NuTide:302: A phase Ib study to assess the safety, pharmacokinetics and clinical activity of the ProTide NUC-3373 when combined with standard agents used in colorectal cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS719-TPS719 ◽  
Author(s):  
T.R. Jeffry Evans ◽  
Sarah Patricia Blagden ◽  
Janet Shirley Graham ◽  
Kristen Keon Ciombor ◽  
Aimery De Gramont ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Human Study ◽  
Resistance Mechanisms ◽  
Primary Objective ◽  
Clinical Activity ◽  
Cancer Resistance ◽  
Phase Ib ◽  
Anti Cancer ◽  
Tumour Activity ◽  
Clinical Trial Information

TPS719 Background: Although 5-fluorouracil-based chemotherapies (5-FU, capecitabine, and floxuridine) remain the cornerstone of combination therapies for colorectal cancer (CRC), their clinical utility is limited by key cancer resistance mechanisms associated with breakdown, transport, and activation. These agents require intracellular conversion to the active metabolite fluorodeoxyuridine-monophosphate (FUDR-MP) before they can exert their core anti-cancer activity through inhibition of the enzyme thymidylate synthase (TS). NUC-3373 is a phosphoramidate transformation of FUDR-MP designed to bypass the key resistance mechanisms associated with 5-FU. Results from the first-in-human study of NUC-3373 (NuTide:301) in patients with advanced solid tumours demonstrated a favourable PK/PD profile for NUC-3373, with a longer plasma t1/2 (9.7 hours) than 5-FU (8-14 minutes) and much higher levels of the active anti-cancer metabolite, FUDR-MP (Ghazaly et alESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes (TS-T), depleting the pool of dTMP within 2-4 hours. Methods: NuTide:302 is a two-part, Phase Ib study in patients with CRC who have relapsed after ≥ 2 prior lines of 5-FU-containing therapies. The primary objective is to identify a recommended NUC-3373 dose when administered every 2 weeks in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD, and anti‐tumour activity. In Part 1, approximately 12 patients will be administered NUC-3373 with leucovorin (LV) to determine if LV is beneficial in augmenting the formation of TS-T. If so, it will be administered in Part 2. In Part 2, the following combination agents will be administered with NUC-3373 (±LV): oxaliplatin; oxaliplatin + bevacizumab; oxaliplatin + panitumumab; irinotecan; and irinotecan + cetuximab. Up to 62 patients will be enrolled in cohorts of 3-6, in a modified 3+3 design. Enrollment to Part 1 initiated in September 2018. Clinical trial information: NCT03428958.

NuTide: 302—A phase Ib study of the ProTide NUC-3373 in combination with standard therapies in advanced colorectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS274-TPS274
Author(s):  
Kristen Keon Ciombor ◽  
Janet Shirley Graham ◽  
Francesca Aroldi ◽  
Andrew L. Coveler ◽  
Benjamin L. Schlechter ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Utility ◽  
De Novo ◽  
Dihydropyrimidine Dehydrogenase ◽  
Human Study ◽  
Resistance Mechanisms ◽  
Primary Objective ◽  
Nucleotide Synthesis ◽  
Phase Ib ◽  
The Us

TPS274 Background: Although 5-FU-based regimens such as FOLFOX and FOLFIRI remain the cornerstone of treatment for patients (pts) with colorectal cancer (CRC), their clinical utility is limited by resistance mechanisms and toxicity. Anti-cancer activity of 5-FU is dependent on conversion to an active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. However, due to multiple limitations including: reliance on enzymatic activation; catabolism by dihydropyrimidine dehydrogenase (DPD) and a short plasma half-life, 5-FU is not efficiently converted to FUDR-MP. NUC-3373, a phosphoramidate transformation of FUDR-MP, was designed to bypass the key resistance mechanisms that limit the clinical utility of 5-FU. NUC-3373 demonstrated a favorable PK/PD profile and promising efficacy signals in the first-in-human study (NuTide:301) in pts with advanced solid tumors. NUC-3373 has a longer plasma t1/2 (9.7 hours) than 5-FU (8-14 minutes) and generates high intracellular levels of FUDR-MP (Ghazaly et al ESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes, depleting the pool of deoxythymidine monophosphate (dTMP) within 2-4 hours. Methods: NuTide:302 is a three-part, Phase Ib study in pts with advanced CRC who have relapsed after ≥2 prior lines of 5-FU-containing therapies. Primary objective is to identify a RP2D of NUC-3373 when administered weekly and q2w in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD and anti‐tumor activity. In Part 1, patients are receiving NUC-3373 with leucovorin (LV) to determine if LV augments TS inhibition. In Part 2, NUC-3373 (±LV) will be administered in dose escalating cohorts, in a modified 3+3 design, with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected in Part 2 will be combined with biologics targeting VEGF or EGFR pathways. To date, 22 pts have received study treatment. Recruitment is ongoing in the US and Europe. Clinical trial information: NCT03428958.

A phase Ib study of NUC-3373 in combination with standard therapies in advanced/metastatic colorectal cancer (NuTide:302).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 93-93
Author(s):  
Andrew L. Coveler ◽  
Farasat Kazmi ◽  
Kristen Keon Ciombor ◽  
Janet Graham ◽  
Lisa Jane Rodgers ◽  
...  
Keyword(s):  
Safety Profile ◽  
Safety Data ◽  
Resistance Mechanisms ◽  
Clinical Activity ◽  
Data Series ◽  
Rapid Progression ◽  
Phase Ib ◽  
Toxic Metabolites ◽  
Anti Cancer ◽  
Cancer Agent

93 Background: 5-FU is a key anti-cancer agent used across a broad range of tumors. The anti-cancer metabolite of 5-FU, fluorodeoxyuridine-monophosphate (FUDR-MP), binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair. 5-FU is often dosed with leucovorin (LV) to enhance the binding of FUDR-MP to TS. NUC-3373 is a targeted inhibitor of TS designed to bypass 5-FU resistance mechanisms associated with transport, activation and breakdown and avoid the generation of toxic metabolites such as FUTP and FBAL. NUC-3373 has a longer plasma t1/2 (~10 hours) than 5-FU (8-14 minutes), generating substantially higher intracellular levels of FUDR-MP and lower levels of the toxic metabolites FUTP and FBAL. Part 1 interim data from the NuTide:302 study demonstrated NUC-3373’s favorable PK and safety profile was unaffected by LV. Therefore, all subsequent patients in NuTide:302 are receiving NUC-3373 + LV. Here we present the next data series from NuTide:302. Methods: NuTide:302 is a 3-part, Phase Ib study in patients with advanced CRC who have relapsed after ≥2 prior lines of fluoropyrimidine- containing therapies. In Part 1, patients are receiving NUC-3373 with or without LV. In Part 2, NUC-3373 +LV is being administered in dose-escalation cohorts with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected from Part 2 will be combined with biologics targeting VEGF and EGFR pathways. Results:36 patients have been treated in Part 1: 21 received 1500 mg/m2 NUC-3373 ± LV q2w; 11 received 1500 mg/m2NUC-3373 + LV q1w; and 4 received 2500 mg/m2 NUC-3373 + LV q1w. Clinical activity has been observed including tumor shrinkages and stabilization of disease for up to 5 months following rapid progression (≤2 months) on prior lines of therapy. One fluoropyrimidine-refractory patient demonstrated a 28% reduction in target lesions and achieved a stable disease of 5 months after rapid progression on CAPOX (2 months) and FOLFIRI (1.5 months). Safety data for all patients treated with NUC-3373 ± LV in Part 1 of NuTide:302 is shown below. Updated data on the clinical activity and safety of NUC-3373 will be presented. Clinical trial information: NCT03428958. Conclusions:NUC-3373 ± LV has shown clinical activity in heavily pre-treated CRC patients, including tumor shrinkage in a fluoropyrimidine-refractory patient. The safety profile of NUC-3373 ± LV is very encouraging: no neutropenia or hand-foot syndrome of any grade and no diarrhea or mucositis above Grade 2. NUC-3373 +LV is currently being dose escalated further in Part 1 and dosed with either oxaliplatin (NUFOX) or irinotecan (NUFIRI) in Part 2 of NuTide:302. [Table: see text]

Cancer Treatment with Liposomes Based Drugs and Genes Co-delivery Systems

2018 ◽  
Vol 25 (28) ◽  
pp. 3319-3332 ◽  
Author(s):  
Chuanmin Zhang ◽  
Shubiao Zhang ◽  
Defu Zhi ◽  
Jingnan Cui
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Resistance Mechanisms ◽  
Delivery Systems ◽  
Cell Cycle Checkpoints ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Cancer Models ◽  
Anti Cancer

There are several mechanisms by which cancer cells develop resistance to treatments, including increasing anti-apoptosis, increasing drug efflux, inducing angiogenesis, enhancing DNA repair and altering cell cycle checkpoints. The drugs are hard to reach curative effects due to these resistance mechanisms. It has been suggested that liposomes based co-delivery systems, which can deliver drugs and genes to the same tumor cells and exhibit synergistic anti-cancer effects, could be used to overcome the resistance of cancer cells. As the co-delivery systems could simultaneously block two or more pathways, this might promote the death of cancer cells by sensitizing cells to death stimuli. This article provides a brief review on the liposomes based co-delivery systems to overcome cancer resistance by the synergistic effects of drugs and genes. Particularly, the synergistic effects of combinatorial anticancer drugs and genes in various cancer models employing multifunctional liposomes based co-delivery systems have been discussed. This review also gives new insights into the challenges of liposomes based co-delivery systems in the field of cancer therapy, by which we hope to provide some suggestions on the development of liposomes based co-delivery systems.

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8008-8008 ◽  
Author(s):  
David R. Spigel ◽  
Scott N. Gettinger ◽  
Leora Horn ◽  
Roy S. Herbst ◽  
Leena Gandhi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Human Lung Cancer ◽  
Clinical Activity ◽  
Anti Cancer ◽  
Prior Surgery ◽  
Prior Systemic Therapy ◽  
Dose Levels ◽  
Clinical Trial Information

8008 Background: Human lung cancer expresses high levels of PD-L1, which may inhibit anti-cancer immune responses. MPDL3280A, a human monoclonal Ab containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with squamous or nonsquamous NSCLC received MPDL3280A IV q3w at doses between 1-20 mg/kg in a Ph I expansion study. Pts were treated for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. Results: As of Jan 10, 2013, 53 NSCLC pts were evaluable for safety and treated at doses of ≤1 (n=2), 10 (n=10), 15 (n=19) and 20 mg/kg (n=22). Pts had a median age of 61 y (range 24-83 y), 98% were PS 0-1, 89% had prior surgery and 55% had prior radiotherapy. 98% of pts received prior systemic therapy. Pts received treatment for a median duration of 106 days (range 1-324) of MPDL3280A. The incidence of all G3/4 AEs, regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), dyspnea (4%) and fatigue (4%). No G3-5 pneumonitis or diarrhea was reported. 37 NSCLC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses were observed at dose levels between 1 and 20 mg/kg, with all responses ongoing or improving. An ORR of 24% (9/37) was observed in pts with squamous and nonsquamous histologies, including several with rapid tumor shrinkage. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). The 24-week PFS was 48%. Analysis of biomarker data from archival tumor samples demonstrated a correlation between PD-L1 status and efficacy. Pts who were PD-L1 tumor status–positive showed an ORR of 100% (4/4) and a PD rate of 0% (0/4), while pts who were PD-L1 tumor status–negative showed an ORR of 15% (4/26) and a PD rate of 58% (15/26). Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A. Clinical trial information: NCT01375842.

Efficacy and safety of lorlatinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) with one or more prior ALK tyrosine kinase inhibitor (TKI): A phase I/II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9006-9006 ◽  
Author(s):  
Alice Tsang Shaw ◽  
Sai-Hong Ignatius Ou ◽  
Enriqueta Felip ◽  
Todd Michael Bauer ◽  
Benjamin Besse ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Primary Objective ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Resistance Mutations ◽  
Small Cell Lung ◽  
Cns Metastases ◽  
Grade 3 ◽  
Clinical Trial Information

9006 Background: Lorlatinib is a selective, potent, brain-penetrant, next generation ALK/ROS1 TKI active against most known resistance mutations. In Ph I of this Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were heavily pre-treated. In Ph II of this study, efficacy was explored based on prior ALK TKI tx as well as safety across all patients treated at the recommended Ph II dose. Methods: In this ongoing Ph II study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets, were enrolled into 6 expansion cohorts (EXP) based on prior tx (EXP 1-5, ALK+) and rearrangement status (EXP 6, ROS1+). Pts received lorlatinib 100mg QD. Primary objective was ORR and intracranial ORR (IC-ORR) by independent central review (ICR). Results: Efficacy (ALK+ pts with prior tx): At data cut-off (15 Aug 2016), 82 ALK+ pts were enrolled in cohorts EXP 2-5, received C1 no later than 31 Mar 2016 and were evaluated for ORR (ITT population); 52 were evaluated for IC-ORR and 35 were evaluated for IC-ORR response based on target lesions only (≥5mm; no prior radiotherapy or progression post prior radiotherapy). Confirmed response rates by ICR are reported in the table below. Safety (all pts): 116 ALK/ROS1+ pts were evaluated for safety at data cut-off. Most common tx-related AEs (TRAEs) and grade 3/4 TRAEs were hypercholesterolemia (90%, 17%) and hypertriglyceridemia (72%, 17%). Dose interruptions and reductions due to TRAEs were reported in 29% and 20% of pts, respectively. 14% of pts had tx-related SAEs. 5 pts (4%) discontinued tx due to TRAEs and there were no tx-related deaths. 74/116 pts (64%) remain on tx. Conclusions: Lorlatinib showed compelling clinical activity, with substantial IC activity, in ALK+ pts who received ≥1 prior ALK TKI, many of whom were heavily pre-treated. Clinical trial information: NCT01970865. [Table: see text]

ABC-08: A phase Ib, multi-centre, open-label study of a first-in-class nucleotide analogue NUC-1031 in combination with cisplatin in patients with locally advanced/metastatic biliary tract cancers.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS544-TPS544 ◽  
Author(s):  
Mairead Geraldine McNamara ◽  
John A. Bridgewater ◽  
Daniel H. Palmer ◽  
Harpreet Singh Wasan ◽  
David Ryder ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Standard Dose ◽  
Performance Status ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Cancer Resistance ◽  
Open Label ◽  
Ecog Performance Status ◽  
Biliary Tract Cancers ◽  
Phase Ib

TPS544 Background: The UK ABC-02 study established cisplatin and gemcitabine as the reference regimen for first-line treatment of patients (pts) with advanced biliary tract cancers (BTCs) (median overall survival (OS): 11.7 months). No clinical studies since ABC-02 have reported an extension in OS, and therefore effective new agents/combinations are required. NUC-1031 was designed to improve on gemcitabine’s relatively poor efficacy by overcoming its associated key cancer resistance mechanisms, through cellular uptake independent of nucleoside transporters, activation independent of deoxycytidine kinase and protection from cytidine deaminase inactivation, resulting in over 200x the intracellular levels of the anti-cancer metabolite, dFdCTP, greater stability and reduction in the generation of toxic metabolites. NUC-1031 showed activity as monotherapy in a phase I/II study in 7 pts with BTC, refractory to all standard treatments (Blagden et al ASCO 2015; abstract 2514). Methods: ABC-08 is a multi-centre phase Ib study of NUC-1031 combined with cisplatin in pts with non-resectable or recurrent/metastatic cholangiocarcinoma, gallbladder or ampullary carcinoma, aged ≥18 years with an ECOG performance status of 0-1, who have received no prior systemic therapy. The starting dose for NUC-1031 is 625 mg/m2 administered IV on days 1 and 8 in combination with cisplatin (standard dose of 25 mg/m2) (21 day schedule). The dose will be escalated sequentially in cohorts of 3-6 pts using an accelerated titration procedure (725mg/m2, 825mg/m2, 925mg/m2). Treatment will continue until intolerable toxicity/progressive disease. The primary endpoints are safety and RP2D. Secondary endpoints are progression-free survival, OS, response rate and pharmacokinetic endpoints, including assessments of multiple plasma and intracellular analytes: NUC-1031, cisplatin, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU, and will be correlated with safety profile and clinical activity. Planned accrual is 15-24 pts over 2 years. Cohort 1 has been completed without dose-limiting toxicities. Enrolment to cohort 2 is on-going. Clinical trial information: NCT02351765.

NuTide 302: A phase IB study to assess the safety, pharmacokinetics and clinical activity of NUC-3373 in combination with standard agents used in colorectal cancer treatment.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. TPS3617-TPS3617
Author(s):  
Sarah Patricia Blagden ◽  
T.R. Jeffry Evans ◽  
Essam Ahmed Ghazaly ◽  
Chathunissa Gnanaranjan ◽  
Aimery De Gramont ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Treatment ◽  
Clinical Activity ◽  
Phase Ib ◽  
Colorectal Cancer Treatment

Anticancer activity in patients with advanced ovarian and biliary tract cancers treated with NUC-1031 and a platinum agent.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3030-3030
Author(s):  
Sarah Patricia Blagden ◽  
Jennifer Bré ◽  
Peter Mullen ◽  
Chathunissa Gnanaranjan ◽  
Essam Ahmed Ghazaly ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Single Agent ◽  
Nucleotide Metabolism ◽  
Clinical Activity ◽  
Phase Ib ◽  
Platinum Resistant ◽  
Anti Cancer ◽  
Platinum Agent ◽  
Cancer Activity

3030 Background: The inhibition of cellular nucleotide metabolism to promote apoptosis is a key principle of cancer therapy. This, in combination with platinum-induced DNA-damage, is key to promoting anti-cancer activity in a variety of tumors, including ovarian, biliary tract, lung, breast and bladder. NUC-1031, a phosphoramidate transformation of gemcitabine is designed to overcome resistance mechanisms that limit the efficacy of this nucleoside analog. NUC-1031 has shown broad clinical activity across multiple solid tumors as both a single agent and in combination with platinum agents. We show potential synergism between NUC-1031 and a platinum agent in advanced ovarian (OC) and biliary tract (BTC) cancers. Methods: PRO-002 was a phase Ib study; 25 patients (pts) with recurrent OC who had exhausted all other therapy options received NUC-1031 + carboplatin. 17 pts were considered platinum resistant (10) or platinum refractory (7). ABC-08 is a phase Ib study, 14 pts with advanced BTC treated in the first-line setting with NUC-1031 + cisplatin. Results: In PRO-002, strong efficacy signals were observed in non-platinum-responsive patients. Of the 17 response-evaluable platinum-resistant or refractory pts, 5 partial responses (PRs) and 11 stable diseases (SDs) were achieved, resulting in an ORR of 29% and a DCR of 94%. NUC-1031 + carboplatin was well-tolerated with no unexpected AEs; DLTs were myelosuppression and fatigue. Encouraging response rates were also observed in ABC-08 compared to historical standard of care (ABC-02). One CR (7%), 6 PRs (43%) and 1 SD (7%) were observed, resulting in an ORR of 50%. NUC-1031 + cisplatin was well-tolerated, with no unexpected AEs or DLTs. Complementary in vitro evidence suggests that the beneficial interaction occurs whereby platinum treatment sensitizes cells to NUC-1031. Conclusions: Increasing evidence suggests that NUC-1031 in combination with a platinum agent may have synergistic properties, leading to enhanced anti-cancer activity. In both OC and BTC, durable tumor shrinkage was observed. This was particularly encouraging in a platinum resistant/refractory OC population. Future studies utilizing both NUC-1031 plus a platinum agent will further elucidate the potential of this therapeutic combination.

Immune checkpoint inhibition (ICI) in combination with SBRT in patients with advanced pancreatic adenocarcinoma (aPDAC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 192-192 ◽  
Author(s):  
Gagandeep Brar ◽  
Changqing Xie ◽  
Charalampos S. Floudas ◽  
M. Pia Morelli ◽  
Suzanne Fioravanti ◽  
...  
Keyword(s):  
Partial Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Correlative Analysis ◽  
Progression Of Disease ◽  
New Treatment ◽  
Grade 3 ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

192 Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.

Updated analysis of the inducible T-cell co-stimulatory receptor (ICOS) agonist, GSK3359609 (GSK609), combination with pembrolizumab (PE) in patients (pts) with anti-PD-1/L1 treatment-naïve head and neck squamous cell carcinoma (HNSCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6517-6517
Author(s):  
Eric Angevin ◽  
Stefanie L. Groenland ◽  
Annette May Ling Lim ◽  
Juan Martin-Liberal ◽  
Victor Moreno ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Human Study ◽  
Clinical Activity ◽  
Metastatic Setting ◽  
Anti Cancer ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Line Of Therapy ◽  
Dose Levels

6517 Background: INDUCE-1 (NCT02723955) is a first-in-human study investigating GSK609, an IgG4 ICOS agonist non-T-cell depleting antibody, as monotherapy and combination therapy with anti-cancer agents that includes PE. A range of GSK609 dose levels (≥0.1–1 mg/kg) having biological and clinical activity were identified and evaluated in the expansion phase with GSK609 0.3 mg/kg selected as the dose for further investigation. Results from the HNSCC expansion cohorts (ECs) showed GSK609 has single agent activity in pts with relapsed/refractory disease, and early clinical activity in combination with PE in pts with anti-PD-1/L1 treatment-naïve disease (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). Updated results from the GSK609/PE HNSCC EC are presented. Methods: Eligible pts for the HNSCC EC had anti-PD-1/L1 treatment-naïve disease, ≤5 prior lines of therapy, measurable disease, and no active autoimmune disease. Pts received GSK609 0.3 mg/kg + PE 200 mg every 3 weeks (wks) until disease progression or unacceptable toxicity, up to 2 years (yrs)/35 cycles. Disease assessments were performed every 9 wks through wk 54 then every 12 wks thereafter. Pts were followed for survival and subsequent anti-cancer therapy. Results: As of 11 October 2019, 34 pts were enrolled and evaluable for efficacy analyses. The median age of this population was 61.5 yrs (range: 37–77); 85% were male; 53% received ≥1 prior line of therapy in the metastatic setting. ORR was 26% (95% CI: 12.9, 44.4; n = 9 with 4 complete and 5 partial responses); disease control rate was 68% (95% CI: 49.5, 82.6; n = 23). Among pts with PD-L1 IHC status by 22C3 pharmDx assay (n = 24; 71%), the majority of pts with a response or stable disease (SD) had PD-L1 CPS status < 20 (11 of 15 pts including 1 SD pt with CPS < 1). Median PFS was 5.6 months (95% CI: 3.9, 6,2). Median OS was not reached at time of analysis (95% CI: 8.2, NR); 6-month OS rate was 84% (95% CI: 66, 93). Treatment-related adverse events were reported in 66% of pts; the majority of events were Grades 1 or 2 with < 10% of pts experiencing ≥ Grade 3 events. Conclusions: This updated analysis with a more mature dataset shows promising clinical activity that supports further randomized investigation of GSK609 in combination with PE with an OS endpoint in HNSCC. Clinical trial information: NCT02723955 .

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