INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6544-6544
Author(s):  
Erminia Massarelli ◽  
Ani Sarkis Balmanoukian ◽  
Maria Vieito ◽  
Christophe Le Tourneau ◽  
Tatiana Hernandez-Guerrero ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Safety Profile ◽  
Kidney Injury ◽  
Advanced Solid Tumors ◽  
Grade 5 ◽  
Grade 3 ◽  
Anti Tumor Activity ◽  
Additional Safety

6544 Background: The KEYNOTE-048 study (Burtness, at al. Lancet 2019;394:1915–28) led to approval of PE in combination with 5-FU/plat for first-line (1L) treatment of head and neck squamous cell carcinoma (HNSCC). The Phase I INDUCE-1 study (NCT02723955) has shown that GSK609±PE has a manageable safety profile in patients (pts) with advanced solid tumors (Hansen, at al. Annals of Oncology 2018;29[suppl_8]:viii404) and that GSK609 combined with PE has anti-tumor activity in pts with anti-PD-1/L1-naïve HNSCC (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). To evaluate the safety of GSK609±PE in combination with 5-FU/plat, we initiated additional safety cohorts. Methods: Pts eligible for GSK609+5-FU/plat had a diagnosis of advanced selected solid tumors and ≤5 prior lines of systemic therapy. Pts eligible for GSK609+PE+5-FU/plat had a diagnosis of recurrent or metastatic 1L HNSCC deemed incurable by local therapies. 5-FU/plat was administered every 3 weeks (Q3W) for 4-6 cycles (Burtness, at al. Lancet 2019;394:1915–28); GSK609 24 or 80 mg ±PE 200 mg were administered Q3W for up to 2 years/35 cycles or until disease progression or unacceptable toxicity. Results: Twenty-nine pts were enrolled in the 5-FU/plat safety cohorts: 10 pts in the GSK609+5-FU/plat cohort and 19 pts in the GSK609+PE+5-FU/plat cohort. With GSK609+5-FU/plat, 9/10 (90%) pts experienced ≥ 1 adverse event (AE). Of 32 AEs of any grade, 9 were Grade ≥3 and 3 were serious AEs (SAEs). Two of the 3 SAEs were related to study treatment (oral mucositis and febrile pancytopenia). With GSK609+PE+5-FU/plat, 18/19 (94.7%) pts experienced ≥ 1 AE. Of 119 AEs of any grade, 24 were Grade ≥3 and 15 were SAEs. Of the 15 SAEs, 11 were related to study treatment (febrile neutropenia [n=4], colitis [n=2], diarrhea [n=1], vomiting [n=1], acute kidney injury [n=1], cardiac chest pain [n=1] and lung infection [n=1]). For all cohorts, no Grade 5 AEs were observed. For 10 pts evaluable for confirmed best overall response in all cohorts, 2 pts had partial response, 6 pts had stable disease and 2 pts were nonevaluable. No difference in GSK609 exposure was observed relative to GSK609 monotherapy. Conclusions: The safety profile of GSK609 in combination with 5-FU/plat±PE is manageable. Most AEs were Grades 1 or 2 and consistent with PE and chemotherapy toxicities. Continued follow-up to investigate long-term safety and efficacy of this combination is warranted. Clinical trial information: NCT02723955 .

Update on pilot study on antitumor efficacy of intravenously applied synergistic combinations of diflunisal, PAS, and aspirin in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22114-e22114
Author(s):  
Joachim Drevs ◽  
Susanne D'Urso ◽  
Martin Dayton ◽  
Lukas Martinez ◽  
Jonas Mueller-Huebenthal ◽  
...  
Keyword(s):  
Pilot Study ◽  
Tumor Marker ◽  
Solid Tumors ◽  
Ph Sensitive ◽  
Advanced Solid Tumors ◽  
Informed Consent Form ◽  
Anti Tumor Activity

e22114 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of Diflunisal, Paraaminosalicylic acid (PAS) and Aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance and its update is presented. Methods: A total of 65 patients (n=65) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of Diflunisal and Aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response and tumor marker where available. Results: Out of 65 patients treated 8 patients suffered from colorectal cancer, 17 from breast cancer, 6 from ovarian cancer, 3 from lung cancer, 3 from gastric cancer, 3 from glioblastoma, 3 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 2 from pancreatic cancer, 1 from choledochus cancer, 3 from prostate cancer, 5 from sarcomas, 2 from head and neck cancer, 1 from melanoma, 1 from cervical cancer, and 1 from thyroid cancer, respectively. Side effects related to the therapy have been fatigue grade I (30%), nausea grade I (13,3%), tinnitus (25%), hypertension (2,5%), dyspnea (3,3%) and burning sensation in tumor areas (65%). 33 patients were evaluable for metric response, 20 for metabolic and 19 for tumor marker response assessment. For tumor marker follow up 11 % had a CR, 53 % a PR, 26 % a SD of > 3 month and 11 % a PD. For metric follow up 3 % had a CR, 33 % a PR, 39 % a SD of > 3 month and 24 % a PD. For metabolic follow up 10 % had a CR, 35 % a PR, 35 % a SD of > 3 month and 20 % a PD. Conclusions: This continuing pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous Diflunisal, PAS and Aspirin in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study should be performed.

Evaluation of the safety of C-1311 administered in a phase I dose-escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2069-2069 ◽  
Author(s):  
N. Isambert ◽  
M. Campone ◽  
E. Bourbouloux ◽  
M. Drouin ◽  
A. Major ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Recommended Dose ◽  
Active Member ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Advanced Malignancy ◽  
Drug Concentrations ◽  
Grade 3

2069 Background: C-1311 is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of other cancer therapies such as the anthracenediones (e.g. mitoxantrone) and the anthracyclines (e.g. doxorubicin). This first-in-man clinical trial was designed to assess the safety profile of C-1311 and determine the recommended dose upon weekly administration for 3 consecutive weeks, within a 28-day cycle. Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases: an initial accelerated phase of cohorts of 1 patient at doubling doses and a modified Fibonacci phase of cohorts of 3 pts at 25–33% dose increments. The maximum tolerated dose (MTD) was defined as the dose at which 2/3 or 2/6 pts experienced a dose-limiting toxicity (DLT). The recommended dose (RD) was defined as the dose level below the MTD, confirmed by expansion of the cohort to 9 pts. Results: 16 pts received doses of 15, 30, 60, 120, 240, 480 and 640 mg/m2/wk. The 2 pts treated at 640 mg/m2 experienced a DLT (grade 3 neutropenia preventing the administration of the 2nd and 3rd dose of the first cycle respectively). The RD was defined as 480 mg/m2/wk (cohort of 9 pts). Six additional pts were treated at the RD in an extension study in which one of the first 2 doses was given orally. Overall, 2 serious adverse events have been reported as possibly drug-related, both consisting of post-infusion fever without evidence of infection, resolving within 24 hours. Transient neutropenia was the only recurring grade 3 or 4 drug-related adverse event (AE). Grade 1 or 2 AEs most commonly reported as drug-related were nausea, asthenia, vomiting and diarrhea. Stable disease was observed in 3 patients with advanced malignancy. One pt had a stable course over > 8 cycles, and two had stable courses over 4 cycles. Plasma drug concentrations were linear and proportional to dose. Conclusions: The recommended phase 2 dose of 480 mg/m2, weekly × 3 q 28 days, offers a predictable safety profile and excellent tolerability. [Table: see text]

Pilot study on antitumor efficacy of intravenously applied synergistic combinations of salicylic acids in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13508-e13508
Author(s):  
Joachim Drevs ◽  
Holger Spangenberger ◽  
Matthias Jenny ◽  
Jonas Mueller-Huebenthal ◽  
Izumi Kamijo ◽  
...  
Keyword(s):  
Pilot Study ◽  
Tumor Marker ◽  
Solid Tumors ◽  
Ph Sensitive ◽  
Advanced Solid Tumors ◽  
Informed Consent Form ◽  
Anti Tumor Activity ◽  
Salicylic Acids

e13508 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Using this differentiation a new therapy method has been developed for targeted chemotherapy. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of diflunisal, paraaminosalicylic acid (PAS) and aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance. Methods: A total of 30 patients (n=30) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of diflunisal and aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response. Results: Out of 30 patients treated 4 patients suffered from colorectal cancer, 11 from breast cancer, 2 from ovarian cancer, 2 from lung cancer, 2 from gastric cancer, 2 from glioblastoma, 1 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 1 from pancreatic cancer, 1 from choledochus cancer, 1 from prostate cancer, respectively. Side effects related to the therapy have been fatigue (6,7%), nausea (13,3%), tinnitus (10%), hypertension (6,7%), dyspnea (3,3%) and burning sensation in tumor areas (3,3%). Out of 30 patients treated, until today 14 were evaluable for metric response, 12 for metabolic and 13 for tumor marker response assessment. For tumor marker follow up 2 patientis (6,7 %) had a CR, 6 (20 %) a PR, 4 (13,3 %) a SD of > 3 month and 1 (3,3 %) a PD. For metric follow up 0 patients (0 %) had a CR, 6 (20 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. For metabolic follow up 1 patients (3,3 %) had a CR, 3 (10 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. Conclusions: This pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous salicylic acids in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study will be performed.

Axitinib plus crizotinib in patients with advanced solid tumors and metastatic renal cell carcinoma (mRCC): Preliminary phase 1b results.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2551-2551 ◽  
Author(s):  
M Dror Michaelson ◽  
Shilpa Gupta ◽  
Neeraj Agarwal ◽  
Russell Zelig Szmulewitz ◽  
Thomas Powles ◽  
...  
Keyword(s):  
Disease Progression ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Advanced Solid Tumors ◽  
Anaplastic Lymphoma ◽  
Grade 5 ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Factor C ◽  
Experienced Grade

2551 Background: Axitinib (AX) is a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) and a standard treatment for mRCC. Upregulation of mesenchymal-epithelial transition factor (c-MET) is implicated in resistance to VEGFR-directed therapy. An ongoing ph Ib study (NCT01999972) evaluated the safety and efficacy of AX + crizotinib (CZ), a TKI of c-MET, anaplastic lymphoma kinase (ALK), and ROS1. Methods: mRCC patients (pts) with advanced solid tumors were treated with AX + CZ in a dose escalation phase (DESC). After determining maximum tolerated dose (MTD) (modified toxicity probability interval), mRCC pts were enrolled into 2 cohorts in a dose expansion phase (DEXP). Cohort 1 (C1) was treatment-naïve and C2 had 1–2 prior therapies. The primary objectives were to assess the tolerability of AX + CZ, to obtain the MTD, and to select the recommended phase II dose. Results: As of Aug 5, 2016, 24 pts were screened and 22 pts treated in the DESC. Pts received AX 3 mg twice daily (BID) + CZ 200 mg BID (n = 5); AX 3 mg BID + CZ 250 mg BID (n = 3); AX 5 mg BID + CZ 200 mg BID (n = 4); or AX 5 mg BID + CZ 250 mg BID (n = 10) in a median 4 (range 1–23) cycles. There were no cycle 1 dose-limiting toxicities. One pt discontinued due to an AX-related alanine aminotransferase increase. Fifteen (68.2%) pts experienced Grade 3–4 adverse events (AEs), none in ≥2 pts; 1 pt had a Grade 5 AE (disease progression). AX 5 mg BID + CZ 250 mg BID was established as the MTD. Most frequent AEs in the MTD group were fatigue (70.0%), nausea (70.0%) and diarrhea (60.0%). In the ongoing DEXP, 15 pts have been treated at the MTD (n = 11 in C1, and 4 C2). Response evaluation (RECIST) is ongoing, with 1 complete response (CR), 3 partial responses (PR) and 4 stable disease (SD) in 10 pts in C1, and 1 PR and 2 SD in 4 pts in C2. Overall, 10 (66.7%) pts experienced Grade 3–4 AEs and 1 pt had a Grade 5 AE (disease progression). Most frequent AEs (≥60% pts) were nausea and diarrhea. Conclusions: We have identified AX 5 mg BID + CZ 250 mg BID as the MTD for combination therapy. This regimen has manageable toxicities and exhibits antitumor activity in treatment-naïve and pretreated mRCC. Further studies in VEGFR, c-MET, ALK and ROS1 tumor types are warranted. Clinical trial information: NCT01999972.

Studies on the efficacy of pyrotinib in the treatment of HER-2 positive advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15639-e15639
Author(s):  
Shaoshuang Fan ◽  
Da Jiang ◽  
Yalei Lv ◽  
Yanzhi Cui ◽  
Yan Kong ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Metastatic Breast ◽  
Clinicopathological Characteristics ◽  
Metastatic Colon Cancer ◽  
Advanced Solid Tumors ◽  
Line Treatment ◽  
Her 2 ◽  
Medical Order ◽  
Grade 3

e15639 Background: To explore the efficacy and safety of pyrotinib in the treatment of HER-2 positive advanced solid tumors patients. Methods: Patients with HER-2 positive advanced solid tumors in oncology department of our hospital from October 2018 to Janurary 2020 were collected. All the patients were given oral pyrotinib 400mg once a day in a 28-day cycle. The clinicopathological characteristics, treatment history, and curative effect were collected, and the adverse reactions related to the treatment were recorded. Results: 13 patients with HER-2 positive advanced solid tumors were enrolled, including 11 patients with metastatic breast cancer, 3 patients with metastatic colon cancer, 3 patients with gastric cancer. Among them, 10 patients were evaluated for efficacy and(or) side effect, of which 3 patients were excluded because they were not taken pyrotinib according to the medical order or they had no complete follow up data. The total mPFS was 5.63 months (95%CI: 2.533-5.467), partial remission (PR) were 3 cases(30%), stead diease(SD) were 6 cases(60%), progress diease was 1 case(10%). The overall response rate (ORR) and the disease control rate (DCR) were 23.1%, 69.2%, respectively. 2 patients received first-line treatment and 11 patients received second-or-further-line treatment. 11 cases of trastuzumab were changed to anti-HER-2 after treatment failure, of which 2 cases were treated with pirotinib after trastuzumab and lapatinib failed treatment. 12 cases with HER-2 overexpression and 1 case with HER-2 amplification. The incidence of pyrotinib side effects was 100%, which occurred in the first cycle of treatment and was common in grade 1 and 2. The common symptoms were diarrhea (100%), hand and foot skin reaction (38%), rash (8%), etc. Grade 3 to 4 adverse events occurred in 1 patient (8%) received pyrotinib plus capecitabine. 1 patient reduced pyrotinib dosage because of diarrhea. Nevertheless, diarrhea did not lead to discontinuation. Conclusions: The treatment of HER-2 positive advanced solid tumors with pyrotinib have good exact affect, and the toxicity could be controlled.

scholarly journals O83 Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A2.1-A2
Author(s):  
Ronnie Shapira-Frommer ◽  
Marloes GJ van Dongen ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
Fang Liu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Grade 5 ◽  
Crossover Phase ◽  
Grade 3 ◽  
Ecog Ps

BackgroundMK-5890 is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses. This first-in-human phase 1 study of MK-5890 evaluated the safety and efficacy of escalating doses of MK-5890 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.MethodsKey eligibility criteria included histologically or cytologically confirmed advanced solid tumor, measurable disease by RECIST v1.1, and ECOG PS ≤1. MK-5890 was tested alone (dose range, 2-700 mg) or with pembrolizumab (fixed dose, 200 mg). Patients with disease progression following MK-5890 monotherapy were eligible to cross over to combination treatment. The primary objective was safety and tolerability. Objective response rate by investigator per RECIST v1.1 was also evaluated. The database cutoff for this analysis was May 30, 2019.ResultsOf 44 patients enrolled, 25 received MK-5890 and 19 received MK-5890 plus pembrolizumab; their median age was 59.0 years, 61.4% were female, 47.7% had ECOG PS 1, and 13.6% previously received immune checkpoint inhibitor therapy. In the initial phase, dose-limiting toxicities (DLTs) were reported in 3 patients receiving MK-5890 and 1 patient receiving MK-5890 plus pembrolizumab; all DLTs were associated with infusion-related adverse events. Maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) were reported in 40 patients (90.9%): 22 patients (88.0%) receiving MK-5890 and 18 patients (94.7%) receiving MK-5890 plus pembrolizumab. The most common TRAEs were fatigue (28.0%) and infusion-related reactions (28.0%) with MK-5890 and fatigue (36.8%) and pruritus (31.6%) with MK-5809 plus pembrolizumab. Grade 3-4 TRAEs were reported in 10 patients (22.7%): 6 patients (24.0%) receiving MK-5890 and 4 patients (21.1%) receiving MK-5890 plus pembrolizumab; no grade 5 events were observed. One patient (4.0%) achieved a partial response (PR) with MK-5890 and 1 patient (5.3%) achieved a PR with MK-5890 plus pembrolizumab. Fourteen patients entered the crossover phase to receive MK-5890 plus pembrolizumab. In the crossover phase, no DLTs were reported. TRAEs were reported in 12 patients (85.7%); the most common were pruritus (21.4%), rash (21.4%), and headache (14.3%). One patient (7.1%) reported grade 3-4 TRAEs of increased amylase and increased lipase; no grade 5 events were observed. Two patients (14.3%) achieved a complete response and 2 patients (14.3%) achieved a PR.ConclusionsTreatment with MK-5890, alone and in combination with pembrolizumab, demonstrated an acceptable safety profile. Early antitumor activity was observed in patients with advanced solid tumors in both monotherapy and combination therapy arms.

291 Phase Ib study of selicrelumab (CD40 agonist) in combination with atezolizumab (anti-PD-L1) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A318-A318
Author(s):  
Fabrice Barlesi ◽  
Martijn Lolkema ◽  
Kristoffer Staal Rohrberg ◽  
Cinta Hierro ◽  
Aurelien Marabelle ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Dose Range ◽  
Injection Site Reaction ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Cell Lung Carcinoma ◽  
Phase Ib ◽  
Grade 3 ◽  
Anti Tumor Activity

BackgroundSelicrelumab is a human IgG2 agonistic anti-CD40 monoclonal antibody. Binding of the antibody to CD40 expressed on antigen-presenting cells results in T- cell priming and T-cell dependent anti-tumor activity. In response to T-cell activation, tumor cells express programmed-death ligand 1 (PD-L1) that can suppress effector T-cells. Atezolizumab interrupts this feedback loop by blocking PD-L1, thereby supporting the combination with selicrelumab.MethodsThis phase Ib open-label, multicenter, dose escalation (DE)/expansion clinical study (NCT02304393) investigated safety, pharmacokinetic (PK), pharmacodynamics (PD) and efficacy of selicrelumab in combination with atezolizumab in unselected patients with advanced/metastatic solid tumors, not amenable to standard therapy. In DE cohorts, a single dose of selicrelumab was given, either by intravenous (IV) infusion at a 16 mg fixed dose or subcutaneously (SC) at a range from 1 to 64 mg/dose. In dose-expansion cohorts (small bowel and colorectal cancer, head and neck squamous cell carcinoma [HNSCC] and non-small cell lung carcinoma), patients received multiple doses of selicrelumab SC at a dose of 16 mg. In all treatment cohorts, patients received atezolizumab at a fixed dose of 1200 mg IV Q3W.ResultsIn this study, 140 patients were treated. This included 95 patients in DE cohorts (6 patients in the IV cohort, 89 patients in the SC cohorts) and 45 patients in dose-expansion cohorts. In the IV cohort, infusion related reaction was the most frequent treatment-related adverse event (TRAE; 50%), while Grade ≥ 3 TRAE occurred in 1 patient (16.7%). In this cohort one dose-limiting toxicity (DLT) was reported (Grade 3 pancytopenia). In the SC cohorts, the most frequent TRAE was injection site reaction (ISR; 92%). Four DLTs were reported in four patients: three Grade 3 ISR and one Grade 3 transaminase increase. Grade ≥ 3 TRAE were reported in 22 patients (16.4%). Anti-tumor activity was observed across cohorts receiving SC selicrelumab (dose range 1 to 36 mg). Eight of 80 evaluable patients in DE cohorts experienced objective responses (9% ORR). In the dose-expansion HNSCC cohort, three of 16 evaluable patients responded (15.8% ORR). There were no objective responses in the IV cohort. Treatment with selicrelumab resulted in significant peripheral B-cell depletion and activation and CD8+ T cell proliferation.ConclusionsTreatment with selicrelumab in combination with atezolizumab was well tolerated in patients with advanced solid tumors. Signals of clinical and PD activity were observed. However, efficacy of the combination in this unselected population was limited, when compared to monotherapy efficacy of atezolizumab.Trial RegistrationNCT02304393Ethics ApprovalThis study was approved by the local IRB at each participating study site.

Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3002-3002 ◽  
Author(s):  
Suzanne Louise Topalian ◽  
Mario Sznol ◽  
Julie R. Brahmer ◽  
David F. McDermott ◽  
David C. Smith ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Tumor Regression ◽  
Safety Data ◽  
Phase Iii ◽  
Advanced Solid Tumors ◽  
Activated T Cells ◽  
Immune Resistance

3002^ Background: Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian et al., NEJM 2012). Here we present long-term safety and efficacy outcomes from a phase I study of nivolumab, a PD-1 blocking mAb, in patients (pts) with advanced solid tumors. Methods: Pts enrolled between 2008-2012 received nivolumab (0.1−10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Tumors were assessed by RECIST 1.0 after each 4-dose cycle. Pts received ≤12 cycles until unacceptable toxicity, confirmed progression, or CR. Results: 304 pts with non-small cell lung cancer (NSCLC, n=127, squamous and nonsquamous), melanoma (MEL, n=107), renal cell (RCC, n=34), colorectal (n=19) or prostate cancer (n=17) were treated. Durable ORs (CR/PR) were observed in MEL, NSCLC and RCC (Table); in 54 responders with ≥1 yr follow-up, 28 lasted ≥1 yr. Median OS in these heavily pretreated pts (47% with 3-5 prior systemic therapies) compared favorably with expected outcomes as of July 2012. Drug-related AEs (any grade) occurred in 72% (220/304) and G3/G4 AEs in 15% (45/304) of pts. Drug-related pneumonitis occurred in 3% (10/304), including G3/G4 in 1% (3/304), resulting in 3 deaths early in the trial, which led to increased clinical monitoring and an emphasis on management algorithms. Nivolumab-related pneumonitis characteristics and management will be summarized. Updated survival and safety data from Feb 2013 (≥1 yr follow-up all pts) will be presented, including OS at 3 yr. Conclusions: Nivolumab produced sustained survival with a manageable long-term safety profile in advanced MEL, NSCLC and RCC, supporting its ongoing clinical development in controlled phase III trials with survival endpoints. Clinical trial information: NCT00730639. [Table: see text]

A first-in-human phase I study of CYH33, a phosphatidylinositol 3-kinase (PI3K) α selective inhibitor, in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15645-e15645 ◽  
Author(s):  
Xiao-Li Wei ◽  
Rui-hua Xu ◽  
Hongyun Zhao ◽  
Yang Zhang ◽  
Ben-Yan Zou ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Pik3ca Mutation ◽  
Selective Inhibitor ◽  
Advanced Solid Tumors ◽  
Mutation Status ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

e15645 Background: PI3Kα is the only subtype in PI3K family of which activated mutations occur frequently in tumors. CYH33 is a potent PI3Kα–selective inhibitor with anti-tumor activity in xenograft models. An open-label, Phase I dose-escalation & expansion study of CYH33 monotherapy (NCT03544905) is underway in patients (pts) with advanced solid tumors. Methods: This study evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of CYH33 administered daily orally in 28-day cycles until intolerable toxicity or disease progression (PD). Adult pts with advanced solid tumors who have progressed despite standard therapies are enrolled to this trial, and pts with or without PIK3CA mutant are eligible for dose-escalation and pts with PIK3CA mutant are eligible for dose-expansion. Results: As of the cut-off date 20 Dec 2019, 17 pts (median age 47.0 y) were enrolled in the first 6 dose levels (1mg, 5mg, 10mg, 20mg, 40mg and 60mg) of the dose-escalation cohorts, and 3 pts were enrolled in expansion cohort of 40 mg. Cohorts 1 mg to 20 mg were completed without dose-limiting toxicities (DLT), cohort 40mg was completed with 1 DLT (Grade 3 hyperglycemia) out of 6 evaluable pts, and 3 enrolled pts at 60 mg are still in the DLT evaluation. Most frequent treatment-related adverse events (TRAEs) (all grades, ≥ 20%) included hyperglycemia (17 pts, 85%), decreased appetite (5 pts, 25%), diarrhea (4 pts, 20%). Grade≥3 TRAEs were hyperglycemia (8 pts, 40%), nausea (1 pt, 5%) and decreased appetite (1 pt, 5%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. The preliminary PK profile of CYH33 showed dose proportionality across the tested dose levels, half-life (t1/2) was about 20 hours with minimum accumulation, and the maximum concentration (Cmax) achieved 2-4 hours after dosing. Over all, among 15 tumor response evaluable pts, partial response (PR) was observed in 2 pts treated with 40mg (1 colorectal cancer with unknown PIK3CA mutation status, 1 breast cancer with PIK3CA mutant), and stable disease (SD) was observed in 3 pts with unknown PIK3CA mutation status. After the cut-off date, 1 more pt (ovarian cancer with PIK3CA mutation) treated with 40mg achieved PR, so that 2 out of 3 enrolled PIK3CA mutant pts treated with 40mg achieved PR. Conclusions: The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Clinical trial information: 03544905.

Phase I trial of 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3088-3088
Author(s):  
James Nguyen ◽  
Geraldine Helen O'Sullivan Coyne ◽  
Naoko Takebe ◽  
Abdul Rafeh Naqash ◽  
Jessica Mukherjee ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Phase I ◽  
Solid Tumors ◽  
Dna Methyltransferase ◽  
Phase I Trial ◽  
Kidney Injury ◽  
Advanced Solid Tumors ◽  
Hypomethylating Agents ◽  
Best Response ◽  
Grade 3

3088 Background: The nucleoside analog Aza-TdC inhibits DNA methyltransferase 1 (DNMT1), which regulates methylation-mediated silencing of tumor suppressor genes. Aza-TdC offers an improvement over traditional DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity. Aza-TdC has also shown improved preclinical antitumor activity compared to other hypomethylating agents in some solid tumor xenograft models. In an ongoing phase I trial, we evaluate the safety and activity of Aza-TdC in patients (pts) with advanced solid tumors. Methods: Adult pts with solid tumors whose disease has progressed on standard therapy or for which there is no standard therapy were treated with Aza-TdC administered orally once a day for 5 days of each week for 2 weeks in 21-day cycles. The study followed Simon accelerated titration design 3, with 1 pt per dose level at 100% dose increments. Accelerated titration continued until 1 pt experienced a dose-limiting toxicity (DLT) or 2 pts experience drug-related grade 2 toxicity at any dose level, after which, a 3 + 3 dose escalation design was used. Intrapatient dose escalation was allowed. Correlative studies included pharmacokinetic assays and pharmacodynamic assays in circulating tumor cells. Results: As of January 2021, a total of 18 pts have been enrolled on study. Median pt age is 61.5 years (range 35-84). Tumor types included colorectal adenocarcinoma (5 pts), sarcoma (3), breast carcinoma (2), and ovarian carcinoma (2). The DLTs at 48 mg were grade 3 rash and grade 3 acute kidney injury in one pt and < 75% of dosing completed in another pt due to grade 3 myelosuppression. Among the 10 pts treated at 32 mg, 1 pt experienced a DLT: grade 4 neutropenia. The maximum tolerated dose (MTD) is 32 mg. Grade 3 or 4 toxicities across all cycles possibly attributable to study drug were leukopenia (6), lymphopenia (6), neutropenia (4), rash (2), febrile neutropenia (1), anemia (1), thrombocytopenia (1), acute kidney injury (1), elevated AST (1), elevated ALT (1), diarrhea (1), and dehydration (1). Of the 14 pts evaluable for response, 11 had a best response of stable disease, and 3 had a best response of progressive disease. Median cycles on study is 4 (range 1-10+). A pt with clear cell ovarian carcinoma has been on study for > 10 cycles with stable disease. Conclusions: At the MTD of 32 mg, Aza-TdC is safe and well tolerated with a toxicity profile similar to currently approved hypomethylating agents. Global DNA methylation profiling, RNAseq, and DNMT immunohistochemical analyses of tumor biopsies are planned for the currently accruing dose expansion cohort. Funded by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT03366116.

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