Biomarker results supporting selection of RP2D from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with nab-paclitaxel in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3110-3110
Author(s):  
Anneleen Daemen ◽  
Aleksandr Pankov ◽  
Shravani Barkund ◽  
Haiying Zhou ◽  
Maureen Duff ◽  
...  
Keyword(s):  
Steady State ◽  
Glucocorticoid Receptor ◽  
Solid Tumors ◽  
Preclinical Studies ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Phase 1B ◽  
Cortisol Levels ◽  
Pre Treatment ◽  
Tumor Types

3110 Background: Preclinical studies have shown that activation of the glucocorticoid receptor (GR) leads to resistance to chemotherapeutics (eg taxanes) and antiandrogens across multiple tumor types, while GR inhibition enhances therapeutic efficacy. ORIC-101 is a potent, selective, and orally bioavailable small molecule GR antagonist undergoing clinical development in combination with nab-paclitaxel in patients with advanced solid tumors and in combination with enzalutamide in patients with metastatic prostate cancer. Methods: 21 patients were enrolled in the dose escalation portion of the phase 1b study, which evaluated both intermittent (5 days on, 2 days off for 21 days) and continuous dosing regimens of ORIC-101 across 5 cohorts (NCT03928314). Tumor tissue was obtained pre-treatment for 19 out of 21 patients, and on study or at the end of treatment for 11 patients. GR protein status was retrospectively evaluated using a proprietary IHC assay optimized for staining nuclear GR in the epithelial compartment of major tumor type tissues. Biopsies were also profiled with RNA-seq to evaluate a proprietary GR activation signature as a potentially predictive and pharmacodynamic (PD) biomarker. Blood-derived peripheral blood mononuclear cells (PBMCs) were collected for 20 patients along with the pre-treatment biopsy, in the morning of days 1, 5 and/or 8 of Cycle 1, and 2.5 or 6 hours after ORIC-101 administration. Blood cortisol levels were also simultaneously measured. PD modulation in PBMCs was assessed by RT-qPCR for biomarkers FKBP5, GILZ and PER1, selected for their consistent stimulation by GR and reversal with ORIC-101 in preclinical studies and observed PD modulation in healthy volunteers administered ORIC-101. Results: Nuclear GR protein was detected in most pre-treatment biopsies regardless of tumor type, and on treatment reduction of GR protein was observed across dose levels. At physiological systemic cortisol levels, ORIC-101 demonstrated PD suppression in PBMCs on days 1, 5 and 8 in the majority of patients. Cortisol levels increased post-dose in these patients due to negative feedback between cortisol and GR. Steady-state target engagement was not consistently demonstrated with the intermittent regimen. In healthy volunteer studies of ORIC-101, steady-state target suppression was consistently achieved after 7 consecutive daily doses of 200 or 350 mg of ORIC-101. Thus, continuous ORIC-101 administration was selected as the recommended phase 2 dose (RP2D) regimen, aimed at achieving sustained GR suppression for optimal chemotherapy re-sensitization. Conclusions: Biomarker data from patients enrolled in the phase 1b study provide evidence of on-target tumor cell eradication and PD modulation and support the RP2D and the tumor types selected for the ongoing dose expansion portion of the study. Clinical trial information: NCT03928314.

A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2654-TPS2654 ◽  
Author(s):  
Matthew David Hellmann ◽  
Toshio Shimizu ◽  
Toshihiko Doi ◽  
F. Stephen Hodi ◽  
Sylvie Rottey ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Phase ◽  
Phase 1B

TPS2654 Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177.

BET inhibitor molibresib for the treatment of advanced solid tumors: Final results from an open-label phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3618-3618 ◽  
Author(s):  
Sophie Cousin ◽  
Jean-Yves Blay ◽  
Irene Braña Garcia ◽  
Johann S. De Bono ◽  
Christophe Le Tourneau ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Treatment Discontinuation ◽  
Tolerability Profile ◽  
Repeat Dose ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Total Cohort ◽  
Tumor Types

3618 Background: Molibresib is an orally available, small molecule bromodomain and extra-terminal domain (BET) protein inhibitor under investigation for treatment of advanced solid tumors. Methods: This was an open-label, single- and repeat-dose, 2-part, Phase 1/2 study including patients (aged ≥16 years) with advanced solid tumors. Part 1: patients received different oral doses of molibresib (2–100mg QD; amorphous free-base formulation) to determine recommended Phase 2 dose. Part 2 (expansion cohort): patients with various tumor types received the bioequivalent besylate formulation (75mg) to explore clinical activity at recommended dose. Safety and efficacy (response rate [RR] based on RECIST 1.1 criteria, progression-free survival [PFS], and overall survival [OS]) were evaluated for the total cohort (patients from Part 1 and 2). Safety, pharmacokinetic, pharmacodynamic, and efficacy per tumor type were evaluated in Part 2. Results: Part 1 only data have previously been reported. Overall, 196 patients were included in the total cohort (1 patient in Part 1 was counted twice). In the all treated population, 195 patients (median age 58 years; 46% male) received ≥1 dose of molibresib (Part 1: n = 93; Part 2: n = 102). Adverse events (AEs) were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. Of different tumor types in Part 2, NUT carcinoma (NC) had the lowest frequency of TRAEs (10/12 [83%]) and AEs leading to permanent treatment discontinuation (1/12 [8%]). In total cohort, 3/31 NC patients and 1/35 with castration-resistant prostate cancer (CRPC) achieved a confirmed partial response. A further 67/196 (34%) achieved stable disease (SD). In Part 2, RR in 12 NC patients was 8% (CI: 0.2–38.5); 50% had SD and median PFS was 4.8 months with median OS of 5.0 months. In CRPC patients, RR was 4% (CI: 0.1–21.9); 22% had SD; median PFS was 8.0 months with median OS of 9.1 months. Plasma concentrations for molibresib and active metabolites were similar between different tumor types. Gene expression analysis from pre- and post-dose biopsy samples collected from 10 mCRPC patients showed transcriptional downregulation of Myc target genes upon treatment with molibresib. Conclusions: Molibresib demonstrated a manageable safety and tolerability profile with single agent activity observed in selected patients with NC and CRPC. Clinical trial information: NCT01587703 .

Preliminary results of molecular screening for FGFR alterations (alts) in the RAGNAR histology-agnostic study with the FGFR-inhibitor (FGFRi) erdafitinib.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4081-4081
Author(s):  
Christophe Massard ◽  
Shubham Pant ◽  
Gopa Iyer ◽  
Martin H. Schuler ◽  
Olaf Witt ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Efficacy And Safety ◽  
Molecular Screening ◽  
Primary Analysis ◽  
Eligibility Criteria ◽  
Genomic Databases ◽  
Wide Range ◽  
Tumor Types

4081 Background: FGFR alts (mutations and fusions) have been reported in multiple advanced solid tumors at varying frequencies. These alts may function as oncogenic drivers of disease independent of the underlying tumor type. RAGNAR is an ongoing phase 2, histology-agnostic trial investigating the efficacy and safety of erdafitinib, a selective pan-FGFRi, in patients (pts) with advanced solid tumors and FGFR alts. Little is known about the incidence, diversity or predominant FGFR alts across solid tumors in the clinical setting. Here, we provide an update on molecular screening and enrollment in the primary analysis population. Methods: Pts with advanced solid tumors were molecularly screened for eligible FGFR alts via central next generation sequencing (NGS) or review of local NGS reports. Underlying tumor type, FGFR alts, demographics and key disease characteristics were collected at baseline. Results: From Nov 2019 to Jan 2021, 5758 pts were molecularly screened (central or local) in 15 countries. 191 pts (3.3%) fulfilled primary analysis molecular eligibility criteria; 110 pts were enrolled. Among pts enrolled, 14 (12.7%) had central screening and 96 (87.3%) had local NGS reports. Eligible FGFR alts were identified in 19 tumor types, including rare cancers and ones (eg, pancreatic) with a very low prevalence of FGFR alts in genomic databases (Table). Median age was 57 y, and 19 pts (17.3%) were < 40 y. Gender distribution was even. Conclusions: Findings from molecular screening in the RAGNAR study indicate a wide range of FGFR-altered tumor types, including a notable number of cancers where eligible FGFR alts were considered exceedingly rare (eg, pancreatic). These results demonstrate the feasibility of conducting clinical trials on pts with rare genetic alts by adopting a histology-agnostic design and using both central testing and local NGS reports for molecular screening. This approach also helps investigate rare tumors, where histology-specific trials are challenging. Efficacy and safety results from the RAGNAR study will help define the benefit of erdafitinib in FGFR-altered advanced solid tumors. Clinical trial information: NCT04083976. [Table: see text]

A phase 1b study of ruxolitinib (Rux) + gemcitabine (G) ± nab-paclitaxel (N) in patients (pts) with advanced solid tumors.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 439-439
Author(s):  
Todd Michael Bauer ◽  
Manish R. Patel ◽  
Tina Evans Wood ◽  
Thomas J. George ◽  
Fitzroy W. Dawkins ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Malignant Cell ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Study ◽  
Multiple Tumor ◽  
Phase 1B ◽  
Tumor Types ◽  
Clinical Disease Progression

439 Background: Aberrant activation of the JAK-STAT pathway has been associated with increased malignant cell proliferation and survival. Rux, a potent JAK1/2 inhibitor, was evaluated in combination with G±N in advanced solid tumors. Methods: This was an open-label study of Rux + G, without N (regimen A) or with N (regimen B) in advanced solid tumors. The objective of the dose-finding phase (reported here) was to identify MTDs of Rux + G and Rux + G/N. See Table for evaluated cohorts. Results: Among 42 pts enrolled, median age was 62.5 years, 81% had pancreatic cancer (PC), 50% had 1 prior regimen and 12% had 2 prior regimens. Discontinuations were mainly due to radiological or clinical disease progression (86% of pts). Median treatment durations: 55.5 d (A) and 97.5 d (B). 4 pts in B had DLTs: Grade (Gr) 3 pneumonia (n = 1, SAE), Gr 3 neutropenia (n = 1) and Gr 4 thrombocytopenia (n = 2). Table summarizes AEs. The most common Gr 3/4 hem AEs (lab) were anemia (88% A, 85% B) and thrombocytopenia (81% A, 89% B). SAEs occurring in ≥ 2 pts were abdominal pain (n = 4, A), sepsis (n = 2, A), dehydration, anemia and asthenia (n = 2 each, B). Rux + G was tolerated with standard doses of G. Rux + G/N was tolerated with reduced doses of G/N or concomitant GCSF. These combinations were not pursued further, therefore MTDs were not defined. ORRs were 2/16 (13%) in A and 10/26 (39%) in B. ORRs in PC pts: 8/34 (24%); 2/14 (14%) in A and 6/20 (30%) in B. Conclusions: Rux + G or Rux + G/N at the doses investigated were generally safe and well tolerated in pts with advanced PC and other solid tumors. ORRs were noted in multiple tumor types including PC. Clinical trial information: NCT01822756. [Table: see text]

423 Safety and preliminary efficacy of intratumoral cavrotolimod (AST-008), a spherical nucleic acid TLR9 agonist, in combination with pembrolizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A449-A449
Author(s):  
Steven O’Day ◽  
Cesar Perez ◽  
Trisha Wise-Draper ◽  
Glenn Hanna ◽  
Shailender Bhatia ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Solid Tumors ◽  
San Francisco ◽  
Institutional Review Boards ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Tlr9 Agonist ◽  
Phase 1B ◽  
Spherical Nucleic Acids

BackgroundSpherical nucleic acids (SNAs) are nanostructures consisting of radially oriented, densely packed oligonucleotides arranged in a spherical 3D architecture. SNAs have different properties than linear oligonucleotides, including increased cellular uptake, which may enhance efficacy. Cavrotolimod (AST-008) is an SNA toll-like receptor 9 (TLR9) agonist designed to robustly activate innate and adaptive immune responses. Cavrotolimod is in development for the treatment of advanced solid tumors in combination with PD-1 blockade. Prior studies demonstrated that cavrotolimod, alone and in combination with PD-1 blockade, increased circulating levels of Th1-type cytokines and activated peripheral T cells and NK cells.MethodsAST-008-102 is an ongoing Phase 1b/2 study (NCT03684785). The Phase 1b dose escalation stage examined intratumoral (IT) cavrotolimod at doses of 2, 4, 8, 16, and 32 mg in combination with pembrolizumab in patients with advanced solid tumors. Cavrotolimod was dosed once weekly for 8 weeks and once every 3 weeks thereafter. The Phase 2 dose expansion stage is examining cavrotolimod 32 mg IT in combination with IV pembrolizumab for the treatment of advanced Merkel cell carcinoma (MCC) and in combination with IV cemiplimab for the treatment of advanced cutaneous squamous cell carcinoma (CSCC). Both cohorts are enrolling patients with documented progression of disease on PD-(L)1 blockade. This analysis provides interim results of the Phase 1b stage.ResultsIn the Phase 1b stage, 20 patients were enrolled across all planned dose levels. No dose-limiting toxicities, grade (G)4 toxicities, or treatment-related serious adverse events (AEs) were observed. The most common AEs were injection site reactions (ISRs) and flu-like symptoms. All treatment-related AEs were < G3 except agitation and ISR (1 each). At data cutoff, ORR is 21% (4 of 19 evaluable patients) in a heterogeneous population with solid tumors. All 4 responders (2 melanoma and 2 MCC patients) have ongoing responses, with duration of response exceeding 52 weeks in 2 patients. Three of 4 responders had disease progression on PD-1 blockade at the time of enrollment, and one patient had a prior response to PD-1 blockade, but subsequently relapsed off therapy. Regression of both injected and noninjected lesions was observed. Gene expression analyses demonstrated increased IT infiltration by cytotoxic immune cells in both injected and noninjected tumors. The highest dose (32 mg) was selected for the Phase 2 stage.ConclusionsIT administration of cavrotolimod appears to be safe and well tolerated in combination with pembrolizumab. Durable responses have occurred in patients previously experiencing progressive disease on PD-1 blockade.Trial RegistrationNCT03684785Ethics ApprovalThe study was approved by Institutional Review Boards of Dana-Farber Cancer Institute (IRB #18-584), John Wayne Cancer Institute (WIRB #20183064), University of Miami (IRB #20180957), University of Iowa (IRB #201810763), University of Cincinnati (WIRB #20183064), University of Washington (WIRB #20183064), MSKCC (IRB #20-174), UC San Francisco (WIRB #20183064), U Colorado (WIRB #20183064), Northwestern (IRB #STU00211083), U Arizona (WIRB #20183064), UC Irvine (WIRB #20183064), U Pitt (WIRB #20183064), and Washington University (WIRB #20183064).

265 Phase 1b study of avelumab + M9241 (NHS-IL12) in patients with advanced solid tumors: interim analysis results from a urothelial carcinoma (UC) dose-expansion cohort

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A291-A291
Author(s):  
Jean-Laurent Deville ◽  
Alain Ravaud ◽  
Marco Maruzzo ◽  
Theodore Gourdin ◽  
Michele Maio ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Interim Analysis ◽  
Maintenance Treatment ◽  
Advanced Solid Tumors ◽  
First Line ◽  
Platinum Based Chemotherapy ◽  
Phase 1B ◽  
Expansion Cohort

BackgroundAvelumab is an anti–PD-L1 monoclonal antibody approved for the treatment of advanced UC after disease progression during or following platinum-based chemotherapy and as maintenance treatment in patients whose disease has not progressed with first-line platinum-based chemotherapy.1–3 M9241 is an immunocytokine composed of 2 heterodimers of IL-12 fused to the heavy chains of a human antibody targeting DNA released from necrotic tumor cells.4 During dose-escalation, avelumab + M9241 was well tolerated and showed promising antitumor activity in patients with advanced solid tumors, including 2 objective responses in patients with UC.5 We report on an interim analysis of efficacy and safety from the dose-expansion part of JAVELIN IL-12 (NCT02994953).MethodsEligible patients had locally advanced or metastatic UC that had progressed on first-line therapy, were aged =18 years, had an Eastern Cooperative Oncology Group performance status of 0/1, and were immune checkpoint inhibitor naive. Patients received the recommended phase 2 dose5 of avelumab 800 mg intravenously once weekly (QW) in combination with M9241 16.8 µg/kg subcutaneously Q4W for the first 12 weeks, then continued the combination with avelumab Q2W. The primary endpoints were confirmed best overall response (BOR) per investigator assessment (RECIST 1.1) and safety. The expansion cohort followed a 2-stage design. During stage 1 (single-arm part of the study), 16 patients were enrolled and treated. A futility analysis based on BOR was planned to determine if stage 2 (randomized controlled part of the study) would be initiated.ResultsAt data cut-off (Jun 3, 2020), 16 patients had received avelumab + M9241 for a median duration of 8 weeks (range, 4.0–25.0 weeks). No complete or partial responses were observed; the study failed to meet the criterion (>2 responders) to initiate stage 2. Two patients (12.5%) had stable disease, 13 (81.3%) had progressive disease, and 1 (6.3%) was not evaluable. Any-grade treatment-related adverse events (TRAEs) occurred in 15 patients (93.8%); the most common (in =4 patients) were pyrexia (50.0%), nausea (37.5%), asthenia (31.3%), anemia (25.0%), and hyperthermia (25.0%); grade 4 gamma-glutamyltransferase increased occurred in 1 patient (6.3%). No TRAEs led to death. Pharmacodynamic effects on the peripheral immune system and results of pharmacokinetic and biomarker analyses will also be reported.ConclusionsThe predefined efficacy criterion to proceed to stage 2 was not met. The combination was well tolerated; no new safety signals emerged and the profile was consistent with the dose-escalation part of the study.5Trial RegistrationNCT02994953Ethics ApprovalThe study was approved by each site’s independent ethics committee.ConsentN/AReferencesBavencio(avelumab) injection [package insert]. Rockland, MA: EMD Serono, Inc; New York, NY: Pfizer Inc; 2020.Health Canada. https://www.canada.ca/en/health-canada.html. Accessed July 31, 2020.US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed July 31, 2020.Fallon J, Tighe R, Kradjian G, et al. The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget. 2014;5:1869–1884.Strauss J, Vugmeyster Y, Sznol M, et al. Phase 1b, open-label, dose escalation study of M9241 (NHS-IL12) plus avelumab in patients (pts) with advanced solid tumours. Ann Oncol. 2019;30(5 Suppl):Abstract 4062.

Suboptimal clinician awareness of appropriate NTRK fusion testing and TRK inhibitor use in solid tumors.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 229-229
Author(s):  
Ryan P. Topping ◽  
Krista Marcello ◽  
Terrence Fagan ◽  
Timothy A. Quill ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Progressive Disease ◽  
Inhibitor Therapy ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Educational Activities ◽  
Time Period ◽  
Trk Inhibitors ◽  
Therapeutic Alternatives ◽  
Selection Of

229 Background: Since late 2018, 2 TRK inhibitors—larotrectinib and entrectinib—have been approved by the EMA and FDA for treating patients with advanced solid tumors harboring an NTRK fusion and progressive disease or no therapeutic alternatives. It is recommended that testing for NTRK fusions occur as early as possible after a diagnosis of advanced disease in patients with solid tumors to inform potential use of TRK inhibitors. Methods: Between April 2018 and April 2021, we conducted multiple live and online educational activities for oncology healthcare professionals (HCPs) on NTRK fusion testing and/or TRK inhibitor treatment for varied solid tumors. Each activity included polling questions designed to assess HCP knowledge and practice patterns. In this analysis, we assessed HCP responses to these questions to evaluate awareness of expert recommendations on NTRK fusion testing and the selection of TRK inhibitor therapy for appropriate patients. Results: In 6 live and online activities with data from April 2018 to April 2021, 29% of HCPs (n = 844) indicated that they ordered molecular profiling to test for NTRK fusions in all solid tumors in their current practice. Of note, low rates of testing were reported in TRK inhibitor/ NTRK testing-focused activities throughout this time period, with no significant increase over time. In assessing different patient cases across 8 activities where experts recommended TRK inhibitor therapy as optimal, many HCPs did not select a TRK inhibitor, with considerable variance by tumor type (Table). *For all cases, experts selected larotrectinib and/or entrectinib as optimal treatment. †HCP respondents. GBM, glioblastoma; GI, gastrointestinal; MSI-H, microsatellite instability-high; PD, progressive disease; PTC, papillary thyroid cancer.Conclusions: The rate of broad testing for NTRK fusions across patients with solid tumors remains low, and many HCPs lack awareness of when to consider a TRK inhibitor. Educational activities designed to address these deficiencies would be of clear benefit to HCPs treating patients with advanced solid tumors. A detailed analysis of HCP trends will be presented.[Table: see text]

Trial in progress: Phase 1a/b study of PF-07284890 (brain-penetrant BRAF inhibitor) with/without binimetinib in patients with BRAF V600-mutant solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3152-TPS3152
Author(s):  
Vivek Subbiah ◽  
Martin Gutierrez ◽  
Carey K. Anders ◽  
George Ansstas ◽  
Taofeek K. Owonikoko ◽  
...  
Keyword(s):  
Disease Progression ◽  
Solid Tumors ◽  
Dose Level ◽  
Solid Tumor ◽  
Human Study ◽  
Tumor Type ◽  
Overall Response ◽  
Secondary Endpoints ◽  
Phase 1B ◽  
Brain Involvement

TPS3152 Background: BRAF inhibitors have transformed treatment (Tx) for patients (pts) with BRAF V600-mutant cancers, but long-term efficacy is limited by disease progression in the brain, due to poor brain penetration. PF-07284890 is a potent, selective, highly brain-penetrant, small-molecule inhibitor of BRAF V600 mutations. This first in human study will assess the PK, safety, and preliminary clinical activity of PF-07284890, as monotherapy and in combination with binimetinib (MEK inhibitor), in pts with BRAF V600-mutated advanced solid tumors with/without brain metastases. Methods: Phase 1a/1b open-label, multicenter, dose-finding study (NCT04543188). Pts will be ≥18 y with a histologically confirmed advanced/metastatic solid tumor including primary brain tumor (PBT), confirmed BRAF V600 mutation, and presence/absence of brain involvement. Pts will have disease progression despite prior Tx without alternative Tx options. Pts with brain metastasis/PBT > 4 cm and/or symptomatic brain disease will be excluded initially, but allowed based on emerging PK. Phase 1a is a dose escalation study of PF-07284890 (monotherapy and combination). ̃35 pts will be enrolled to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of PF-07284890 (monotherapy and combination). Cohorts of 2-4 pts will be treated at each dose level of PF-07284890 until MTD/RDE determination (PF-07284890 starting dose: 50 mg QD; binimetinib 45 mg BID). Bayesian Logistic Regression Model will be used to inform dose level decisions. At least 6 pts each for monotherapy and combination will be treated at MTD/RDE. Phase 1a primary endpoints: Cycle 1 dose-limiting toxicities; MTD/RDE; AEs; lab abnormalities; and dose interruptions, modifications and discontinuations due to AEs. Secondary endpoints include PK parameters and overall response (RECIST; overall and intracranial; RANO for PBT). Phase 1b is a dose expansion and drug-drug interaction study to further evaluate PF-07284890 + binimetinib. Cohorts 1-4 (̃40 pts each) will enroll pts based on tumor type, brain involvement (asymptomatic/symptomatic), and prior Tx. Cohort 5 (̃20 pts) will include pts with any solid tumor including leptomeningeal metastases. Cohort 6 (̃10 pts) will assess the effect of PF-07284890 + binimetinib on CYP3A activity using midazolam as a substrate. Phase 1b primary endpoint: overall response (RECIST; overall and intracranial; RANO for PBT). Secondary endpoints: duration of response; progression-free survival; disease control rate; time to response; overall survival; AEs; lab abnormalities; and dose interruptions, modifications and discontinuations due to AEs; and PK parameters. For both Phase 1a and 1b, Tx will continue until disease progression, unacceptable toxicity or patient refusal. Study began enrolling pts in January 2021 and is ongoing. Clinical trial information: NCT04543188.

Phase 1b study of the oral gemcitabine ‘Pro-drug’ LY2334737 in combination with capecitabine in patients with advanced solid tumors

2015 ◽  
Vol 33 (2) ◽  
pp. 432-439 ◽  
Author(s):  
Jeffrey R. Infante ◽  
Karim A. Benhadji ◽  
Grace K. Dy ◽  
Gerald Fetterly ◽  
Wen Wee Ma ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Phase 1B

scholarly journals 523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
Elaine Shum ◽  
Matthew Reilley ◽  
Yana Najjar ◽  
Adil Daud ◽  
John Thompson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Checkpoint Blockade ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

Sign in / Sign up

Export Citation Format

Share Document