Safety of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3063-3063
Author(s):  
Melissa Lynne Johnson ◽  
Manish R. Patel ◽  
Mohamad Cherry ◽  
Yoon-Koo Kang ◽  
Kensei Yamaguchi ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
T Cell Response ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Median Treatment

3063 Background: LAG-3, an immune checkpoint receptor involved in T-cell regulation, is frequently co-expressed with PD-1. LAG-3 and PD-1 signaling contributes to immune cell exhaustion and reduces the immune response to tumor cells. Dual inhibition of PD-1 and LAG-3 may reactivate the T-cell response better than blockade of either individual pathway. Here, we report combined safety data from 4 trials investigating BI 754111, an anti-LAG-3 mAb, in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: Data from 2 phase I dose-escalation/expansion trials, 1 phase I imaging trial, and 1 phase II trial were included. Eligible patients had advanced and/or metastatic solid tumors with measurable disease and an Eastern Cooperative Oncology Group performance status ≤1. Patients received BI 754111 (intravenously [iv], 4–800 mg) in combination with BI 754091 (iv, 240 mg fixed dose) every 3 weeks (q3w). Patients remained on treatment until progressive disease or unacceptable toxicity. In each trial, safety was assessed by incidence and severity of adverse events (AEs), and graded according to Common Terminology Criteria for AEs, version 5. Results: Overall, 321 patients were treated with BI 754111 in combination with BI 754091 (200 [62%] male; median age, 63 years [range 18–88]). Median treatment exposure was 85 days (range 9–625). Of these patients, 282 (87.9%) had any AE (G≥3 in 99 [30.8%]). 285 patients received the 600 mg recommended phase II dose of BI 754111 plus BI 754091 240 mg q3w. Median treatment exposure in these patients was 74 days (range, 8–590). The table shows the 3 most common AEs and 4 most common immune-related AEs, and their frequency. 21 (7.4%) patients had AEs leading to study drug discontinuation, most commonly infusion-related reactions (IRRs) in 6 (2.1%) patients. Serious AEs (all-cause) occurred in 77 patients (27.0%), most commonly pleural effusion in 6 (2.1%) and deep vein thrombosis in 4 (1.4%) patients. 2 patients (0.7%) experienced an AE resulting in death (cardiac tamponade and acute kidney injury, both related to underlying diseases). Conclusions: The combination of BI 754111 and BI 754091 had a manageable safety profile, similar to other checkpoint inhibitors. Clinical trial information: NCT03156114, NCT03433898, NCT03697304, NCT03780725 . [Table: see text]

Phase I dose escalation study of recombinant interleukin-21 (rIL-21; BMS-982470) in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced or metastatic solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3112-TPS3112 ◽  
Author(s):  
Laura Quan Man Chow ◽  
Michael S. Gordon ◽  
Theodore F. Logan ◽  
Scott J. Antonia ◽  
Shailender Bhatia ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Clinical Outcomes ◽  
Dose Escalation ◽  
Fixed Dose ◽  
Weekly Schedule ◽  
Advanced Solid Tumors ◽  
Biologic Activity

TPS3112 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2. Nivolumab, a PD-1 receptor blocking antibody, has shown durable antitumor activity in pts with various solid tumors in two phase I clinical trials. The cytokine rIL-21 has also shown antitumor activity in selected solid tumors. We hypothesized that combining rIL-21-induced stimulation of T-cell and NK-cell function in conjunction with T-cell checkpoint blockade using nivolumab could enhance biologic activity resulting in improved clinical outcomes, as compared with either agent alone. We describe a novel phase I study investigating the biologic activity and clinical outcomes of the combination in pts with advanced solid tumors. Methods: This ongoing study (N=160) includes a dose escalation phase (Part 1) using a 3 + 3 design followed by an expansion phase (Part 2). In Part 1 (N=60), successive pt cohorts with advanced solid tumors are being treated with escalating doses of rIL-21 (10, 30, 50, 75, or 100 µg/kg IV) on two distinct schedules (Arms A and B) in combination with fixed-dose nivolumab (3 mg/kg q 2 weeks) in 6 week cycles. Arm A administers rIL-21 on a weekly schedule, given on day 1 in weeks 1–4 of the 6 week cycle. Arm B administers rIL-21 at 3x per week during weeks 1 and 3 of the 6 week cycle. In Part 2, pts with renal cell carcinoma (N=50) or non-small cell lung carcinoma (N=50) will each be randomized to treatment at the maximum tolerated dose (MTD) or maximum administered dose, if no MTD is determined, for Arm A or Arm B. Therapy for pts who are stable or responding in Parts 1 and 2 may be continued for up to 2 years or until treatment discontinuation criteria are met. Primary objectives are to evaluate the safety of rIL-21 + nivolumab, and to define the MTD of the 2 schedules. Secondary and exploratory objectives include a preliminary assessment of the antitumor activity, pharmacokinetics, immunoregulatory activity (peripheral blood, tumor) and immunogenicity of this combination. Clinical trial information: NCT01629758.

A phase I study of CD40 agonist ABBV-927 plus OX40 agonist ABBV-368 with or without the PD-1 inhibitor budigalimab in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3147-TPS3147
Author(s):  
John D. Powderly ◽  
Anthony Tolcher ◽  
Patricia LoRusso ◽  
Martha Elizabeth Blaney ◽  
Daniel Dacosta ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Group Performance ◽  
Costimulatory Molecule ◽  
Eastern Cooperative Oncology Group ◽  
Cell Activity ◽  
Advanced Solid Tumors ◽  
Disease Specific

TPS3147 Background: CD40 is a key costimulatory molecule for both the innate and adaptive immune systems that is essential for T-cell activation and proliferation. OX40 is a costimulatory molecule that is involved in enhancing nascent immune responses and concomitantly acts to suppress regulatory T-cell activity. ABBV-927 and ABBV-368 are potent agonistic antibodies against CD40 and OX40, respectively. This open-label, Phase 1 study will evaluate the doublet combination of ABBV-927 and ABBV-368 and the triplet combination of ABBV-927, ABBV-368, and the programmed cell death protein-1 (PD-1) inhibitor budigalimab in patients with advanced solid tumors. Methods: For this study (NCT03893955), patients must be ≥18 y with an Eastern Cooperative Oncology Group performance status of 0-1. Patients must have an advanced solid tumor that has progressed on standard therapies. Disease-specific cohorts will include patients with non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Patients with NSCLC must have previously received a PD-1/PD-ligand 1 inhibitor and a platinum-based therapy and no more than one prior immunotherapy. Patients with TNBC must not have received immunotherapy. Patients with uncontrolled central nervous system metastases will be excluded. The recommended Phase 2 dose (RP2D) will first be identified with ABBV-927 + ABBV-368 in patients with solid tumors (Arm A) and will be expanded in disease-specific cohorts including TNBC. The RP2D of ABBV-927 + ABBV-368 + budigalimab will be identified in patients with NSCLC (Arm B). The primary endpoints are determination of the RP2D of ABBV-927 + ABBV-368, the RP2D of ABBV-927 + ABBV-368 + budigalimab, and overall response rate; duration of response, progression-free survival, safety, and pharmacokinetics are secondary endpoints. Screening began on 21 May 2019, and enrollment is ongoing. Clinical trial information: NCT03893955 .

scholarly journals 535 A phase I/II study of REGN7075 (EGFRxCD28 costimulatory bispecific antibody) in combination with cemiplimab (anti–PD-1) in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A565-A565
Author(s):  
Nehal Lakhani ◽  
Melissa Johnson ◽  
Roman Groisberg ◽  
Hyunsil Han ◽  
Kerry Casey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Group Performance ◽  
Bispecific Antibodies ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2544-2544
Author(s):  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Advanced Solid Tumors ◽  
Grade 3

2544 Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors

2006 ◽  
Vol 59 (4) ◽  
pp. 467-475 ◽  
Author(s):  
Matthew G. Fury ◽  
David B. Solit ◽  
Yungpo Bernard Su ◽  
Neal Rosen ◽  
F. M. Sirotnak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Fixed Dose ◽  
High Dose ◽  
Advanced Solid Tumors

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
R. Sangha ◽  
C. Ho ◽  
L. Beckett ◽  
D. H. Lau ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Gene Copy ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Egfr Inhibition ◽  
Biomarker Analysis

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

A phase Ib proof-of-concept study of LBH589 (LBH) and everolimus (EVE) in advanced solid tumors enriched for Epstein-Barr virus (EBV)-related cancers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3098-3098
Author(s):  
Daniel Shao-Weng Tan ◽  
Quan Sing Ng ◽  
Dawn Qingqing Chong ◽  
Guek Eng Lee ◽  
Thuan Tong Tan ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Cell Response ◽  
Maximum Tolerated Dose ◽  
T Cell Response ◽  
Advanced Solid Tumors ◽  
Mtor Inhibition ◽  
Minor Response ◽  
Barr Virus ◽  
Ebv Dna

3098 Background: Histone deacetylase and mTOR inhibition circumvent critical EBV-oncogenic pathways with preclinical studies demonstrating lytic induction in EBV infected cells, as well as immunomodulatory and antiangiogenic effects. Methods: Patients (Pt) with advanced solid tumors enriched for EBV–related cancers were enrolled to determine safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity. LBH was instituted 7-days prior to combination treatment. NPC pt received antiviral prophylaxis of either acyclovir (Ac) or valaciclovir (Vc). Serum EBV DNA levels (EBNA-1) were measured weekly and plasma cytokines profiled using a 31-plex Luminex panel. Results: 15 pt have been treated (M:F 13:2, median age 50, R: 38-63) 10 NPC, 5 non-NPC (colon, RCC, breast, gastric, sarcoma) at 3 dose levels – LBH (3x/wk)-EVE (daily):10-2.5, 10-5, 15-5. Two dose limiting toxicities of G4 (grade) thrombocytopenia were observed at LBH15-RAD5. Significant adverse events (AE) (G≥3) were dysphagia (1) and thrombocytopenia (3). Common AEs (G1/2) included fatigue (80%), anorexia (60%), mucositis (53%), xerostomia (26%), dysphagia (26%). Two minor responses were seen (1 NPC, 1 breast) and 2 pt (1 NPC, 1 RCC) had prolonged stable disease (>16 weeks). Modulation of EBV DNA titres was seen only in NPC pt, with median fold-change from baseline of 10.9 (0.05-174). Pt on Ac prophylaxis (n=5) had significant increases in DNA titres (9-174 fold), while those on Vc (n=4) were less pronounced (0.05-11 fold, p<0.03), with one pt (with minor response) having persistent decline in EBV titres. In a limited pt subset (n=9, 30 timepoints), plasma cytokine profiles were consistent with a T-cell response, specifically, elevated levels of FLT3L, IFN-gamma, IL-13 and IL-17. PK and PBMC target modulation studies are being analysed. Conclusions: LBH-EVE results in induction of EBV DNA titres with an associated host T cell response. MTD is LBH10-EVE5 in Asian pt, majority of whom had NPC. A pre-planned expansion cohort that incorporates multi-parametric functional imaging exploring two schedules of LBH in combination with EVE5 is ongoing.

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