phase 1 ◽  
Chinese Patients ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Verification ◽  
Open Label

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.

scholarly journals A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000530 ◽  
Author(s):  
Aung Naing ◽  
Justin F Gainor ◽  
Hans Gelderblom ◽  
Patrick M Forde ◽  
Marcus O Butler ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Wide Range ◽  
Tumor Types ◽  
Tumor Biopsies

BackgroundSpartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.MethodsIn the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).ResultsPatients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.ConclusionsSpartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration numberNCT02404441.

TRIDENT-1: A global, multicenter, open-label Phase II study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9637-TPS9637
Author(s):  
Robert Charles Doebele ◽  
Jessica Jiyeong Lin ◽  
Misako Nagasaka ◽  
Viola Weijia Zhu ◽  
Nashat Y. Gabrail ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Resistance Mutations ◽  
Open Label ◽  
Phase 2 Study

TPS9637 Background: Repotrectinib is a next-generation ROS1/TRK inhibitor with > 90-fold greater potency than crizotinib against ROS1 and > 100-fold greater potency than larotrectinib against TRK. Preclinical studies demonstrated inhibitory activity of repotrectinib against ROS1 resistance mutations, including the solvent-front mutation (SFM) G2032R. In the phase 1 portion of the study, repotrectinib was found to be well tolerated with encouraging antitumor activity including a 91% confirmed overall response (cORR) in TKI-naïve ROS1+ NSCLC pts. In ROS1+ NSCLC pts who received 1 prior chemo and 1 prior TKI, the cORR was 57% at the clinical dose of 160 mg QD or above. Intra-cranial (IC) activity was observed in ROS1+ NSCLC pts with measurable CNS disease (100% IC-ORR in TKI-naïve and 75% IC-ORR in patients with 1 prior TKI). Encouraging antitumor activity was observed in pts with NTRK+ solid tumors. Methods: A global phase 2 study was initiated and is actively enrolling. The primary endpoint for the Phase 2 study is cORR assessed by BICR (Blinded Independent Central Review) using RECIST v1.1, in each expansion cohort in pts with advanced solid tumors that harbor a ROS1 or NTRK1/2/3 gene fusion. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), IC-ORR, IC-PFS, and quality of life assessments. All pts need to have RECIST 1.1 measurable disease confirmed by BICR and ECOG performance score ≤1. Repotrectinib is administered at 160 mg QD for 14 days and, if tolerated, the dose can be increased to 160 mg BID. Approximately 320 pts (≥12 years old) will be enrolled into 6 defined expansion cohorts, depending on the status of previous treatment with TKIs and cancer types (see table below). Clinical trial information: NCT03093116 . [Table: see text]

A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3161-TPS3161 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Sai-Hong Ignatius Ou ◽  
Melissa Lynne Johnson ◽  
James Christensen ◽  
Karen Velastegui ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Intracellular Signaling ◽  
Tumor Regression ◽  
Phase 1 ◽  
Small Gtpases ◽  
Cellular Growth ◽  
Clinical Activity ◽  
Ras Signaling ◽  
Phase 2 ◽  
Expansion Cohort

TPS3161 Background: RAS proteins are part of the family of small GTPases which regulate intracellular signaling pathways responsible for cell growth, migration, survival and differentiation. Oncogenic point mutations in RAS in codons 12, 13, and 61 occur in up to one-third of all human cancers and result in constitutive activation of RAS signaling, playing a key role in uncontrolled cellular growth and malignant transformation. Mutant KRASG12C in particular comprises approximately 14% of lung adenocarcinoma and 4% of colon adenocarcinoma, and less commonly in certain other types of cancer. For decades, KRAS was considered undruggable due to its high affinity for GTP/GDP and the lack of a clear binding pocket. Recent discoveries have enabled the development of compounds, including MRTX849, that covalently bind to KRASG12C at the cysteine at residue 12, lock the protein in its inactive GDP-bound conformation, and inhibit KRAS-dependent signal transduction. MRTX849 is a potent, orally-available, mutation-selective small molecule covalent inhibitor of KRASG12C. MRTX849 inhibits KRASG12C signaling in cell lines harboring this mutation, and results in tumor regression in a broad spectrum of KRASG12C animal models. Methods: This multi-center, Phase 1/2, multiple expansion cohort trial evaluates the safety, pharmacokinetics (PK), metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumor malignancies with a KRAS (p.G12C) mutation. The study starts with an evaluation of dose and regimen of MRTX849 using a combination of the accelerated titration and modified toxicity probability interval designs, with MRTX849 initially administered once daily in a continuous regimen expressed in 3-week cycles. As potentially viable regimens are identified, Phase 1b expansion cohorts will be opened to provide greater safety and PK data for determination of the recommended Phase 2 dose (RP2D) and regimen. In Phase 2, separate cohorts of patients by histological diagnosis, including non-small cell lung cancer, colorectal, and other solid tumors, will be enrolled and evaluated for clinical activity using a predictive probability design. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT03785249.

First-in-human phase I/II study of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination in patients with advanced solid and hematologic cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3006-3006
Author(s):  
Ryan C Lynch ◽  
Johanna C. Bendell ◽  
Ranjana H. Advani ◽  
Gerald Steven Falchook ◽  
Pamela N. Munster ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Study ◽  
Systemic Exposure ◽  
Predictive Biomarkers ◽  
Clinical Activity ◽  
Phase 2 ◽  
Tumor Cell Death

3006 Background: Homologous recombination (HR) is an essential, high-fidelity mechanism to repair DNA double strand breaks (DSBs). Inhibition of HR in cancer cells leads to accumulation of unrepaired DSBs and tumor cell death. This is the first reporting of the first-in-human study of CYT-0851, an oral, first-in-class, small molecule inhibitor of RAD51-mediated DNA repair. Methods: Patients (pts) with advanced hematologic and solid tumors were treated with continuous 28-day cycles of increasing doses of CYT-0851 with an accelerated titration and 3+3 trial design. Primary objectives included safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D) (Phase 1), and antitumor activity (Phase 2). Secondary and exploratory objectives included pharmacokinetics (PK), pharmacodynamics (PD) and predictive biomarkers of response. Results: As of an 8 Dec 2020 data cutoff (DCO), 23 pts with advanced cancers (Sarcoma n = 8, Breast n = 4, Non-Hodgkin’s Lymphoma n = 5; Pancreas n = 3; Ovarian n = 2; mucoepidermoid carcinoma n = 1) were enrolled in 6 cohorts (15 mg, 20 mg, 30 mg, and 45 mg BID; 90 mg and 130 mg QD). No pts experienced a dose-limiting toxicity and escalation continues per protocol to identify the MTD. 6 pts (26.1%) experienced a CYT-0851-related adverse event with only Gr 1/2 nausea (n = 3, 13%) and constipation (n = 2, 8.7%) occurring in > 1 pt. There has been no reported CYT-0851-related myelosuppression, serious adverse events, study discontinuation, or death. Preliminary PK analyses showed dose proportional systemic exposure with a half-life of ̃3 days supporting transition from BID to QD dosing. PD effects were observed with increases in ɣH2AX in on-treatment circulating tumor cells compared to baseline at exposures associated with preclinical anti-tumor activity. Ten pts were response evaluable prior to the DCO. Two partial responses by Lugano and RECIST v1.1 criterion were achieved in pts with DLBCL (-74%) and myxofibrosarcoma (-30%) at 45 mg BID with treatment ongoing at 126+ and 250+ days. An additional two pts, with pancreatic cancer (-19%) and follicular lymphoma (-42%) had stable disease with tumor shrinkage at 45 mg BID for 111 and 99+ days. Conclusions: CYT-0851, a first-in-class inhibitor of RAD51-mediated HR, is well tolerated, with linear PK, target-directed PD effects and promising antitumor activity across different tumor types. CYT-0851 is the first DNA-damage repair (DDR) therapeutic with demonstrated clinical activity in both hematologic malignancies and solid tumors. Dose escalation continues to establish the RP2D, with planned expansion in 7 disease-specific cohorts in hematologic and solid cancers. Clinical trial information: NCT03997968.

A phase I/II, open-label, dose-escalation, and cohort-expansion study evaluating the safety, pharmacokinetics, and therapeutic activity of OBI-999 in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3657-TPS3657
Author(s):  
Apostolia Maria Tsimberidou ◽  
Jaffer A. Ajani ◽  
Pei Hsu ◽  
I-Ju Chen ◽  
Tillman E. Pearce
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Dose Range ◽  
Objective Response ◽  
Membrane Microdomains ◽  
Clinical Activity ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Tumor Cell Death

TPS3657 Background: Aberrant glycosylation is a hallmark of cancer. Glycosphingolipids (GSLs), glycans conjugated to a lipid (ceramide) core, are essential for the recruitment of immune-related proteins to specific membrane microdomains. Globo H (GH) is a GSL found on normal cells but highly overexpressed on various epithelial tumors playing a role in tumor development and progression. GH is a promising target for immunotherapy. OBI-999 is an ADC composed of a human recombinant immunoglobulin G (IgG) monoclonal antibody that selectively and specifically binds to GH, attached by a linker to the antimitotic agent monomethyl auristatin E (MMAE). Its mechanism of action is based on tumor-selective delivery of MMAE to GH-expressing tumors with subsequent tumor cell death. Preclinical studies demonstrated that OBI-999 antibody binds specifically to the GH antigen, and antitumor efficacy was noted in breast, gastric, pancreatic, and lung cancer xenograft models. The pharmacokinetics (PK) of OBI-999 were determined in normal and tumor-bearing mice, rats, and monkeys. Exposure of OBI-999 increased proportionally with dose. No sex difference or accumulation was seen. The primary objectives are to determine dose limiting toxicities (DLTs), the maximum tolerated dose (MTD), and the phase 2 recommended dose (P2RD). The secondary objectives are to assess the rates of objective response and clinical benefit, the duration of progression-free survival, the immunogenicity of OBI-999, and the PK and pharmacodynamics (PD) of OBI-999 and MMAE. Methods: In Part 1, a "3+3" dose-escalation part of the study, up to 30 patients with advanced solid tumors refractory to ≥1 line of systemic therapy, who cannot tolerate standard therapy, or for whom no standard treatment is available, regardless of GH status will be treated. OBI-999 will be administered as a 60-minute IV infusion using a dose range of 0.4, 0.8, 1.2, 1.6, and 2.0 mg/kg on day 1 of every 21-day cycle. In Part 2, the cohort-expansion portion of the study, patients will be treated at the MTD or at a lower RP2D as determined by cumulative toxicities and tolerability profile. The study will determine the preliminary clinical activity and safety of OBI-999 in up to 155 patients with advanced solid tumors, pancreatic, gastric, esophageal, and colorectal cancer according to a Simon two-stage phase 2 design. Patients must have GH overexpression defined as an H-score of ≥100 according to an FDA Investigational Device Exempt (IDE) validated IHC assay. Clinical trial information: NCT04084366 .

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).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
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.

Bgb-A425, an investigational anti-TIM-3 monoclonal antibody, in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors: A phase I/II trial in progress.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3146-TPS3146
Author(s):  
Jayesh Desai ◽  
Tarek Meniawy ◽  
Brandon Beagle ◽  
ZheZhen Li ◽  
Song Mu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Response ◽  
T Cell ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Tumor Types

TPS3146 Background: While immune surveillance plays a critical role in preventing tumor proliferation and metastasis, tumors develop resistance mechanisms to suppress and/or escape the immune system. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and programmed cell death protein-1 (PD-1) function as immune checkpoint receptors on tumor-infiltrating lymphocytes. Overlap in expression and function suggests TIM-3 and PD-1 cooperate to maximize effector T-cell exhaustion, leading to a decreased antitumor immune response. Although blockade of TIM-3 alone is unlikely to result in an efficacious antitumor immune response, combined TIM-3/PD-1 blockade may enhance the antitumor properties of anti-PD-1 therapies alone. BGB-A425 is an investigational IgG1-variant monoclonal antibody against TIM-3. Tislelizumab, an anti-PD-1 antibody, was engineered to minimize binding to FcɣR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This phase 1/2 study will assess the safety/tolerability, pharmacokinetic (PK) profile, and antitumor activity of BGB-A425 in combination with tislelizumab in patients with advanced solid tumors. Methods: This is an open-label phase 1/2 study (NCT03744468) of BGB-A425 in combination with tislelizumab in patients with histologically/cytologically confirmed advanced, metastatic, unresectable solid tumors. Phase 1 will determine the recommended phase 2 dose (RP2D) for combination treatment; phase 2 will assess the antitumor effects of the combination in select tumor types. In phase 1, up to 42 patients will be enrolled into sequential cohorts of increasing doses of intravenous (IV) BGB-A425 in combination with tislelizumab 200 mg IV, based on a 3+3 study design. During Cycle 1, patients will receive BGB-A425 alone on Day 1 followed by tislelizumab alone on Day 8. If no dose-limiting toxicities are observed, patients will receive both BGB-A425 and tislelizumab sequentially on Day 29 and every 21 days thereafter. Once the RP2D is determined, the combination therapy will be evaluated in up to 120 patients with select tumor types in phase 2. Safety/tolerability profile and RP2D determination (phase 1) and objective response rate per RECIST v1.1 (phase 2) are primary objectives; secondary objectives include antitumor activity, PK profile, and immunogenicity of combination therapy. Clinical trial information: NCT03744468 .

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