Abstract CT067: 2-hydroxyoleic acid (2-OHOA), a novel activator of sphingomyelin synthase with antitumor activity in refractory glioblastoma: results of the first-in-human dose-escalation (DE) study in patients with advanced solid tumors (AST) and refractory gliomas/glioblastomas

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

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Phase I, First‐in‐Human, Dose‐Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors

The Oncologist ◽

10.1634/theoncologist.2018-0740 ◽

2018 ◽

Vol 24 (4) ◽

pp. 455 ◽

Cited By ~ 4

Author(s):

Johanna C. Bendell ◽

Manish R. Patel ◽

Kathleen N. Moore ◽

Cynthia C. Chua ◽

Hendrik‐Tobias Arkenau ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Human Dose

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A phase Ib dose-escalation study of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) in combination with bevacizumab with or without paclitaxel in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.2514 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 2514-2514 ◽

Cited By ~ 4

Author(s):

L. Naumovski ◽

M. S. Gordon ◽

P. N. Munster ◽

P. Hegde ◽

J. Fredrickson ◽

...

Keyword(s):

Monoclonal Antibody ◽

Antitumor Activity ◽

Solid Tumors ◽

Dose Escalation ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Phase Ib ◽

Humanized Monoclonal Antibody

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps3112 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS3112-TPS3112 ◽

Cited By ~ 1

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.

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First-in-human, dose-escalation, safety, and PK study of a novel 5T4-ADC in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.tps2603 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. TPS2603-TPS2603

Author(s):

Geoffrey Shapiro ◽

Patricia LoRusso ◽

Ulka N. Vaishampayan ◽

Muaiad Kittaneh ◽

John Frederick Hilton ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Advanced Solid Tumors ◽

Human Dose

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Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

10.21203/rs.3.rs-125321/v1 ◽

2020 ◽

Author(s):

Yanshuo Cao ◽

Ming Lu ◽

Yu Sun ◽

Jifang Gong ◽

Jie Li ◽

...

Keyword(s):

Antitumor Activity ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Fixed Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Phase 1 Trial ◽

Open Label Phase ◽

Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

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Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2016.70.1508 ◽

2017 ◽

Vol 35 (18) ◽

pp. 2028-2036 ◽

Cited By ~ 54

Author(s):

Howard A. Burris ◽

Jeffrey R. Infante ◽

Stephen M. Ansell ◽

John J. Nemunaitis ◽

Geoffrey R. Weiss ◽

...

Keyword(s):

T Cell ◽

Antitumor Activity ◽

Solid Tumors ◽

T Cell Activation ◽

Dose Escalation ◽

Costimulatory Molecule ◽

Progression Free Survival ◽

Advanced Solid Tumors ◽

Free Survival ◽

Metastatic Rcc

Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity—grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation—chemokine induction, T-cell stimulation, regulatory T cell depletion—was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

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A phase Ib trial of ARQ 501, a selective checkpoint activator, in combination with docetaxel in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13053 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13053-13053 ◽

Cited By ~ 4

Author(s):

C. Li ◽

J. Nemunaitis ◽

N. Senzer ◽

G. Edelman ◽

S. Glasner ◽

...

Keyword(s):

Dna Damage ◽

Antitumor Activity ◽

Solid Tumors ◽

Dose Escalation ◽

Cytotoxic Agents ◽

Ca 125 ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Advanced Solid Tumors ◽

Cell Death Pathway

13053 Background: ARQ 501 is a DNA damage checkpoint activator. It directly activates DNA damage response pathways without inducing primary DNA damage, resulting in selective apoptosis in a broad range of cancer cells. The cell death pathway of ARQ 501 is mediated by E2F1, and is independent of p53. In preclinical models, ARQ 501 demonstrates potent anticancer activity with a high therapeutic index. In these models, the addition of a variety of cytotoxic agents, including docetaxel, greatly enhances the anti-tumor activity of ARQ 501. Therefore, clinical investigation of this combination is warranted. Methods: Phase 1b dose escalation study in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of ARQ 501 in combination with docetaxel. Two schedules have been investigated. In one, ARQ 501 was administered for 5 consecutive days with a single docetaxel infusion at 50 to 100 mg/m2 given on day 3. In the other, a single dose of ARQ 501 was given in combination with a single docetaxel infusion on day 1. Both schedules were repeated every 3 weeks. Pharmacokinetic data were collected during study weeks 1 and 4 and tumor evaluations performed every 6 weeks. Results: To date, the first ARQ 501 treatment schedule has been given to 9 evaluable patients, and the second to 7 patients with a wide variety of tumor types. The combination is well tolerated and exhibits favorable, apparently linear, pharmacokinetics. ARQ 501 does not alter docetaxel pharmacokinetic parameters in patients. The most common grade 3 and 4 adverse events are neutropenia (4.9%) and anemia (4.4%). Of the 16 patients receiving at least 8 weeks of treatment, 12 have achieved a response of stable disease or better, including four responses (2 unconfirmed PRs based on RECIST, and 2 responses based on CA-125 decreases). Conclusions: The combination of ARQ 501 with docetaxel demonstrates clinical tolerability, favorable pharmacokinetics, and signs of antitumor activity. Further dose escalation is ongoing to determine a recommended phase II regimen. [Table: see text]

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