Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with renal cell carcinoma (RCC) from a phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4545-4545 ◽  
Author(s):  
Igor Puzanov ◽  
Jeffrey Alan Sosman ◽  
Armando Santoro ◽  
Robert E. Martell ◽  
Grace K. Dy ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Dose Escalation ◽  
Clear Cell ◽  
Single Agent ◽  
Vegf Receptor ◽  
Chromophobe Rcc ◽  
Best Response ◽  
Met Inhibitor ◽  
Clear Cell Rcc

4545 Background: Inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptor are standard therapy for RCC, and the MET signaling pathway is implicated in tumor angiogenesis. Tivantinib is an oral, selective MET inhibitor. In several tumor models, tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Previously, dose escalation established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with RCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. Results: 20 pts (mean age, 60 yr) including 16 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts received treatment at the RP2D (n = 19) or tivantinib 360 mg BID plus sorafenib 200 mg BID (n = 1). 4 pts are still on study. 16 pts (13 with clear cell RCC) received ≥ 1 previous systemic therapy (median, 2; range, 0-4) including VEGF (14 pts) and/or mTOR (5 pts) inhibitors. The most common (≥ 25%) adverse events were rash (65%), diarrhea (45%), alopecia (40%), hypophosphatemia (35%), and fatigue, stomatitis, palmar-plantar erythrodysesthesia syndrome, and pruritus (25% each). Best response was partial response (PR) in 3 pts (all clear cell RCC pts) and stable disease (SD) in 15 pts (11 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts). 7 pts with SD had ≥ 10% tumor size reduction. The overall response rate (ORR) and disease control rate (DCR; PR + SD) were 15% and 90%, respectively. Median progression-free survival (mPFS) was 12.7 mo (95% CI, 7.1-14.5 mo). In 14 pts previously treated with a VEGF inhibitor, best response was 2 PR and 10 SD, the ORR and DCR were 14% and 86%, respectively, and mPFS was 12.7 mo (95% CI, 5.3-NR mo). Conclusions: Oral combination therapy with tivantinib plus sorafenib was well tolerated and exhibited preliminary anticancer activity in pts with RCC, including pts pretreated with VEGF inhibitors.

Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with NRAS wild-type or mutant melanoma from a phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8519-8519 ◽  
Author(s):  
Julie Ann Means-Powell ◽  
Alex A. Adjei ◽  
Igor Puzanov ◽  
Grace K. Dy ◽  
Laura Williams Goff ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Dose Escalation Study ◽  
Met Inhibitor ◽  
Unacceptable Toxicity

8519 Background: The MET receptor tyrosine kinase is implicated in tumor cell proliferation, invasion, and metastasis, and is activated in NRAS mutant melanoma. Tivantinib is an oral, selective MET inhibitor currently in phase II/III clinical trials. Tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity in several tumor models. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with melanoma or other tumors. Pts were treated until disease progression or unacceptable toxicity. Results: 16 pts with melanoma (median age, 66 yr) received treatment at the RP2D, and 3 pts are still on study. 12 pts received ≥ 1 previous systemic anticancer treatment (median, 1.2; range, 0-5) including ipilimumab (2 pts) or MEK inhibitor (1 pt). Common adverse events (≥ 25%) were rash (50%), diarrhea and fatigue (44% each), anorexia (38%), stomatitis and nausea (31% each), and anemia, weight decrease, and hypophosphatemia (25% each). Best responses were complete response (CR) in 1 pt, partial response (PR) in 3 pts, and stable disease (SD) in 3 pts. 4 pts had progressive disease and 5 pts were not evaluable (3 pts had not reached first assessment time, 1 pt withdrew consent, and 1 pt had unacceptable toxicity). The overall response rate and disease control rate were 25% and 44%, respectively. Median progression-free survival (mPFS) was 5.3 mo (95% CI, 1.6-12.9 mo). Among 8 pts with NRAS mutations, mPFS was 9.2 mo (95% CI, 5.3-12.9 mo) and responses were 1 CR, 1 PR, and 2 SD. Conclusions: Tivantinib plus sorafenib combination therapy was well tolerated and exhibited preliminary anticancer activity in pts with melanoma. Dual inhibition of MET and angiogenesis may be an effective treatment strategy in NRAS-mutant melanoma.

c-Met abnormatities in patients with genitourinary (GU) malignancies and outcomes with c-MET inhibitors.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 407-407
Author(s):  
Denis Leonardo Fontes Jardim ◽  
Debora De Melo Gagliato ◽  
Gerald Steven Falchook ◽  
Jennifer J. Wheler ◽  
Ralph Zinner ◽  
...  
Keyword(s):  
Phase I ◽  
Cell Cancer ◽  
Single Agent ◽  
Median Number ◽  
Tyrosine Kinase Receptor ◽  
Best Response ◽  
Met Amplification ◽  
Genetic Abnormalities ◽  
Met Inhibitor ◽  
Metastatic Sites

407 Background: c-MET is a tyrosine kinase receptor involved in cancer growth, migration, development of metastasis and angiogenesis. Deregulation of this gene has been associated with poor prognosis and resistance to treatment in prostate, bladder and renal cell cancer (RCC). Methods: Patients with GU malignancies referred to the phase I clinic were evaluated for the presence of c-MET mutation and amplification. Their outcomes on protocols containing c-METinhibitors were also analyzed. Results: c-MET amplification was detected in 7 out of 97 (7.2%) patients (4/27 renal, 1/18 urothelial and 2/12 adrenocortical carcinoma), while c-MET mutation/variant in 3 out of 53 (5.7%) patients (2/20 renal and 1/15 prostate cancer). No demographic characteristics were associated with either c-MET abnormalities, but patients tested positive for either mutation or amplification had a higher number of metastatic sites (median number of sites of 4 versus 3 for wild type patients). Median overall survival from phase I consult was 4.4 and 10.6 months for patients with and without a c-MET alteration, respectively. Twenty-nine (25%) patients were treated under a protocol containing a c-MET inhibitor. Overall 6 (21%) patients had a partial response (all prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (0.4-19.7) for all treated patients. No responses were detected in patients with a c-MET genetic abnormality or treated with a specific c-MET inhibitor as a single agent. Conclusions: c-MET mutation and amplification are present in different GU malignancies conferring a worse prognosis for patients referred to the phase I program. We observed activity of c-MET inhibitors for patients without c-MET genetic abnormalities and when c-MET inhibition was combined with other targets/drugs.

Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with hepatocellular carcinoma (HCC) from a phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4117-4117 ◽  
Author(s):  
Robert E. Martell ◽  
Igor Puzanov ◽  
Wen Wee Ma ◽  
Armando Santoro ◽  
Grace K. Dy ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Vegf Inhibitors ◽  
Dose Escalation Study ◽  
Multikinase Inhibitor ◽  
Best Response ◽  
Met Inhibitor

4117 Background: The multikinase inhibitor sorafenib is standard of care for pts with advanced HCC. Tivantinib, an oral, selective MET inhibitor, demonstrated synergistic antitumor activity when combined with sorafenib in several tumor models. The phase 1 dose-escalation study assessed the safety profile of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase 2 dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with HCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. After a safety review in HCC pts in other studies and a report of febrile neutropenia in this study, the tivantinib dose for newly enrolled pts was reduced to 240 mg BID. Results: 20 pts with HCC (mean age, 62 yr; Child-Pugh [CP] A [n = 14], or CP B [n = 6]) were treated at the RP2D (n = 10) or at the reduced tivantinib dose plus sorafenib (n = 10). 10 pts received ≥ 1 previous systemic anticancer treatment (median, 0.5; range, 0-3). The most common adverse events (≥ 25%) were rash (40%), palmar-plantar erythrodysesthesia syndrome (35%), fatigue and diarrhea (30% each), and nausea and anorexia (25% each). Neutropenia was reported in 2 pts. Best response was 1 complete response (CR), 1 partial response (PR), and 12 stable disease (SD). Overall response rate and disease control rate were 10% and 70%, respectively. Median progression-free survival (mPFS) was 3.5 mo (95% CI, 2.8-11.1 mo). Among 8 pts previously treated with vascular endothelial growth factor (VEGF) inhibitors (6 sorafenib; 1 sunitinib; 1 sorafenib plus sunitinib), best response was 1 CR, 1 PR, and 3 SD, and mPFS was 15.9 mo (95% CI, 1.6-15.9 mo). 2 pts are still on study. Conclusions: The combination of tivantinib (360 mg BID) plus sorafenib (240 mg BID) was well tolerated. Preliminary evidence of antitumor activity indicates that combined inhibition of MET and angiogenic signals may have therapeutic potential in this setting, including pts pretreated with VEGF inhibitors.

A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Hongming Pan ◽  
Tianshu Liu ◽  
Jason Tsai ◽  
Yapeng Zhao
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Left Ventricular Systolic Dysfunction ◽  
Single Agent ◽  
Left Ventricular ◽  
Chinese Patients ◽  
Vegf Receptor ◽  
Advanced Solid Tumors

3061 Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]

First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3550-3550 ◽  
Author(s):  
Rui-hua Xu ◽  
Miao-Zhen Qiu ◽  
Yang Zhang ◽  
Xiao-Li Wei ◽  
Chaohong Hu
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Egfr Expression ◽  
Human Dose

3550 Background: MRG003 is a novel antibody drug conjugate (ADC) composed of a fully human anti-EGFR IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG003 is presently being tested in an ongoing phase I study for safety, pharmacokinetics, and preliminary antitumor activity in patients (pts) with solid tumors (CTR20180310). Methods: In the phase I dose escalation study of a traditional (3+3) design, pts with relapsed or refractory cancers received single agent MRG003 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. The starting dose of MRG003 is 0.1 mg/kg, followed by 0.3, 0.6, 1.0, 1.5, 2.0, 2.5, and 3.0 mg/kg. Observations included adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity which is assessed every two cycles. Results: A total of twenty-two pts with colorectal (CRC, n = 15), nasopharyngeal (NPC, n = 3), head and neck (H&N, n = 2), esophageal (EC, n = 1), and duodenal (DC, n = 1) cancer were enrolled in the dose escalation. The median age of pts was 56.5 years. The MTD identified was 2.5 mg/kg. Commonly observed adverse events were anemia (50%), AST increase (41%), decreased appetite (41%), rash (36%), pruritus (36%), asthenia (36%), and proteinuria (32%). Majority of AEs were mild to moderate in severity. EGFR expression in patients’ tumor samples was determined retrospectively by a validated IHC method in a central laboratory. Nine out of 22 pts tested were EGFR positive. Among these 9 EGFR positive pts, one with NPC in the 2.5 mg/kg cohort had partial response, four had stable disease (one with H&N in the 1.5 mg/kg, one each with NPC and H&N in the 2.0 mg/kg, and one with EC in the 2.5 mg/kg cohorts). The disease control rate (DCR) at doses ≥1.5 mg/kg was 100% for the EGFR positive pts. Conclusions: The dose escalation study of MRG003 showed manageable safety profiles and encouraging preliminary antitumor activity in pts with EGFR-positive solid tumors. MRG003 is currently being evaluated as a single agent in phase I dose expansion cohorts to further assess safety, PK, and antitumor activity. Clinical trial information: CTR20180310 .

Phase Ib (COSMIC-021) trial of cabozantinib (C) in urothelial carcinoma (UC) or C in combination with atezolizumab (A) in patients (pts) with UC, castrate resistant prostate cancer (CRPC) or renal cell carcinoma (RCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS683-TPS683 ◽  
Author(s):  
Sumanta K. Pal ◽  
Ulka N. Vaishampayan ◽  
Daniel E. Castellano ◽  
Andrea Necchi ◽  
Carla M.L.- Van Herpen ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Clinical Activity ◽  
Expansion Stage ◽  
Treatment Naïve ◽  
Phase 1B ◽  
Clear Cell Rcc

TPS683 Background: C is an inhibitor of tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). Preclinical and clinical studies suggest that C promotes an immune-permissive tumor environment which may enhance response to immune checkpoint inhibitors (ICI) such as the anti-PD-L1 mAb, A. C is approved for pts with advanced RCC and has shown encouraging clinical activity in combination with a PD-1 targeting mAb in RCC, UC, and CRPC (Nadal et al 2017). A is approved for pts with advanced UC after prior platinum-containing chemo and for chemo-naïve pts with platinum ineligible UC or PD-L1+ cisplatin ineligible UC. Combination of C with A may enhance treatment efficacy in pts with genitourinary (GU) cancers. Here, we present the study design of an ongoing phase 1b trial of C + A which includes cohorts with advanced RCC, UC, and CRPC. Methods: This global multicenter, phase 1b, open-label trial will assess the safety, tolerability, activity, and pharmacokinetics of C or C + A (NCT03170960). The study comprises a dose-escalation stage and an expansion stage. The dose-escalation stage (3+3 design) is completed. C 40 mg qd + 1200 mg A q3w is the recommended dose for the expansion stage. In the expansion stage, 18 cohorts (each 30 pts) will be enrolled including 7 cohorts with GU cancers: (1) treatment naïve clear cell RCC; (2) non-clear cell RCC, treatment naïve or following systemic anticancer therapy; (3) UC after prior platinum-based therapy; (4) treatment naïve cisplatin-ineligible UC; (5) treatment naïve cisplatin-eligible UC; (6) UC after prior ICI therapy and (7) CRPC after prior enzalutamide and/or abiraterone. In addition, an exploratory cohort (30 pts) will evaluate single agent 60 mg C in pts with UC after prior ICI therapy. Pts will continue treatment as long as they experience clinical benefit per investigator or until unacceptable toxicity. The primary objective of the expansion stage is the objective response rate per RECIST 1.1 per investigator for each cohort. Secondary objectives will assess safety including immune related AEs. Clinical trial information: NCT03170960.

Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): Phase I results.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 600-600 ◽  
Author(s):  
Molika Emmeline Keeler ◽  
Elizabeth Riley Kessler ◽  
Brandon Bernard ◽  
Sarah Weisdack ◽  
Kathryn M. Breaker ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Clear Cell ◽  
Objective Response ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Reversible Posterior Leukoencephalopathy Syndrome ◽  
Posterior Leukoencephalopathy ◽  
Term Tolerability ◽  
Clear Cell Rcc

600 Background: PD-L1- and VEGF-targeted therapies have improved survival for mRCC pts and mechanisms of synergy have been reported. We conducted a phase I/II study to evaluate the safety and efficacy of pembro and cabo in mRCC pts. Phase I data are presented here. Methods: mRCC pts received pembro and cabo in a standard 3+3 dose escalation to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and objective response rate (ORR). Cabo was dosed at 40mg QD and 60mg QD in the first and second cohorts, respectively. Pembro was dosed at 200mg IV Q3W in all cohorts. The DLT window was 21 days. Scans were obtained every 9 weeks. Treatment beyond progression was allowed. Results: Eight pts (6M, 2F) were enrolled in the dose escalation cohort with cabo 40mg (5 pts) or 60mg (3 pts) and pembro 200mg. Two pts were not evaluable for DLT due to missing ≥25% of the planned cabo doses in C1, not related to DLT. Median age was 52.5 yrs (range 40-68). Seven pts had clear cell RCC and 1 pt had non-clear cell RCC. Seven pts had MSKCC intermediate risk and 1 pt had MSKCC poor risk. All pts had prior nephrectomy. Median number of prior therapies was one (range 1-3). No DLTs were observed. Drug-related G1 and G2 adverse effects included fatigue (87.5%), weight loss (75%), anorexia (50%), diarrhea (50%), dysgeusia (50%), and abnormal LFTs (50%). One pt had SAE of G3 reversible posterior leukoencephalopathy syndrome during C4, attributed to cabo. One pt each developed G3 hypertension, G3 anorexia, and G3 confusion, all occurring outside the DLT window. No dose reductions were needed at the 40mg cohort. One pt in the 60mg cohort required dose reduction to 40mg after C5. All patients were evaluable for response: 2 PR (at 60 mg cohort), 5 SD [median duration SD 18 wks (range 9-36+)], 1 PD; ORR 25%; clinical benefit rate 87.5%. No correlation was seen between PD-L1 status (archival tissue) and response. Conclusions: The MTD was determined to be pembro 200 mg Q3W and cabo 60 QD. Enrollment in the phase II dose expansion is ongoing and the MTD may be adjusted based on additional pt experience and long-term tolerability. There was encouraging early efficacy. This is an investigator-initiated study sponsored by Merck. Clinical trial information: NCT03149822.

386 Phase I/Ib first-in-human study of HEK-NIZ985, a recombinant IL-15/IL-15Rα heterodimer, alone and in combination with spartalizumab, in adults with advanced and metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A411-A411
Author(s):  
Rom Leidner ◽  
Andrea Wang-Gillam ◽  
Sumati Gupta ◽  
Robert Wesolowski ◽  
Douglas McNeel ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Human Study ◽  
Primary Objective ◽  
Time Dependent ◽  
Open Label ◽  
Dose Proportional

BackgroundHEK-NIZ985 (NIZ985) is a recombinant heterodimer of IL-15/IL-15Rα that expands effector lymphocytes and antitumor activity in animal models and a human clinical trial. We report interim data from the first-in-human study of NIZ985.MethodsCNIZ985X2102J is an open-label Phase I/Ib dose-escalation/expansion trial evaluating the safety of subcutaneous NIZ985 three-times-weekly (TIW; 2-weeks-on/2-weeks-off) or once-weekly (QW; 3-weeks-on/1-week-off) as a single agent (SA) or in combination (CM) dosing with 400 mg of the PD-1 inhibitor spartalizumab every 4 weeks, in adults with metastatic/unresectable solid tumors. SA dosing was 0.25–4 µg/kg TIW or 2–10 µg/kg QW; CM dosing was 1 µg/kg TIW or 2–4 µg/kg QW. The primary objective was to characterize the safety and tolerability of NIZ985 ± spartalizumab. Data are presented for dose escalation, and CM-TIW expansion.ResultsOverall, 83 patients entered dose escalation (n=47) or CM-TIW expansion (n=36), of whom 63.8% (30/47) and 69.4% (25/36), respectively, had received ≥3 prior lines of antineoplastic treatment. At data cut-off (March 2, 2020), 91.6% (76/83) had discontinued study treatment. Adverse events (AEs) are summarized below (table 1). There were no dose-limiting toxicities during the first 28-day cycle in any cohort. Systemic skin AEs (Cycle 2) occurred in three SA-TIW patients receiving 2 or 4 µg/kg (bullous pemphigoid, purpura, vasculitis), limiting TIW escalation and initiating QW dose exploration; these were not observed at 1 µg/kg TIW (± spartalizumab) or for QW doses up to 10 µg/kg. CM-TIW dose expansion was therefore at 1 µg/kg; the recommended QW expansion dose is currently undetermined. For SA NIZ985, best overall response (RECIST 1.1) was stable disease (SD; 8/27 patients [29.6%]). Objective responses for NIZ985 plus spartalizumab (3/56 partial response [PR; 5.3%], 15/56 SD [26.8%]) occurred in both immuno-oncology treatment (IO)-naïve and IO-experienced patients, including 5/8 IO-experienced melanomas (cutaneous: 3 SD, 1 PR; uveal: 1 SD). Systemic NIZ985 exposure was approximately dose-proportional after first dose for ≥1 µg/kg TIW and <10 µg/kg QW, with time-dependent clearance without accumulation. Proliferation of peripheral CD8+ and NK lymphocytes, and increased inflammatory cytokines, were observed for both dosing schedules.Abstract 386 Table 1Adverse event summaryConclusionsNIZ985 is safe and tolerable at both TIW and QW dosing ± spartalizumab. It displays approximately dose-proportional, time-dependent PK, and a biomarker and lymphocyte response profile consistent with target engagement. Limited antitumor activity was reported during dose escalation; however, preliminary responses in both IO-experienced and IO-naïve patients were seen in combination with spartalizumab that warrant further investigation.Ethics ApprovalThe study was approved by an independent ethics committee and/or institutional review board at each participating site.

scholarly journals Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3807
Author(s):  
Pierangela Sepe ◽  
Arianna Ottini ◽  
Chiara Carlotta Pircher ◽  
Andrea Franza ◽  
Melanie Claps ◽  
...  
Keyword(s):  
Renal Cell ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Case Reports ◽  
Treatment Options ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Mtor Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

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