MLN2480, an investigational oral pan-RAF kinase inhibitor, in patients (pts) with relapsed or refractory solid tumors: Phase I study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2547-2547 ◽  
Author(s):  
Drew Warren Rasco ◽  
Anthony J. Olszanski ◽  
Amita Patnaik ◽  
Guillermo Espino ◽  
Rachel Neuwirth ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Human Study ◽  
Maculopapular Rash ◽  
Post Dose ◽  
Raf Kinase ◽  
Grade 3

2547 Background: MLN2480 is an investigational pan-RAF kinase inhibitor. In vivo, MLN2480 showed antitumor activity in melanoma, colon, lung, and pancreatic cancer xenograft models. This first-in-human study aimed to evaluate the safety of MLN2480, determine the MTD/recommended phase 2 dose (RP2D), and evaluate pharmacokinetics (PK) and preliminary efficacy. Methods: Pts aged ≥18 yrs with advanced solid tumors who had failed/were not candidates for standard therapy received oral MLN2480 every other day (Q2D) in 22-d cycles, with dose escalation (3+3 design) based on DLTs in cycle 1. AEs were graded per NCI-CTCAE v4.03. Blood samples for plasma PK assessment were taken pre-dose and at multiple times post-dose, d 1 and 21, cycle 1. Results: 24 pts (10 male, median age 64.5 yrs [range 37–83]) have been treated at 20, 40, 80, 135, 200, and 280 mg (n=4, 3, 3, 3, 4, and 7), respectively. The most common tumors included colorectal cancer in 11 pts and non-small-cell lung cancer in 2 pts. Pts received a median of 2 (range 1–6) cycles. 2 pts treated at 280 mg had DLTs: grade 3 macular rash and grade 3 periorbital edema. 20 pts had drug-related AEs, including fatigue 46%, arthralgia 25%, maculopapular rash 21%, and myalgia 17%. 4 pts had drug-related grade ≥3 AEs, which included the 2 DLTs listed above, anemia, dyspnea, and fatigue. No keratocanthomas/ squamous cutaneous carcinomas have been seen to date. 4 pts discontinued due to AEs. There were 3 on-study deaths (1 treatment-related per investigator; dyspnea and respiratory failure). At 20–200 mg MLN2480 PK data (13 pts) exhibited rapid absorption (median Tmax 2 hr), low fluctuation at steady state (mean peak to trough ratio 2.1), and mean accumulation half-life of 67 hr. Overall mean accumulation was 2.6-fold following repeated Q2D dosing for 21 d. Steady-state (d 21) exposures increased in an approximately dose-proportional manner over 20–200 mg range. No pts had an objective response to date; no pts with BRAF mutation enrolled to date. Conclusions: In this first-in-human study (n=24), the safety profile of MLN2480 up to 200 mg Q2D was acceptable. Accrual continues at 200 mg to confirm the MTD. Melanoma expansion cohorts are planned at the RP2D using a Q2D 28-d cycle. Clinical trial information: NCT01425008.

Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2528-2528 ◽  
Author(s):  
Alex A. Adjei ◽  
Patricia LoRusso ◽  
Antoni Ribas ◽  
Jeffrey Alan Sosman ◽  
Anna C. Pavlick ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Peripheral Blood ◽  
Human Study ◽  
Mek Inhibitor ◽  
Investigational Drug ◽  
Advanced Solid Tumors ◽  
Post Dose ◽  
Dose Escalation Study ◽  
Grade 3

2528 Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ≥18 y; ECOG PS 0–2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3+3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ≥6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ≥3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n=3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median Tmax of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, Emax of blood pERK modulation was 56–99%, and time-averaged modulation over the dosing interval at steady-state was 76–98% at MTD. This range correlates well to the 76–89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4–11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.

The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15081-e15081
Author(s):  
Min Yuan ◽  
Juemin Fang ◽  
Zhongzheng Zhu ◽  
Wei Mao ◽  
Hui Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Grade 3

e15081 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

Phase II trial of surufatinib plus toripalimab for disease progression after first-line chemotherapy with platinum and fluoropyrimidine in advanced gastric or gastroesophageal junction adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16040-e16040
Author(s):  
Lin Shen ◽  
Ming Lu ◽  
Zhendong Chen ◽  
Feng Ye ◽  
Yanqiao Zhang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
First Line ◽  
Duration Of Treatment ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Grade 3

e16040 Background: Surufatinib is a novel small-molecule kinase inhibitor targeting VEGFRs, FGFR and CSF-1R, simultaneous targeting of angiogenesis through VEGFRs/FGFR1 and modulating tumor immune microenvironment through CSF-1R may be a uniquely potent strategy to enhance antitumor activity. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Encouraging efficacy of surufatinib plus toripalimab treating patients with advanced solid tumors was reported at 2020 AACR. This is an ongoing, multicenter, open-label, single-arm, phase II study to evaluate the efficacy and safety of surufatinib in combination with toripalimab in various solid tumors. Here we report the results of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Patients with histologically confirmed gastric or GEJ adenocarcinoma who have failed first-line of systemic chemotherapy were enrolled. Surufatinib 250 mg once a day (QD) will be orally administrated and toripalimab 240 mg will be intravenously administered every 3 weeks. Primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: As of Dec 31, 2020, a total of 21 gastric or GEJ adenocarcinoma patients were enrolled. The median age was 58 years old, and 81% of the patients were male. Median duration of treatment was 3 months (surufatinib, 3 months; toripalimab, 3 months). Among 15 patients with at least one post-baseline efficacy evaluation, 2 patients achieved confirmed partial response (PR), with 3 additional unconfirmed PR. And there were 6 in stable disease (SD), 3 in progressive disease (PD) and one not evaluable per RECIST v1.1. There were 5 in PR, 7 in SD and 2 in PD per irRECIST, respectively. The confirmed and unconfirmed ORR were 13.3% (95% CI: 1.7%-40.5%) and 33.3% (95% CI: 11.8%-61.6%), respectively. The disease control rate (DCR) was 73.3% (95% CI: 44.9%-92.2%) per RECIST v1.1. Median PFS was 3.71 months (95% CI: 1.41-unknown). 14.3% (3/21) of patients had treatment-related adverse events (TRAEs) of ≥ Grade 3. The most common TRAEs of ≥ Grade 3 were herpes zoster (4.8%), lymphopenia (4.8%), lymphocyte count decreased (4.8%), white blood cell count decreased (4.8%), liver injury (4.8%) and anaemia (4.8%). 4.8% (1/21) of patients had serious TRAEs. One patient died due to unknown reasons. Conclusions: Surufatinib plus toripalimab appeared to show encouraging activity in advanced gastric or GEJ adenocarcinoma with manageable safety profile. Such combination could be a promising strategy for advanced gastric or GEJ adenocarcinoma in the future. Clinical trial information: NCT04169672.

Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3536-3536 ◽  
Author(s):  
D. Olmos ◽  
A. Allred ◽  
R. Sharma ◽  
A. Brunetto ◽  
D. Smith ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Performance Status ◽  
Human Study ◽  
Preliminary Evaluation ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Levels

3536 Background: Polo-like kinase-1 (Plk1), part of a family of highly conserved serine-threonine kinases, has multiple roles in mitotic progression, is over-expressed and also associated with poor prognosis in some tumor types. GSK461364 is a potent and selective ATP-competitive inhibitor of Plk1 (Ki 2.2nM) with demonstrated antiproliferative activity in vitro and in vivo. Methods: Adult patients (pts) with relapsed/refractory advanced solid tumors with performance status of 0–2 and adequate organ function were eligible. Sequential cohorts of 2–6 patients each received escalating doses of GSK461364 administered as a 4h intravenous infusion (Schedule [Sch] 1: D1,8,15 q28 or Sch 2: D1,2,8,9,15,16 q28). Primary objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSK461364. Secondary objectives included preliminary evaluation of anti-tumor activity. Results: 27 pts (20 male, 7 female) were evaluated. Four dose levels, 50mg (n = 2), 100 mg (n = 3), 150 mg (n = 3) and 225 mg (n = 8) were evaluated in Sch 1. Three dose levels, 25 mg (n = 2), 50 mg (n = 2) and 100 mg (n = 7) were evaluated in Sch 2. Dose-limiting toxicities (DLTs) observed were Gr 4 sepsis, in Sch 1 at 225 mg dose, Gr 4 pulmonary embolism (PE) and Gr 4 neutropenia >7d in Sch 2, both at 100 mg dose. Other Sch 1 adverse events (AEs) with a maximum grade ≥3 were fatigue and anemia (both, n = 2), pleuritic pain, pelvic pain, abdominal discomfort, constipation, vomiting, neutropenia, and deep vein thrombosis (all, n = 1). Other Sch 2 AEs with a maximum grade ≥3 were PE, renal failure, thrombocytopenia, and catheter-related infection (all n = 1). The most common adverse events (AEs) regardless of attribution, Sch and dose level were phlebitis (n = 9), fatigue (n = 9), nausea (n = 7), anemia (n = 6), anorexia (n = 6), diarrhea (n = 6), and infusion site reaction (n = 5). Preliminary PK data indicate that AUC and Cmax were proportional across doses; mean values were CLs ∼72–85L/hr, Vss ∼550–1200L and t1/2 ∼11.5hr. Phospho-histone H3, a marker of mitotic arrest, was detected, in circulating tumor cells, 24 hrs after first dose. Stable disease >5m has been observed in 2 esophageal cancer pts. Conclusions: Dose escalation continues in Sch1, Sch2 has been expanded at 75mg. An MTD has not yet been defined. [Table: see text]

Phase II study of brigatinib in ROS1 positive non-small cell lung cancer (NSCLC) patients previously treated with crizotinib: Barossa cohort 2.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9040-9040
Author(s):  
Haruko Daga ◽  
Seiji Niho ◽  
Jun Sakakibara-Konishi ◽  
Hiroshi Tanaka ◽  
Yasushi Goto ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Independent Review ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps ◽  
Nsclc Patients ◽  
Age Range

9040 Background: Brigatinib is a next-generation tyrosine kinase inhibitor targeting ALK and ROS1. Crizotinib is the first drug approved for the treatment of ROS1 fusion-positive NSCLC. Standard treatment for crizotinib-resistant ROS1 positive NSCLC is not established. Barossa is a multicenter, phase II basket, study of brigatinib in patients with ROS1 positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naïve ROS1 positive NSCLC patients were enrolled in the cohort 1, and ROS1 positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2. Patients with ROS 1 positive solid tumors other than NSCLC were enrolled in the cohort 3. This time we report the cohort 2 results. Methods: Patients with advanced, previously treated with crizotinib, ROS1 positive NSCLC received brigatinib at a dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary end point was objective response rate (ORR; RECIST 1.1) by independent review. Key secondary endpoint was PFS, OS, and safety. The sample size was set at 19 patients, with a one-sided alpha of 0.05, beta of 0.2, and threshold and expected values for primary endpoint of 20% and 50%, respectively. Results: From July 2019 and Jan 2020, 19 patients were enrolled from 9 institutions. Baseline characteristics as follows: median age (range): 60 (31-75) years; women, n = 10 (53%); ECOG PS of 0 to 1, n = 18 (95%); never smoker, n = 11 (58%); tumor histopathological type: adenocarcinoma, n = 18 (95%). Five and 6 patients achieved PR and SD, respectively at data cutoff date of 30 Oct 2020. The ORR was 26.3% (90%CI, 11.0-47.6), and the disease control rate was 57.9% (95%CI, 33.5-79.7). The median duration of follow-up for PFS was 12.0 months. The median PFS was 7.3 months (95% CI, 1.3-9.3), and the 1-year PFS rate was 26.9% (95%CI, 9.2-48.6). Grade ≥3 TRAEs were CPK increased (21.1%), infection (5.3%), AST and/or ALT increased (5.3%), hypercalcemia (5.3%), anorexia (5.3%), hypoxia (5.3%), erythema (5.3%), hypertension (5.3%). Pneumonitis was observed in one patient (5.3%, Grade 2). No treatment-related death was observed. Conclusions: Brigatinib has modest activity for ROS1 positive NSCLC patients previously treated with crizotinib. The safety profile of brigatinib was consistent with previous studies. Enrollment of the cohort 1 for ROS1 inhibitor-naïve NSCLC patients is ongoing, and the data will be presented at a future congress. Clinical trial information: JapicCTI-194851.

Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
Author(s):  
Jean-Charles Soria ◽  
John H. Strickler ◽  
Ramaswamy Govindan ◽  
Seungjean Chai ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

scholarly journals Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial

Liver Cancer ◽  
2021 ◽  
pp. 1-11
Author(s):  
Masatoshi Kudo ◽  
Kenta Motomura ◽  
Yoshiyuki Wada ◽  
Yoshitaka Inaba ◽  
Yasunari Sakamoto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Group Performance ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Clinical Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
Recist 1.1 ◽  
Phase 1B ◽  
Grade 3

<b><i>Introduction:</i></b> Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. <b><i>Methods:</i></b> Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. <b><i>Results:</i></b> Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (<i>n</i> = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (<i>n</i> = 5 [22.7%]), and decreased appetite (<i>n</i> = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9–34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9–54.9%) per mRECIST for HCC. <b><i>Conclusion:</i></b> Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

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 TQB2450 plus anlotinib in patients with advanced triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1074-1074
Author(s):  
Jiayu Wang ◽  
Binghe Xu ◽  
Tao Sun ◽  
Quchang Ouyang ◽  
Yiqun Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Dose Escalation ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Expansion Phase ◽  
Qt Interval Prolongation ◽  
Grade 3

1074 Background: TQB2450 is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). Anlotinib is an antiangiogenic small molecule, multi-target tyrosine kinase inhibitor that has improved clinical outcomes in various solid tumors. This phase 1b study aims to evaluate the safety and efficacy of TQB2450 plus anlotinib for patients with advanced triple-negative breast cancer (TNBC) after the failure of standard therapy. Methods: This ongoing study included a dose-escalation phase and an expansion phase. Advanced TNBC patients with prior anthracyclines and/or taxanes treatment and failed at least first-line therapy were enrolled. In the dose-escalation phase, eligible patients received anlotinib (8mg, 10mg, and 12mg, qd, days 1-14; 21 days per cycle) plus TQB2450 (1200mg, day 1; 21 days per cycle) following the conventional 3+3 design. If the starting dose of 10mg anlotinib led to ≥2 dose-limiting toxicities (DLTs), 8mg anlotinib would be administered. After the dose-escalating phase, eligible patients were enrolled into the expansion cohort. The primary endpoint was objective response rate (ORR), and the secondary endpoints were overall survival (OS), disease control rate (DCR), progression-free survival (PFS), and safety. Results: Between May 29, 2019, and December 31, 2020, in the dose-escalation phase, three patients receiving 10mg anlotinib plus 1200mg TQB2450 had no DLTs in the first cycle, neither did three patients with 12mg anlotinib plus TQB2450. Next, 28 patients with advanced TNBC received 12 mg anlotinib plus TQB2450 in the expansion phase. Finally, a total of 34 patients were included with median age of 49.5 (32-70) and median prior lines of 2 (1-6). Numbers of patients with prior platinum therapy: 16, prior anthracycline therapy: 32. The ORR was 26.47% (9/34) and DCR was 82.35% (28/34). The median PFS was 8.57 months. Seventeen patients experienced grade 3 treatment-related AEs (TRAEs). Most frequently occurring (>5%) grade 3 TRAEs were QT interval prolongation (17.65%), hypertension (14.71%), diarrhea (8.82%), hand-foot syndrome (HFS) (8.82%), and hypertriglyceridemia (5.88%). Conclusions: TQB2450 plus anlotinib showed an acceptable safety profile with promising activity for previously anthracyclines and/or taxanes-treated advanced TNBC patients. Clinical trial information: NCT03855358 .[Table: see text]

Salvage immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combination therapy for metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16567-e16567
Author(s):  
Anish B. Parikh ◽  
Sarah P. Psutka ◽  
Yuanquan Yang ◽  
Katharine Collier ◽  
Abdul Miah ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Immune Checkpoint Inhibitor ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Kaplan Meier ◽  
Grade 3 ◽  
Combination Regimens

e16567 Background: ICI/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setting remain unknown. Methods: We retrospectively reviewed charts for adult patients (pts) receiving an ICI/TKI combination in any line of tx for mRCC of any histology at one of two academic centers as of May 1, 2020. ICIs included pembrolizumab (Pm), nivolumab (Ni), ipilimumab (Ip), or avelumab (Av); TKIs included sunitinib (Su), axitinib (Ax), pazopanib (Pz), lenvatinib (Ln), or cabozantinib (Ca). Clinical data including pt demographics, histology, International mRCC Database Consortium (IMDC) risk group, tx history, and ICI/TKI tx and toxicity details were recorded. Outcomes included objective response rate (ORR), median progression-free survival (mPFS), and safety, analyzed via descriptive statistics and the Kaplan-Meier method. Results: Of 85 pts, 69 (81%) were male and 67 (79%) had clear cell histology. IMDC risk was favorable (24%), intermediate (54%), poor (20%), and unknown (2%). 39% had ICI/TKI tx in the 1L setting. ICI/TKI regimens included Pm/Ax (33%), Ni/Ca (25%), Ni/Ax (20%), Av/Ax (11%), Ni/Ip/Ca (8%), Ni/Su (2%), and Ni/Ln (1%). ORR and mPFS stratified by line of tx and prior tx are shown in the table. Of 52 pts who received ICI/TKI tx as salvage (after 1L), 52% had a grade 3 or higher (≥G3) adverse event (AE), of which the most common were anorexia (13.5%), diarrhea and hypertension (11.5% each), and fatigue (9.6%). 65% of pts on salvage ICI/TKI tx stopped tx for progression/death, while 16% stopped tx for ≥G3 AE. ≥G3 AE rates by line of tx were 62.5% (2L), 50% (3L), and 45% (≥4L). Conclusions: ICI/TKI combination therapy is effective and safe beyond the 1L setting. Prior tx history appears to impact efficacy but has less of an effect on safety/tolerability. These observations will need to be confirmed in prospective studies.[Table: see text]

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