scholarly journals 340 A phase Ib study of the safety and tolerability of pixatimod plus nivolumab in subjects with advanced solid tumors with an expansion cohort in metastatic pancreatic adenocarcinoma (mPDAC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A366-A366
Author(s):  
Charlotte Lemech ◽  
Keith Dredge ◽  
Darryn Bampton ◽  
Edward Hammond ◽  
Amanda Stanley ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Cancer Patients ◽  
Dose Escalation ◽  
Advanced Cancer Patients ◽  
Phase Ib ◽  
Cytokines And Chemokines ◽  
Reference Number ◽  
Plasma Cytokines ◽  
Expansion Cohort

BackgroundPixatimod is a novel immunomodulatory agent which stimulates dendritic cells (DC) via Toll-Like Receptor (TLR9) pathway to activate natural killer (NK) cells.1 In combination with PD1 inhibitors, it also enhances T cell infiltration in vivo.2 We report on safety, pharmacokinetics (PK) and pharmacodynamics (PD), and antitumor activity of pixatimod plus nivolumab in advanced cancer patients (stage 1) and in an expansion cohort of mPDAC (stage 2).MethodsIn the dose escalation stage (3+3 design), eligible patients (ECOG≤1) with advanced solid malignancies who failed standard therapies received pixatimod once weekly as a 1-hour i.v. infusion plus nivolumab (240 mg, every other week) until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity per RECIST v1.1, PK of pixatimod, and PD (PBMC, plasma cytokines and chemokines). Stage 2 comprised mPDAC subjects who had received no more than one prior line of chemotherapy in the metastatic setting.ResultsThe dose-escalation stage recruited 16 subjects across two cohorts (25 & 50 mg pixatimod). Two dose limiting toxicities (DLTs) in 50 mg cohort were pulmonary edema and multi-organ failure. Of note, the subject with multi-organ failure had substantially higher CA19.9, Pan-immune-Inflammatory Value (PIV = Neutrophils x Platelets x Monocytes/Lymphocytes) and interleukins (IL) IL-1α and IL-23 at baseline compared with the cohort. One DLT occurred in the 25 mg cohort, pneumonitis, which was identified as the MTD. A further 14 mPDAC subjects were recruited to the expansion stage (25 mg). Seven SAEs were reported to be possibly or likely related to the combination. No objective responses were reported in the mPDAC stage, the best response was SD (n = 3). In another submitted abstract by Lemech et al, we report two subjects in the dose escalation stage with MSS mCRC were confirmed PR, and data from the amended study to include an MSS mCRC expansion cohort will also be presented. Time versus concentration data for pixatimod in advanced cancer patients was similar to that previously reported in monotherapy setting. In mPDAC subjects, there was minimal immune activation as evidenced by a lack of change in effector memory T cells or NK cells in PBMC, plasma cytokines and chemokines.ConclusionsPixatimod is well tolerated at 25 mg in combination with nivolumab but did not provide clear clinical benefit or evidence of immune activation in the mPDAC cohort.AcknowledgementsResearch funding was provided by Zucero Therapeutics Ltd and Bristol Myers Squibb (BMS), Australia.Trial RegistrationClinical trial informationACTRN12617001573347.ReferencesBrennan TV, Lin L, Brandstadter JD, Rendell VR, Dredge K, Huang X, et al. Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. J Clin Invest 2016;126(1):207–19.Hammond E, Haynes NM, Cullinane C, Brennan TV, Bampton D, Handley P, et al. Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. J Immunother Cancer 2018;6(1):54.Ethics ApprovalThe clinical trial entitled “An open-label, multi-centre Phase Ib study of the safety and tolerability of IV infused PG545 in combination with nivolumab in patients with advanced solid tumours with an expansion cohort in patients with metastatic pancreatic cancer. Protocol ZU545102” obtained ethics approval from the Royal Adelaide Hospital (HREC Reference number, HREC/17/RAH/195 and the CALHN Reference number, R20170515) and Bellberry Limited (Application No: 2018-08-695). All participants in the study gave informed consent before taking part in ZU545102.

92 NOLATREXED PHASE Ib CLINICAL TRIAL IN A DOSE INTENSIFICAITON SCHEDULE IN ADVANCED CANCER PATIENTS.

2004 ◽  
Vol 52 (Suppl 1) ◽  
pp. S273.1-S273
Author(s):  
Charles Schloss ◽  
Michele Cronin ◽  
Fred Oldham ◽  
Lowell Anthony
Keyword(s):  
Clinical Trial ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Advanced Cancer Patients ◽  
Phase Ib

scholarly journals A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
John H. Strickler ◽  
Christel N. Rushing ◽  
Donna Niedzwiecki ◽  
Abigail McLeod ◽  
Ivy Altomare ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Phase Ib ◽  
Expansion Cohort

Abstract Background Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. Methods All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Results A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. Conclusion The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. Trial registration This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Phase Ib clinical trial of OKN-007 in recurrent malignant glioma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2538-2538 ◽  
Author(s):  
James D. Battiste ◽  
Alexandra Ikeguchi ◽  
Sukyung Woo ◽  
Satish Sharan ◽  
Yan D. Zhao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Recurrent Glioma ◽  
Phase Ib ◽  
Cancer Agent ◽  
Expansion Cohort

2538 Background: Despite therapeutic advances, the median overall survival for patients with recurrent, high-grade gliomas remains poor. Thus, there is an urgent need for efficacious new therapies. The nitrone compound, OKN-007 (disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is a promising novel anti-cancer agent. In orthotopic glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. Methods: NCT01672463 is a phase Ib trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. Patients with recurrence, adequate performance status and organ function, receiving clinically appropriate doses of steroids, with a life expectancy greater than 8 weeks were eligible. OKN-007 was administered by IV. The study comprised a 3+3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until recurrence (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Median age was 51 years (range, 25-62). No dose-limiting toxicities were observed and 60 mg/kg was chosen for the expansion dose. Of 123 adverse events (AE), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAE were fatigue (4.1%) and headache (3.3%). No drug-attributable grade 4 or 5 AE were observed. Grade 3 TEAE included headache, urinary tract infection, and increased prothrombin time (0.8% each). Only two grade 1 AE, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. Conclusions: OKN-007 appears safe for patients with recurrent glioma. The MTD was not reached. Our data suggest that, compared to standard therapy, OKN-007 may prolong OS in recurrent glioma. Based on new data, a trial of OKN-007 plus temozolomide is underway in patients with newly diagnosed glioblastoma (NCT03587038). Clinical trial information: NCT01672463 .

Phase I study of pazopanib (PAZ) in combination with PCI-24781 (PCI) in patients (pts) with metastatic solid tumors with new tumor proliferation imaging correlates in renal cell carcinoma (RCC) and sarcoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS2623-TPS2623
Author(s):  
Thach-Giao Truong ◽  
Jennifer A. Grabowsky ◽  
Stephanie Chen ◽  
Roth Ea ◽  
Andrew H. Ko ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Iii ◽  
Current Status ◽  
Thymidine Uptake ◽  
Tumor Proliferation ◽  
Phase Ib ◽  
Flt Pet ◽  
Expansion Cohort

TPS2623 Background: PAZ is a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT, approved for metastatic RCC and refractory sarcoma based on phase III data showing prolonged PFS (JCO 2010;28:1061-8 and Lancet 2012;379:1879-86). PCI is a potent pan-HDAC inhibitor (pan-HDACi), observed in cell lines to change regulation of genes involved in cell signaling, apoptosis, proliferation, differentiation, and angiogenesis (Anticancer Res 2011;31:1115-23). Pre-clinical models suggest epigenetic modification with an HDACi potentiates PAZ’s efficacy by causing chromatin instability and gene expression changes involved in drug resistance (Can Res 2005;65:3815-22 and BJC 2009;100:758-63). We therefore designed a Phase Ia/b clinical trial combining PCI with PAZ in pts with advanced solid tumors, with an expansion cohort for preliminary efficacy in RCC and sarcoma. Methods: Primary objective of this phase Ia/b study is to evaluate the safety and tolerability of the combination of PAZ and PCI to determine the MTD and RP2D. In phase Ia, we utilized an accelerated phase I design. The phase Ib portion will include up to 20 pts per expansion cohort, for up to 32-70 pts enrolled. In phase 1a, pts receive run-in PCI alone on C1D-7 to D-4. Starting with C1D1, pts receive oral PCI on D1-5, 8-12, 15-19 BID 4 hrs apart and PAZ daily (D1-28) q28D cycle. CORRELATIVES: Pre- and post-treatment (Tx) H3 & H4 acetylation and HDAC activity in PBMCs. In phase Ib, these will also be studied in tumor biopsies. We will measure expression of VEGF, VEGFR, RAD51, HIF, Ki67; and analyze SNPs through genomic profiling. We will correlate response with pre- and post-Tx tumor thymidine uptake using 18F-fluorothymidine (FLT-PET) PET. Current Status: This is the 1st trial exploring the combination of an HDACi with PAZ in RCC and sarcoma, where there is an unmet need for new tolerable therapies. It will study FLT-PET, an imaging correlate that captures tumor proliferation and may have a role as a predictive biomarker. We are currently in phase Ia. Enrollment in the 3rd cohort exploring higher doses of PAZ will begin in Feb 2013. Clinical trial information: NCT01543763.

Sign in / Sign up

Export Citation Format

Share Document