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.

A phase II study of weekly low-dose paclitaxel plus 24-hour infusion of cisplatin as first-line chemotherapy for metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1100-1100
Author(s):  
Y. Shen ◽  
C. Hsu ◽  
S. Kuo ◽  
Y. Lu ◽  
C. Lin ◽  
...  
Keyword(s):  
Low Dose ◽  
Liver Toxicity ◽  
Performance Status ◽  
Metastatic Breast ◽  
Complete Response ◽  
Stage Design ◽  
Conventional Dose ◽  
Her 2 ◽  
Grade 3

1100 Background: The dose and schedule of paclitaxel have been evolving in the past 15 years. However, the lowest effective dose of weekly paclitaxel remains unclear. In this study, we examined if a very low dose of paclitaxel can be effective in MBC. Except for the dose of paclitaxel, the chemotherapy regimen and the patient population of this study were very similar to one of our previous report (Cancer 2002; 95:2044–50). Methods: Women with chemotherapy-naïve metastatic BC, adequate performance status and organ functions were eligible. All patients received paclitaxel, 50 mg/m2 iv 1 hr on D1, 8 and 15, and cisplatin, 40 mg/m2 iv 24 hrs on D1 and 8, every 4 weeks. Patients continued this low-dose regimen until progressive disease (PD) or prohibitive toxicities occurred. Patients who had PD or stable disease (SD) without clinical benefit were shifted to paclitaxel 80 mg/m2 iv 1 hr on D1, 8 and 15, and cisplatin, 40 mg/m2 iv 24 hrs on D1 and 8, every 4 weeks. The primary endpoint was overall response rate (ORR). Simon’s optimal two-stage design (P0, P1,a, and βare 20%, 40%, 0.05, and 0.2, respectively) was adopted. More than 4 objective responses were needed in the first 13 patients, and a total of 43 patients will be enrolled. Results: After a median follow-up duration of 16.5 months, 27 patients were evaluable for response and toxicity. Their median age was 52.7 years (range: 30.1∼69.4). Twenty patients were hormone receptor (+), while 6 patients were Her-2/neu (+). A total of 121 cycles of protocol treatment were administered as of Dec. 2006. There were 0 complete response and 14 partial responses, for an ORR of 51.9%. Nine of 14 responders remain progression-free. The PFS was 9.6 months (95% of CI: 5.53∼13.67%) and the OS not reached. Grade 3–4 anemia, neutropenia, liver toxicity, thrombocytopenia, and skin toxicities were reported in 8, 6, 2, 1, and 1 patients, respectively. Neurotoxicity was common (22/27), but all were grade 1 or 2. Conclusions: The preliminary results of this study suggest that weekly low-dose paclitaxel is as effective as conventional-dose paclitaxel, and the treatment-related toxicities were more acceptable. No significant financial relationships to disclose.

scholarly journals HER 2 NEU METASTATIC BREAST CANCER;

2010 ◽  
Vol 17 (02) ◽  
pp. 211-217
Author(s):  
MUHAMMAD HAFEEZ ◽  
Ahmed Usman ◽  
Mr. SHAHARYAR ◽  
Kafait Ahmad ◽  
MANZER ZIKRYA
Keyword(s):  
Breast Cancer ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Metastatic Breast ◽  
Line Treatment ◽  
First Line ◽  
Her 2 ◽  
Grade 3 ◽  
First Line Treatment

Objective: To evaluate the efficacy and toxicity of low dose sequential docetaxel-capecitabine chemotherapy as first line treatment of HER 2 negative metastatic breast cancer (MBC). Design: Experimental Study, Clinical Trial. Setting: Three different oncology centers, collaborating under the Cancer Research Group Pakistan. Period: From June 2006 to December 2007. Methods: Female breast cancer patients with visceral or visceral and bone metastases and a KPS > 70 were eligible. Results: 38 patients were enrolled. Median agewas 49 years (Range 32-70). With docetaxel treatment, CR was seen in 06 (16%) patients and PR in 20 (53%) with an overall response rate of 69%. Stable disease was seen in 10 (26%) and PD in 02 (05%). Four out of six complete responses were in patients with liver metastases. Thirty six patients received capecitabine. Thirty were evaluable for response. Capecitabine added one CR (3.33%) and six partial responses (20%).Two patients (6.67 %) who had a partial response to docetaxel relapsed during capecitabine treatment. As a result at the completion of the therapy CR was seen in 07 patients (18.42%), PR in 23 patients (60.53%) with SD and PD in, 4 patients (10.53%) each. An overall RR of 78.94 % was seen. Median time to progression was 10.9 months (range, 3-22 months) and at a median follow up time of 24 months (range, 16 -34months) 13 patients have died with an overall survival probability of docetaxel –capecitabine sequential therapy of 0.68. Significant docetaxel specific grade 3/4 toxicities included neutropenia and diarrhea in 14 (36.84%) and 03 (07.89%) respectively. Febrile neutropenia was seen in 06 (15.79%). Capecitabine specific significant grade 3 toxicities included hand-foot syndrome in three patients (8.33%) and diarrhea in 2(5.56%). Stomatitis, dermatitis, fatigue was seen in one patient (2.78 %) each. Conclusions: This treatment schedule of low dose sequential docetaxel - capecitabine is an effective first line treatment of HER 2 negative MBC that provides good overall response rate, manageable toxicity and improved survival.

Phase I study of CNF1010 (lipid formulation of 17-(allylamino)-17-demethoxygeldanamycin: 17-AAG) in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10062-10062 ◽  
Author(s):  
M. W. Saif ◽  
C. Erlichman ◽  
T. Dragovich ◽  
D. Mendelson ◽  
D. Toft ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Malignant Cell ◽  
Gastric Carcinoid ◽  
Advanced Solid Tumors ◽  
Her 2 ◽  
Repeated Dosing ◽  
Grade 3 ◽  
Enzyme Elevation ◽  
Ecog Ps

10062 Background: 17-AAG is a benzoquinone ansamycin that binds to and inhibits the HSP90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0–2, and adequate hematologic, hepatic, renal and cardiac functions received CNF1010 by 1 h intravenous infusion, twice-a-week, three weeks out of four, starting at 6 mg/m2 per dose. Doses were escalated sequentially in single pts (6 and 12 mg/m2) and 3–6 pts (≥ 25 mg/m2) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles were obtained on days 1 and 18. Biomarkers were measured in PBMC’s (HSP70) and plasma (HER-2 ectodomain (HER-2 ECD)). Results: 30 pts (M/F: 14/16; median age 63, range 48–78) with colorectal cancer (11), pancreatic cancer (5), melanoma (5), ovarian (2), others (7) were treated with a median of 2 courses (range: 1–10). There was no dose-limiting toxicity up to 175 mg/m2. One pt at 175 mg/m2 died on study, but drug relation was unclear. Grade 1–2 gastrointestinal toxicities (nausea, vomiting, diarrhea) and serum creatinine elevation were observed. Severe toxicities (grade 3 but no grade 4) consisted of reversible hepatic enzyme elevation, hyperbilirubinemia, fatigue, anemia and hyperglycemia. There were no hematological toxicities. Plasma 17-AAG PK appeared dose-proportional (AUC, Cmax); CL (17 L/h/m2) and t1/2 (5.2 h) were dose independent and unchanged after repeated dosing (day 18). Post-treatment increases in HSP70 were observed in PBMCs and decreases in plasma HER-2 ECD were observed at doses ≥ 83 mg/m2. Minor tumor regressions were seen in 1 pt with duodenal cancer (83 mg/m2), 1 pt with gastric carcinoid (175 mg/m2) and 1 pt with melanoma (175 mg/m2). Conclusion: The threshold of biologic activity for CNF1010 administered by a twice a week schedule appears to be 83 mg/m2. This dosing regimen appears to be optimal and supported by the pharmacokinetic and pharmacodynamic data. The MTD has not yet been determined. Dose escalation of CNF1010 continues at 225 mg/m2. [Table: see text]

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 .

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

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

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

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3099-3099
Author(s):  
Jin Li ◽  
Nong Xu ◽  
Tianshu Liu ◽  
Jianjin Huang ◽  
Yongmei Yin ◽  
...  
Keyword(s):  
Disease Control ◽  
Solid Tumors ◽  
Immune Cell ◽  
Target Lesion ◽  
Advanced Solid Tumors ◽  
Cell Functions ◽  
Potential Clinical Benefit ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

3099 Background: Phosphatidylinositol-3 kinase (PI3K) pathways are important elements of tumor survival and progression, and PIK3C genes are often mutated or overexpressed in many cancers. Additionally, PIK3D (PI3Kδ) modulates immune cell functions in tumors, elaborating another PI3Kδ inhibition feature with a potential clinical benefit. Linperlisib, an oral and highly selective PI3Kδ inhibitor, demonstrated potent anti-tumor activity in syngeneic animals from previous research. In this Phase 1b study, the safety, tolerability, and efficacy of linperlisib is under investigation for patients with advanced solid tumors. Methods: Linperlisib was given orally once daily (QD) in 28-day cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was assessed according to RECIST1.1 criteria. Results: As of December 28, 2020, 70 patients were enrolled in the Phase1b study, with advanced cancers, including colorectal (n = 22), breast (n = 8), lung (n = 8), kidney (n = 5), liver (n = 4), ovarian (n = 1), head and neck (n = 5), and esophageal (n = 1) cancers; sarcomas, (n = 4), small intestinal stromal tumor (n = 3), thymic (n = 2), gallbladder (n = 2), gastric (n = 4), and pancreatic (n = 1) carcinomas. The patients were heavily pretreated with an average of 4 previous lines of therapy. Among the 70 patients, the most common nonhematologic TEAEs (all grades/grade≥3) were proteinuria (37.14%/0%), elevated aspartate aminotransferase (20%/0%), nausea (20%/0%), oral mucositis (2.8%/2.8%), diarrhea (2.8%/2.8%). The most common hematological TEAEs were leukopenia (24.28%/0%) and neutropenia (17.14%/4.28%). There were no unexpected toxicities in this study. Of 42 patients evaluable for response, the overall response rate was 2.38%. Notably, the disease control rate (DCR) was 45.24% from monotherapy treatment. One patient with thymic carcinoma obtained a partial response (80.8% reduction of the target lesion), with a duration of response of more than 6 cycles. The treatment of this subject is continuing. A lung adenocarcinoma subject reached radiological stable disease associated with 13.7% reduction in the target lesion and disease control for approximately 6 months. Conclusions: In this study, the PI3K inhibitor, linperlisib exhibited a favorable safety profile as was previously seen in lymphoma patients. Monotherapy treatment with linperlisib was observed to impart a high DCR in advanced solid cancers of many types. Available data from linperlisib and other PI3K inhibitors suggests that linperlisib may limit tumor growth directly, but also by affecting the tumor immune microenvironment. With these promising indications of clinical tolerability and activity, further investigation of linperlisib alone or in key therapeutic combinations is warranted. Clinical trial information: NCT04049929.

Phase Ib study of the anti-TGF-β monoclonal antibody (mAb) NIS793 combined with spartalizumab (PDR001), a PD-1 inhibitor, in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2509-2509
Author(s):  
Todd Michael Bauer ◽  
Chia-Chi Lin ◽  
Richard Greil ◽  
Maria-Elisabeth Goebeler ◽  
Marie Luise Huetter-Kroenke ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Target Genes ◽  
Preliminary Evidence ◽  
Advanced Solid Tumors ◽  
Target Engagement ◽  
Cell Renal Cell Carcinoma ◽  
Grade 3 ◽  
Immune Exclusion ◽  
Tumor Biopsies

2509 Background: TGF-β plays a key role in regulating the tumor microenvironment. Emerging evidence suggests TGF-β is a key activator of cancer-associated fibroblasts, leading to fibrotic network development and immune exclusion. Preclinical data in murine models showed that TGF-β blockade alleviates intratumoral fibrosis, augmenting the efficacy of PD-1 immunotherapy. NIS793 is a human IgG2 mAb that binds to TGF-β. This study investigates NIS793 + spartalizumab in pts with advanced solid tumors. Methods: Pts initially received NIS793 (0.3–1 mg/kg Q3W) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 + spartalizumab (NIS793 0.3–30 mg/kg Q3W + spartalizumab 300 mg Q3W; or NIS793 20–30 mg/kg Q2W + spartalizumab 400 mg Q4W) in pts with/without prior anti-PD-(L)1 therapy. In dose expansion, pts with non-small cell lung cancer (NSCLC) resistant to prior anti-PD-(L)1 or pts with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). Paired tumor biopsies were required from all pts. The primary objectives were to characterize safety and tolerability of the combination and determine the RDE. Results: By December 1, 2020, 60 pts were treated in the dose-escalation phase, mainly with NIS793 + spartalizumab (n = 49), and 60 pts were treated in dose expansion (MSS-CRC: n = 40; NSCLC: n = 20). Two pts were still receiving treatment. No dose-limiting toxicities were observed, and the RDE was established as 30 mg/kg (2100 mg) NIS793 + 300 mg spartalizumab Q3W. Overall 50% pts experienced ≥1 treatment-related AE (TRAE). The most common were rash (n = 15/120), pruritus (n = 10/120), fatigue (n = 9/120), and nausea (n = 8/120). Grade 3/4 TRAEs occurred in 11% pts, with rash (3%) being the most common. Treatment-related serious AEs were reported in 8 pts; 6 were grade 3/4 in severity. No deaths occurred due to AEs; 3 (2.5%) pts discontinued due to AEs. PK for NIS793 was linearly dose proportional with no obvious correlation between exposure and response. Two pts achieved a partial response (PR; one confirmed in clear cell renal cell carcinoma and one unconfirmed in NSCLC) during dose escalation of the combination. Two confirmed PRs were achieved in the MSS-CRC dose-expansion group. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression and protein analyses in tumor biopsies displayed decreased TGF-β target genes, decreased TGF-β signatures and increased immune signatures suggesting modulation of the TGF-β pathway and preliminary evidence of biological activity. Conclusions: Data showing target engagement and TGF-β pathway inhibition supported the proof of mechanism of NIS793. The RDE of the combination was established and well tolerated in pts with advanced solid tumors. Clinical trial information: NCT02947165.

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