scholarly journals 478 COM701 in combination with BMS-986207 (anti-TIGIT antibody) and nivolumab – preliminary results of safety, tolerability and pharmacokinetics in patients with advanced solid tumors (NCT04570839)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A508-A508
Author(s):  
Ecaterina Dumbrava ◽  
Manish Sharma ◽  
Gini Fleming ◽  
Kyriakos Papadopoulos ◽  
Ryan Sullivan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Solid Tumors ◽  
Pharmacokinetic Parameters ◽  
Tolerability Profile ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Cancer Data ◽  
Preliminary Results ◽  
Favorable Safety

BackgroundCOM701, a novel first-in-class immune checkpoint inhibitor (ICI) binds to poliovirus receptor related immunoglobulin domain containing (PVRIG) leading to enhanced activation of T and NK-cells. COM701 in combination with nivolumab has a favorable safety profile, is well tolerated and demonstrates antitumor activity.1 We hypothesized that the addition of BMS-986207 as a triplet thereby inhibiting the DNAM axis will have an acceptable safety/tolerability profile. We present preliminary results on safety/tolerability and pharmacokinetics (PK) parameters.MethodsUsing an accelerated titration and 3+3 study design we enrolled 14 patients (pts) with advanced solid tumors. Doses of COM701 were 0.3, 1, 3, 10 or 20 [mg/kg IV Q4 wks]; in combination with nivolumab and BMS-986207 (both 480 mg IV Q4 wks). Key objectives were to evaluate the safety and tolerability, to determine the recommended dose for expansion (RDFE) and to characterize preliminary pharmacokinetic parameters. Key inclusion criteria: Age ≥ 18 yrs, histologically confirmed locally advanced or metastatic solid malignancy and has exhausted all available standard treatments. Key exclusion criteria: history of immune-related toxicities on prior immunotherapy treatment leading to discontinuation.ResultsIn the safety population [N=14], 12 pts reported treatment emergent adverse events (TEAEs). The most frequent TEAES [≥3 pts] were fatigue 5 pts (36%), pyrexia 3 pts (21%), vomiting 3 pts (21%). No DLTs were reported in any of the dose levels. The most frequent tumor types enrolled: CRC (n=3), and prostate, melanoma and OVCA/primary peritoneal cancer (n=2 each). Median number of prior therapies was 10 (range 1–19). Four pts had received prior immunotherapy. Serious adverse events [≥2 pts] were 2 pts (14%) with G3 abdominal pain, 2 pts (14%) with vomiting (1pt with G1/2 vomiting, 1 pt with G3 vomiting) all assessed by the investigator as unrelated to study drug. Preliminary PK profiles of COM701 were generally dose proportional.ConclusionsCOM701 in combination with BMS-986207 and nivolumab demonstrates a favorable safety, tolerability and PK profiles. COM701 20 mg/kg has been selected as the RDFE in combination with BMS-986207 and nivolumab (both 480 mg) all administered IV Q4 wks. The expansion cohorts are enrolling pts with platinum resistant ovarian cancer and endometrial cancer. Data cutoff 28 Jun 2021.AcknowledgementsThis study is in collaboration with Bristol Myers Squibb.Trial RegistrationNCT04570839ReferencesVaena, DA, Fleming GF et al. COM701 with or without nivolumab: Results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advanced solid malignancies (NCT03667716). J Clin Oncol 2021;39: (suppl 15; abstr 2504).Ethics ApprovalThe study obtained ethics approval form all the participating sites. All study participants gave informed consent before taking part.- 0002: START2020.15- 0003: 20210109- 0005: IRB20-1549- 0006: 21-060- 0007: IRB-AAAT4904- 0012: 2020-0755- 0013: STMW2020.16- 0015: 20210109

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

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

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13053-13053 ◽  
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]

scholarly journals 949 First-in-human study of the first acid pH-sensitive and recycling CTLA-4 antibody that preserves the immune tolerance checkpoint to avoid immunotherapy-related adverse events in cancer patients

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A998-A998
Author(s):  
Tianhong Li ◽  
Mei Tang ◽  
Karen Kelly ◽  
Hui Amy Chen ◽  
Stacy Joo ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Solid Tumors ◽  
Drug Exposure ◽  
Human Study ◽  
Ph Sensitive ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Lysosomal Degradation ◽  
Acid Ph

BackgroundCTLA-4 is the first immune checkpoint target for cancer immunotherapy. However, the clinical benefit of targeting CTLA-4 has been limited by suboptimal doses and early discontinuation due to immunotherapy-related adverse events (irAE). Our preclinical studies suggest that acid pH-sensitive anti-CTLA-4 antibodies that preserve CTLA-4 recycling and avoid lysosomal degradation are more effective for immunotherapy but largely devoid of immunotherapy-related adverse events (irAE) [1-6]. To test this new hypothesis in human, we initiated first-in-human study evaluating the safety and tolerability of ONC-392 in patients with advanced solid tumors.MethodsONC-392-001 Part A is a dose finding study of ONC 392, IV infusion, Q3W. Patients (pt) with advanced solid tumors who had progressed to standard of care cancer therapies with ≥1 measurable tumor were enrolled. Intra-patient dose-escalation were performed for 4 doses (0.1, 0.3, 1.0 and 3.0 mg/kg) and 6 pts for the final dose of 10.0 mg/kg. The primary endpoints are the safety and tolerability of ONC-392 for identifying recommended Phase II dose (RP2D).ResultsTen pts have received 2-11 cycles of ONC-392 treatment at dose levels ranging from 0.1 to 10 mg/kg. Pt characteristics: median age 62 (range 43-81), female/male: 7/3, White/Asian/Black: 6/3/1. Tumor types: 4 ovarian, 4 NSCLC, 1 cervical and 1 GE junction cancer. Prior line of treatment: 2-7. Six pts were in 10 mg/kg dose level and received 2-4 doses of the drug as of this writing. None of the 10 pts experienced dose limiting toxicity (DLT) or Gr 3-4 adverse events (AEs) in DLT period. The RP2D for ONC-392 monotherapy is 10 mg/kg. After the DLT period, 1 patient developed Gr 3-4 elevated amylase/lipase at 10 weeks after 4 cycle of 10 mg/kg. No other treatment-related severe AE was observed. Among eight evaluable pts, 7/8 (87.5%) had stable disease (SD) after three cycle of treatment, and beneficial clinical efficacy activities was observed in 3/8 (37.5%) pts. Among them, a stage 4B ovarian cancer patient had stayed in treatment for 30 weeks till disease progression, and 2/2 evaluable PD(L)-1 antibody-refractory NSCLC patients were either eligible for surgery or had significant tumor shrinkage.ConclusionsONC-392 monotherapy is well tolerated with very low irAE rate. The RP2D for ONC-392 monotherapy is 10 mg/kg. The acid pH-sensitive anti-CTLA-4 mAb that preserves CTLA-4 recycling and avoids lysosomal degradation was safe and well tolerated. Our work paves the way for significant increase of drug exposure to reach full immunotherapeutic potential of CTLA-4 targeting.AcknowledgementsThe study is sponsored by OncoC4, Inc with the support of NCI SBIR grant R44CA250824.Trial RegistrationNCT04140526ReferencesDu X, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res 2018;28(4):433–447.Du X, et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018;28(4):416–432.Liu Y, Zheng P. How does an anti-CTLA-4 antibody promote cancer immunity? Trends Immunol 2018;39(12):953–956.Zhang Y, et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Research 2019;29(8):609–627.Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci 2020;41(1):4–12.Zhang P, et al. Mechanism- and immune landscape-based ranking of therapeutic responsiveness of 22 major human cancers to next generation anti-CTLA-4 antibodies. Cancers (Basel), 2020;12(2):284.Ethics ApprovalThis study obtained ethic approval from WIRB with Study #20193108. All participants gave informed consent before taking part of the study.ConsentN/A.

scholarly journals Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000453 ◽  
Author(s):  
Jayesh Desai ◽  
Sanjeev Deva ◽  
Jong Seok Lee ◽  
Chia-Chi Lin ◽  
Chia-Jui Yen ◽  
...  
Keyword(s):  
Cell Death ◽  
Antitumor Activity ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Single Agent ◽  
Objective Response ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Phase Ib

BackgroundThe programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.MethodsPatients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.ResultsBetween May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.ConclusionsTislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration numberNCT02407990.

388 Preliminary results from KEYNOTE-A36, a study of GB1275, a first-in-class oral CD11b modulator, alone and with pembrolizumab or chemotherapy in specified advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A413-A413
Author(s):  
Johanna Bendell ◽  
Wells Messersmith ◽  
Drew Rasco ◽  
Andrea Wang-Gillam ◽  
Wungki Park ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Tissue ◽  
Phase 1 ◽  
Cancer Center ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Serial Blood ◽  
Biomarker Analysis

BackgroundGB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342)MethodsThis study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis.ResultsAs of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing.ConclusionsDose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging.Ethics ApprovalThis ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.ReferencePanni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).

scholarly journals Phase Ib Study of the Histone Deacetylase 6 Inhibitor Citarinostat in Combination With Paclitaxel in Patients With Advanced Solid Tumors

2022 ◽  
Vol 11 ◽  
Author(s):  
Michael S. Gordon ◽  
Geoffrey I. Shapiro ◽  
John Sarantopoulos ◽  
Dejan Juric ◽  
Brian Lu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Pharmacokinetic Parameters ◽  
Advanced Solid Tumors ◽  
Histone Deacetylase 6 ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear ◽  
Once Daily ◽  
Phase Ib

BackgroundCitarinostat (CC-96241; previously ACY-241), an oral inhibitor of histone deacetylases (HDACs) with selectivity for HDAC6, has demonstrated synergistic anticancer activity with paclitaxel in multiple solid tumor models. Combination therapy using citarinostat with paclitaxel was evaluated in this phase Ib 3 + 3 dose-escalation study in patients with advanced solid tumors.MethodsPatients with previously treated advanced solid tumors received citarinostat 180, 360, or 480 mg once daily on days 1 to 21 plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was determination of the maximum tolerated dose (MTD). Secondary endpoints included safety, antitumor activity, pharmacokinetics, and pharmacodynamics.ResultsTwenty patients were enrolled and received study treatment; 15 had received prior taxane therapy. No dose-limiting toxicities were reported at any dose; therefore, the MTD was not identified. Citarinostat 360 vs 480 mg was associated with reduced incidence and severity of neutropenia. Three patients experienced a confirmed partial response and 13 achieved stable disease. Pharmacokinetic parameters were linear up to citarinostat 360 mg, the dose at which the highest levels of histone and tubulin acetylation were observed in peripheral blood mononuclear cells.ConclusionsThe combination of citarinostat plus paclitaxel showed an acceptable safety profile, with no unexpected or dose-limiting toxicities and potential evidence of antitumor activity in patients with heavily pretreated advanced solid tumors. Citarinostat 360 mg once daily is considered the recommended phase II dose for use in combination with paclitaxel 80 mg/m2 every 3 of 4 weeks. This trial is registered on ClinicalTrials.gov (NCT02551185).

scholarly journals Safety, Pharmacokinetics, and Preliminary Efficacy of Talazoparib in Japanese Patients With Advanced Solid Tumors: Phase 1 Study

2021 ◽  
Author(s):  
Yoichi Naito ◽  
Yasutoshi Kuboki ◽  
Masafumi Ikeda ◽  
Kenichi Harano ◽  
Nobuaki Matsubara ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Solid Tumors ◽  
Neutrophil Count ◽  
Phase 1 ◽  
Single Agent ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Once Daily

Abstract Background: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies.Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3+3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib.Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose level, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily.Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. Clinical Trial Register: clinicalTrials.govClinical Registration Number: NCT03343054 (November 17, 2017)

scholarly journals 477 COM902 (Anti-TIGIT antibody) monotherapy – preliminary evaluation of safety, tolerability, pharmacokinetics and receptor occupancy in patients with advanced solid tumors (NCT04354246)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A507-A507
Author(s):  
Ecaterina Dumbrava ◽  
Drew Rasco ◽  
Amita Patnaik ◽  
Daniel Vaena ◽  
Kyriakos Papadopoulos ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Adverse Events ◽  
Solid Tumors ◽  
Standard Therapy ◽  
Study Drug ◽  
Receptor Occupancy ◽  
Tolerability Profile ◽  
Preliminary Evaluation ◽  
Advanced Solid Tumors ◽  
Advanced Malignancy

BackgroundCOM902 is an IgG4 fully human high-affinity monoclonal antibody, inhibitor of TIGIT (T cell Ig and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain) binding to poliovirus receptor (PVR). TIGIT blockade by COM902 was shown to enhance anti-tumor immunity in pre-clinical models. We hypothesized that COM902 as monotherapy will have an acceptable safety and tolerability profile in subjects with advanced solid tumors.MethodsUtilizing an accelerated titration and 3+3 study design we enrolled 18 patients (pts) at the following COM902 doses 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg IV Q3 wks. Key primary objectives were to evaluate the safety, tolerability (CTCAE v5.0), to characterize the pharmacokinetics (PK) and to select a recommended dose for expansion (RDFE). An exploratory objective was evaluation of peripheral receptor occupancy (RO). Key inclusion criteria: Age ≥18 yrs, histologically/cytologically confirmed advanced malignancy who have exhausted all available standard therapy or not a candidate for standard therapy. Patients with performance status ECOG 0-1, prior ICI permissible. Dose-limiting toxicities (DLTs) were evaluated within a 21-day window in the 1st cycle of dose escalation.ResultsIn the safety population [N=18], 12 pts reported treatment emergent adverse events (TEAEs). The most frequent TEAES [≥2pts] were fatigue 7 pts (39%) all G1/2, diarrhea 3 pts (17%) all G1/2. Two pts reported DLTs deemed related to study drug, a pt with G2 nausea (single pt cohort, 0.01 mg/kg) and a pt with G3 atrial fibrillation (1 mg/kg). Serious adverse events were reported in 2 pts, 1 pt with atrial fibrillation (deemed by the investigator as possibly related to COM902) and 1 pt with spinal cord compression (deemed by the investigator as unrelated to COM902, related to disease). Preliminary PK profiles were generally dose proportional and peripheral RO above 90% was reported from 0.1 mg/kg dose.ConclusionsCOM902 has an acceptable safety, tolerability and PK profiles. A COM902 3 mg/kg IV Q3 wks is the RDFE. Enrollment into combination cohort (COM902 + COM701), for evaluation of safety/tolerability at the RDFE of both study drugs, combination dose expansion (COM902 + COM701) in pts with HNSCC, NSCLC and CRC-MSS and COM902 monotherapy dose expansion (pts with multiple myeloma) all at the RDFE of study drug(s) are planned. Data cut June 28, 2021.Trial RegistrationNCT04354246Ethics ApprovalThe study obtained approval from IRBs of the participating clinical trial sites. The study participants gave informed consent before taking part.o 0002: MOD01006350 (START)o 0003: 20202320 (West Cancer Center)o 0012: 2020–0195 (MDACC)o 0013: MOD01006350 (START midwest)o 0014: 20202320 (OSU)

scholarly journals Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study

2021 ◽  
Author(s):  
Yoichi Naito ◽  
Yasutoshi Kuboki ◽  
Masafumi Ikeda ◽  
Kenichi Harano ◽  
Nobuaki Matsubara ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Solid Tumors ◽  
Neutrophil Count ◽  
Phase 1 ◽  
Single Agent ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Once Daily

SummaryBackground: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).

scholarly journals 417 Design and rationale of a phase 1 study evaluating AMG 256, a novel, targeted, IL-21 receptor agonist and anti-PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A443-A443
Author(s):  
Gregory Durm ◽  
Sophia Frentzas ◽  
Erik Rasmussen ◽  
Saltanat Najmi ◽  
Nooshin Sadraei
Keyword(s):  
Solid Tumors ◽  
Tumor Immunity ◽  
Renal Cell ◽  
Phase 1 ◽  
List Type ◽  
Solid Organ ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Drug Study ◽  
Interleukin 21

BackgroundCheckpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance.1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer.2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.3 4 AMG 256 is a mutated IL-21 cytokine fused to an anti-PD-1 antibody to combine IL-21 pathway stimulation with checkpoint inhibition—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors.MethodsThis is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies.ResultsN/AConclusionsN/AAcknowledgements• The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.).Trial RegistrationNCT04362748Ethics ApprovalThe study was approved by all institutional ethics boards.ReferencesKluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398.Thompson JA, Curti BD, Redman BG, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034–2039.Lewis KE, Selby MJ, Masters G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology. 2017;7:e1377873.Shen S, Sckisel G, Sahoo A, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol 2020;11:832.

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