Dose escalation and pharmacodynamic study of intravenous adminstration of Reolysin, a live replication competent RNA virus in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3583-3583
Author(s):  
M. H. Ghalib ◽  
K. K. Desai ◽  
R. Gollamudi ◽  
I. Chaudhary ◽  
M. Einstein ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Rna Virus ◽  
Single Agent ◽  
Neutralizing Antibody ◽  
Viral Shedding ◽  
Activating Mutations ◽  
Anti Cancer ◽  
Activating Mutation ◽  
Anti Tumor Activity ◽  
Wall Mass

3583 Background: Reolysin is reovirus serotype 3 - Dearing strain, a double-stranded replication- competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activating mutation in the ras proto-oncogene. Methods: This was a single center dose escalation trial of Reolysin administered intravenously every four weeks in doses ranging from 1X108 to 3X1010 tissue culture infective dose (TCID)50. Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. Results: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients [urine (5), serum (4), saliva (3), and stool (2)]. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a mutation in the ras oncogene. Biopsy from a chest wall mass showed evidence of necrosis and viral replication by electron microscopy. The overall clinical benefit rate was 45% and appeared higher in patients with viral shedding (67%) than those without (33%). Conclusions: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies. [Table: see text]

Pharmacodynamic and safety study of reolysin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14004-14004 ◽  
Author(s):  
R. Gollamudi ◽  
K. Desai ◽  
I. Chaudhary ◽  
M. H. Ghalib ◽  
B. Wong ◽  
...  
Keyword(s):  
Performance Status ◽  
Single Agent ◽  
Neutralizing Antibody ◽  
Open Label ◽  
Viral Shedding ◽  
Cytopathic Effects ◽  
Best Response ◽  
Activating Mutation ◽  
Grade 3 ◽  
Anti Tumor Activity

14004 Background: Reolysin is an intravenous formulation of reovirus serotype 3 - Dearing strain which is a double stranded RNA non-enveloped icosahedral virus capable of inducing cytopathic effects in cancer cells that have an activating mutation in the ras protooncogene. Pre clinical testing has identified cancer cell lines as being susceptible to reovirus infection. Methods: This was an open- label single center phase I safety and dose escalation trial of reolysin administered intravenously over 1 hour on day 0 in a 28 day cycle. Dose escalations were in half log increments. Serum for neutralizing antibody (NA) was drawn at baseline, and days (d) 1, 7, 14, 21, and 28, and serum, stool, saliva, and urine for viral shedding (by RT-PCR) were sampled on d 1,7,14,21, and 28. Response was assessed by imaging studies after 1, 3, 5, and 7 cycles. Results: 18 patients (pt); median age 57 (40–72) years; performance status 0–1; diagnoses - ovarian (6), colorectal (5), and others (7) received 27 cycles of reolysin (median 1, range 1–7) in 6 dose cohorts of 1x108, 3x108, 1x109, 3x109, 1x1010, and 3x1010 tissue culture infective dose (TCID)50. No protocol defined dose limiting toxicities were observed. Drug related grade 2 toxicities included chills (2 pt), and fatigue (3 pt). The only grade 3 event was fever in cycle 7 in a 57 year old woman with progressive breast cancer, treated at a dose of 1x1010 TCID50. She was noted to have 28.5% shrinkage in objective tumor volume. An additional 7 pt had stable disease (SD). No NA was detectable in the serum in any pt at baseline; however all pt developed NA (on d 5 in 5 pt, d 8 in 11 pt, d 14 in 1 pt, and d 28 in 1 pt) during the course of the study. Viral shedding was observed in serum - 5 pt, stool - 3 pt, saliva - 3 pt, and urine - 4 pt. Of interest, 4 of 5 pt with viral shedding had SD as their best response. However, there was no observed relationship between NA formation and SD. Conclusion: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. This preliminary data suggests there is anti-tumor activity of reolysin as a single agent, and warrants further studies either alone or in combination with cytotoxic chemotherapy. [Table: see text]

scholarly journals Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer

2021 ◽  
Author(s):  
Edward Kennedy ◽  
Agnieszka Denslow ◽  
Jacqueline Hewett ◽  
Lingxin Kong ◽  
Ana De Almeida ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Rna Virus ◽  
Neutralizing Antibody ◽  
Repeated Administration ◽  
Oncolytic Viruses ◽  
Drug Candidates ◽  
Novel Approach ◽  
Coxsackievirus A21 ◽  
Anti Tumor Activity

Abstract Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration, but the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21 (CVA21), we demonstrate vRNA delivery, viral replication, spread, and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promoted immune cell infiltration and enhanced anti-tumor activity in combination with anti-PD-1 checkpoint inhibitor. Altogether, the Synthetic RNA virus platform provides an innovative approach that enables repeat intravenous administration of viral immunotherapy.

First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2580-2580 ◽  
Author(s):  
Johann Sebastian De Bono ◽  
Lida A. Mina ◽  
Michael Gonzalez ◽  
Nicola J. Curtin ◽  
Evelyn Wang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dose Escalation ◽  
Synthetic Lethality ◽  
Dose Range ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Ca 125 ◽  
Brca 1 ◽  
Anti Tumor Activity ◽  
Brca Carrier

2580 Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50<1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 µg/d that defined a MTD of 1000 µg/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 µg/d, respectively. Potentially-related adverse events in >10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ≥ 100 µg/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 µg/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ≥ 100 µg/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 µg/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.

A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5103-5103 ◽  
Author(s):  
R. Srinivasan ◽  
W. M. Linehan ◽  
U. Vaishampayan ◽  
T. Logan ◽  
S. M. Shankar ◽  
...  
Keyword(s):  
Renal Carcinoma ◽  
Single Agent ◽  
Activating Mutations ◽  
Best Response ◽  
Pathway Activation ◽  
Molecule Inhibitor ◽  
Dosing Regimens ◽  
Trisomy 7 ◽  
Pharmacodynamic Markers ◽  
Anti Tumor Activity

5103 Background: GSK089 is a potent, orally available small molecule inhibitor of MET and VEGFR2. Activating mutations and/or amplifications in MET have been described in pts with PRC. Two of 4 PRC pts treated with intermittent dosing of GSK089 on a Phase I study sustained partial responses (PR) for 1 and > 3 years respectively. The aim of the current study is to evaluate the efficacy, safety and tolerability of 2 dosing regimens of GSK089 as a single agent in pts with advanced sporadic PRC (SPRC) or hereditary PRC (HPRC). Methods: Adults with advanced PRC are enrolled in 2 cohorts with different dosing schedules of GSK089: cohort 1) 240 mg/day on days 1–5 of every 14 days (5-on/9-off); cohort 2) 80 mg daily. Pts are stratified based on status of MET-pathway activation (activating MET mutation, MET [7q31] amplification, or trisomy 7). The primary endpoint is RECIST response rate, assessed every 8 weeks. Plasma markers reflecting potential effects of MET inhibition and anti-VEGF therapy are analyzed. Results: As of December 15, 2008, 37 pts were enrolled in the 5-on/9-off cohort (19 with MET activation including 5 HPRC, 18 SPRC without MET activation or unknown MET status), and 16 pts in the daily dosing cohort (2 with HPRC, 14 SPRC with unknown MET status). Enrollment is ongoing in cohort 2. In cohort 1, of the 35 evaluable pts, 4 pts (2 HPRC and 2 SPRC) had confirmed PRs and 27 had stable disease (SD) as best response with 6 ≥12mo, 3 ≥ 9mo and 3 ≥ 6mo. Four of 5 HPRC pts (1 not evaluated) had shrinkage (15–53%) in all measurable tumors. Twenty-three SPRC pts had shrinkage (2–58%) in the sum of measurable tumors. In cohort 2, of the 9 evaluable pts, 2 (both SPRC) had confirmed PRs, and 7 had SD. The most frequent adverse events (AEs) associated with GSK089 were fatigue, hypertension, nausea, vomiting, diarrhea, and increased ALT/AST, primarily grades 1 and 2. Preliminary results from cohort 1 indicated that plasma shed Met (sMET) and VEGF increased and sVEGFR2 decreased after 2 cycles with changes maintained after 4 cycles. Conclusions: GSK089 is well tolerated and demonstrates anti-tumor activity in pts with PRC with both 5-on/9-off and daily dosing. VEGF, sVEGFR2, and sMET are promising pharmacodynamic markers for biological activity of GSK089. [Table: see text]

scholarly journals Antiviral antibody responses to systemic administration of an oncolytic RNA virus: the impact of standard concomitant anticancer chemotherapies

2021 ◽  
Vol 9 (7) ◽  
pp. e002673
Author(s):  
Victoria Roulstone ◽  
David Mansfield ◽  
Robert J Harris ◽  
Katie Twigger ◽  
Christine White ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Rna Virus ◽  
Single Agent ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Concomitant Treatment ◽  
Phase I Clinical Trials ◽  
Antiviral Antibody ◽  
The Impact

BackgroundOncolytic reovirus therapy for cancer induces a typical antiviral response to this RNA virus, including neutralizing antibodies. Concomitant treatment with cytotoxic chemotherapies has been hypothesized to improve the therapeutic potential of the virus. Chemotherapy side effects can include immunosuppression, which may slow the rate of the antiviral antibody response, as well as potentially make the patient more vulnerable to viral infection.MethodReovirus neutralizing antibody data were aggregated from separate phase I clinical trials of reovirus administered as a single agent or in combination with gemcitabine, docetaxel, carboplatin and paclitaxel doublet or cyclophosphamide. In addition, the kinetics of individual antibody isotypes were profiled in sera collected in these trials.ResultsThese data demonstrate preserved antiviral antibody responses, with only moderately reduced kinetics with some drugs, most notably gemcitabine. All patients ultimately produced an effective neutralizing antibody response.ConclusionPatients’ responses to infection by reovirus are largely unaffected by the concomitant drug treatments tested, providing confidence that RNA viral treatment or infection is compatible with standard of care treatments.

Phase IA/II Study of Oral Panobinostat (LBH589), a Novel Pan- Deacetylase Inhibitor (DACi) Demonstrating Efficacy in Patients with Advanced Hematologic Malignancies.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 958-958 ◽  
Author(s):  
Oliver G. Ottmann ◽  
Andrew Spencer ◽  
H. Miles Prince ◽  
Kapil N. Bhalla ◽  
Thomas Fischer ◽  
...  
Keyword(s):  
Disease Control ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Symptom Improvement ◽  
Weekly Schedule ◽  
Deacetylase Inhibitor ◽  
Anti Tumor Activity

Abstract Panobinostat (LBH589) is a novel and potent pan-deacetylase inhibitor (DACi) with broad preclinical activity in models of hematologic malignancies. This trial is evaluating panobinostat in patients (pts) with advanced hematologic malignancies with 2 schedules of oral administration: Monday/Wednesday/Friday (MWF) every week or MWF every other week. Each schedule is being assessed in 2 pt groups that differ by disease and the definition of hematologic dose-limiting toxicity (DLT): pts with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM); and pts with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic idiopathic myelofibrosis (CIMF), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL). A 3-parameter Bayesian logistic regression model guides dose escalation, and a minimum of 6 evaluable pts at each dose level is required prior to dose escalation. To date, 128 pts have been enrolled: 79 pts with weekly dosing at 20, 30, 40, 60, and 80 mg/dose; and 49 pts dosed every other week with 30, 45, 60, and 80 mg/dose. The most common diseases have included AML (65 pts), HL (23 pts), and MM (12 pts). Panobinostat has rapid oral absorption (median Tmax 1 h, range 0.5–3 h), AUC and Cmax are dose-related, and mean effective t½ is 16.7 h. The adverse-event (AE) profile has been similar between the 2 schedules; the most common grade 3/4 AEs (≥10%) have been thrombocytopenia (43%), neutropenia (22%), febrile neutropenia (20%), fatigue (20%), and anemia (11%). In pts with lymphoma and myeloma, the principal DLT is thrombocytopenia, whereas in patients with AML, in whom grade 4 thrombocytopenia is not considered dose-limiting, the principal DLT is fatigue. With weekly dosing, the maximum tolerated dose (MTD) is 40 mg/dose in pts with lymphoma and myeloma, whereas the MTD is 60 mg/dose in pts with AML. The MTD has not been established for dosing every other week in either group of pts, but this regimen is not expected to provide greater dose intensity than weekly treatment. Anti-tumor activity has been observed in a group of 13 response-evaluable pts with relapsed/refractory HL, treated at doses ≥30 mg with both schedules: PR by computed tomography (CT), 5/13 pts (38%); metabolic PR by positron emission tomography (PET), 7/12 pts (58%) (PET assessment not performed in 1 pt); symptom improvement in 7 of the 9 pts with disease-related symptoms at baseline (78%); and disease control for up to 16+ cycles. Anti-tumor activity has also been observed in a group of 26 response-evaluable pts with AML, treated at doses ≥40 mg on the weekly schedule: 2 CRs, including 1 pt ongoing >1 yr; 1 pt aleukemic (marrow not assessable due to fibrosis) >10 months; 2 pts ongoing with decreased marrow blasts and disease control for 9 and 12 months. Activity has also been observed with panobinostat doses ≥30 mg in pts with other hematologic malignancies: CIMF (2 pts, both ongoing, 1 pt with decreased splenomegaly and transfusion independence >20 months, 1 pt with decreased splenomegaly >3 months); MDS (1 pt PR); MM (1 pt PR); and CD4+/56+ hematodermic neoplasm (1 pt PR). For future studies of single-agent panobinostat in HL, the recommended regimen is 40 mg p.o. MWF every week. A regimen of 60 mg p.o. MWF every week is recommended for further evaluation of panobinostat’s single-agent activity in AML.

Results of a phase 1 dose-escalation study of AMV564, a novel T-cell engager, alone and in combination with pembrolizumab in patients with relapsed/refractory solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2555-2555
Author(s):  
Niharika B. Mettu ◽  
Alexander Starodub ◽  
Sarina Anne Anne Piha-Paul ◽  
Raghad Muhsin Abdul-Karim ◽  
Gabriel Tinoco ◽  
...  
Keyword(s):  
T Cell ◽  
Combination Therapy ◽  
Injection Site ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Immune Therapy ◽  
Single Agent ◽  
Dose Escalation Study ◽  
Density Methods ◽  
Anti Tumor Activity

2555 Background: Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive tumor environment and are a barrier to immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immunosuppressive factors. AMV564 is a potent T cell engager that selectively depletes MDSC while promoting T cell activation and proliferation, via preferential binding to areas of high CD33 density. Methods: In this 3+3 dose escalation study, patients with relapsed/refractory solid tumors for whom no recognized standard therapy exists received AMV564 once daily via subcutaneous (SC) injection on Days 1-5 and 8-12 of a 21-day cycle, either alone or in combination with pembrolizumab (200 mg IV q3w). Study endpoints included incidence and severity of adverse events (AEs), pharmacokinetics (PK), and preliminary anti-tumor activity (using RECISTv1.1 criteria). Results: As of January 29, 2021, 20 patients were dosed in 3 monotherapy dose cohorts (15, 50, and 75 mcg/day), and 10 patients were dosed in 3 combination therapy cohorts (5, 15, and 50 mcg/day). Enrolled patients were: median age 64 years, 47% female, had received median 3.5 prior lines of therapy; 7 patients (35%) had received prior checkpoint inhibitor therapy (6 monotherapy patients, 1 combination therapy patient). No dose-limiting toxicity was observed and a maximum-tolerated dose was not reached in either the monotherapy or combination therapy cohorts. The most common treatment-related AEs (occurring in > 10% of patients, in order of decreasing frequency) in the monotherapy cohort were pyrexia, injection site reactions, fatigue, anemia, hypotension, pruritis, chills, and nausea. There were 2 cases of grade 2 cytokine release syndrome (CRS) at 75 mcg/day, both of which resolved after anti-IL6 therapy and study treatment was resumed. The most common treatment-related AEs in the combination cohorts (> 10% frequency) were injection site reaction, pyrexia, fatigue, pruritis, and anemia. No cases of CRS were noted in the combination cohorts. In preliminary PK analysis, estimated median plasma half-life for AMV564 after SC injection was > 48 hours, with dose-related increases in peak plasma concentration. Clinical responses were seen with monotherapy and combination therapy, including a complete response (CR) in a monotherapy-treated patient with ovarian cancer refractory to all standard therapies and anti-PD-1 therapy. Conclusions: AMV564 was well tolerated across multiple dose levels as monotherapy and in combination with pembrolizumab. Subcutaneous injection resulted in clinically relevant plasma exposures. Single-agent and combination therapy anti-tumor activity was observed. Further exploration of AMV564 clinical efficacy in expansion cohorts is ongoing. Clinical trial information: NCT04128423.

Phase Ia/Ib dose-escalation study of IBI110 (anti-LAG-3 mAb) as a single agent and in combination with sintilimab (anti-PD-1 mAb) in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2589-2589
Author(s):  
Cai Zhou ◽  
Yayi He ◽  
Shengxiang Ren ◽  
Wei Li ◽  
Jun Zhu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Hepatic Function ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Best Response ◽  
Ecog Ps ◽  
Anti Tumor Activity

2589 Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI110 ± sintilimab in pts with advanced solid tumors. Methods: Enrolled pts, ECOG PS 0-1, had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Pts received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from mono to combo was allowed at progression. The objectives were safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 21 pts (median age: 62 yr [range 43-72]; ECOG PS: 0 [n = 11], 1 [n = 10]) were enrolled. Dose escalation has completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The most common treatment-related adverse event (TRAE) was anaemia (19.0%). TRAEs ≥G3 included anaemia (4.8%), ascites (4.8%) and hepatic function abnormal (4.8%). By investigator-assessment, best response was 1 confirmed partial response (PR) (ovarian cancer, 3 mg/kg IBI110 single agent) and 5 stable disease (SD) in monotherapy. After crossing from mono to combo at progression, 5 pts were observed to have SD. Phase Ib: 12 pts (median age: 60 yr [range 33-72]; ECOG PS: 0 [n = 7], 1 [n = 5]) were enrolled. All dose cohorts in dose escalation except IBI110 5mg/kg+ sintilimab have completed DLT observation and no DLT was observed. The most common TRAE was AST increased (41.7%). TRAEs ≥G3 included hyperglycaemia (8.3%), bilirubin conjugated increased (8.3%) and hepatic function abnormal (8.3%). By investigator-assessment, best response was 2 PR (small cell lung cancer and endometrial cancer) and 6 SD. Conclusions: IBI110 alone or plus sintilimab has acceptable toxicity and shows preliminary antitumor activity. Clinical trial information: NCT04085185.

scholarly journals 470 A phase 1/2, open-label, dose escalation and expansion study of GI-101 as a single agent and in combination with a pembrolizumab, lenvatinib or local RT in advanced solid tumors (KEYNOTE-B59)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A499-A499
Author(s):  
Byoung Chul Cho ◽  
Sang Joon Shin ◽  
Jae-Lyun Lee ◽  
Byoung Yong Shim ◽  
Hyung Soon Park ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Interleukin 2 ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Part D ◽  
Anti Tumor Activity

BackgroundGI-101 is a novel bispecific fusion protein containing CD80 and interleukin-2 (IL-2) variant, designed to exhibit high affinity to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and preferential binding to IL-2Rβ subunit. In various animal models, GI-101 exerted strong anti-tumor efficacy, accompanied by robust stimulation of CD8+ T and NK cell proliferation without a significant increase in regulatory T cells. GI-101 also elicited synergistic anti-tumor efficacy when used in combination with pembrolizumab (anti-PD1 agents), lenvatinib (tyrosine kinase inhibitor) and radiation in in vivo.1 Given the complementary mechanisms of action of GI-101 via blocking CTLA4 with IL-2 activity to enhance the proliferation and activation of effector T and NK cells, it was hypothesized that GI-101 as a single agent or in combination with other immunotherapies, VEGF inhibitors or RT may exert anti-tumor activity in cancers with high unmet needs.MethodsKEYNOTE-B59 (NCT04977453) is an ongoing phase 1/2 study composed of 4 parts. This study is planned to enroll approximately 374 patients across the indications. Patients assigned to Part A and B receive either GI-101 monotherapy (Part A) or GI-101 + 200 mg of pembrolizumab (Part B) via IV infusion on every 3 weeks (q3w). In Part C, patients will receive GI-101 q3w in combination with lenvatinib (oral, once daily). In Part D, patients will be given GI-101 q3w in combination with local tumor irradiation. Each part is initiated with dose-escalation/optimization phases which will enroll patients with advanced solid tumors, except Part D that enrolls advanced melanoma and sarcoma only. This phase utilizes conventional 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of GI-101 as a monotherapy and in combination. Once RP2D is determined, patients will be enrolled in dose-expansion phases of each part that includes specific tumor types, such as solid cancers failed on standard of care, treatment-naïve unselected or CPI-treated solid tumors. Patients with advanced solid tumors and recovered from prior therapy will be enrolled. This study will assess safety, tolerability, dose-limiting toxicities, MTD, RP2D, preliminary anti-tumor activity, and pharmacokinetics/pharmacodynamics of GI-101 as a single agent and in combination.ResultsThis study is currently enrolling patients with advanced or metastatic solid tumors.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by GI Innovation, Inc.Trial RegistrationNCT04977453ReferencePyo KH, Synn CB, Koh YJ, et al. Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeuticantibody candidate with bispecific immuno-oncology target. Cancer Res 2021;81(13_Suppl).Ethics ApprovalThis study was approved by Severance hospital institutions’ Ethics Review Board (IRB); approval number 4-2021-0185, Asan Medical center‘s IRB; approval number 2021-0669.

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

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