Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5013-5013 ◽  
Author(s):  
Sumanta K. Pal ◽  
Neeraj Agarwal ◽  
Yohann Loriot ◽  
Cristina Suarez Rodriguez ◽  
Parminder Singh ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Mucosal Inflammation ◽  
Clinical Activity ◽  
Mri Scans ◽  
Metastatic Sites ◽  
Ecog Ps

5013 Background: Cabozantinib (C), an inhibitor of MET, AXL, and VEGFR, has been shown to promote an immune-permissive environment and has shown promising clinical activity in combination with immune checkpoint inhibitors (ICIs) in solid tumors including renal cell carcinoma and urothelial carcinoma (UC). ICI monotherapy is approved for patients (pts) with locally advanced or metastatic UC with disease progression after platinum-containing chemotherapy. COSMIC-021, a multi-center phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from Cohort 2 in UC pts with prior platinum-containing chemotherapy. Methods: Eligible pts had ECOG PS 0-1 and had progressed on or after a platinum-containing chemotherapy (including pts with disease recurrences < 12 months after the end of perioperative chemotherapy). Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints include safety, duration of response (DOR), PFS, and OS. Results: As of Dec 20, 2019, 30 pts with advanced UC were enrolled with a median follow-up of 16.5 mo (range 12, 21). Median age was 66 yrs (range 44, 84), 73% were male, and 60% had ECOG PS 1. Primary tumor sites were bladder (80%), renal pelvis (10%), and ureter (10%); the most frequent metastatic sites included lung (40%) and liver (27%). Fourteen pts (47%) had received ≥2 prior systemic anticancer therapies. The most common treatment-related AEs (TRAEs) of any grade were asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%). Grade 3/4 TRAEs occurred in 57% of pts, with no grade 5 TRAEs. Confirmed ORR per RECIST v1.1 was 27% (8 of 30 pts), including 2 pts with CR. DCR (CR+PR+SD) was 64%. Median DOR was not reached, with the longest DOR ongoing at 14.3+ mos. Median PFS was 5.4 mo (range 0.0+, 17.3+). Conclusions: C in combination with A demonstrated encouraging clinical activity in pts with advanced UC with an acceptable safety profile. Additional cohorts of pts with advanced UC are being explored in the study. Clinical trial information: NCT03170960 .

Phase 2 study of retifanlimab (INCMGA00012) in patients (pts) with selected solid tumors (POD1UM-203).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2571-2571
Author(s):  
Michele Maio ◽  
Michael Schenker ◽  
Jacques Medioni ◽  
Slawomir Mandziuk ◽  
Margarita Majem ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Low Grade ◽  
Primary Analysis ◽  
Cell Renal Cell Carcinoma ◽  
Metastatic Urothelial Cancer ◽  
Tumor Types

2571 Background: Checkpoint inhibitors (CPIs) are an effective treatment (tx) for many tumor types. Retifanlimab, an investigational humanized anti–PD-1 monoclonal antibody, has shown safety, pharmacology, and clinical activity consistent with the class. POD1UM-203 (NCT03679767) assessed efficacy and safety of retifanlimab in pts with selected solid tumors where CPI monotherapy is highly active. Methods: Eligible pts (≥18 y) had tx-naïve metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score ≥50%), cisplatin ineligible locally-advanced/metastatic urothelial cancer (UC) with PD-L1 expression (combined positive score ≥10%), unresectable/metastatic melanoma, or tx-naïve locally advanced/metastatic clear-cell renal cell carcinoma (RCC). Measurable disease (RECIST v1.1) was required. ECOG PS >1 and prior PD-1/PD-L1 directed tx were exclusions. Retifanlimab was administered as an IV infusion at 500 mg every 4 wks over 30 min. Primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, safety, and pharmacokinetics. Results: A total of 121 pts (35 melanoma, 23 NSCLC, 29 UC, 34 RCC) received ≥1 dose of retifanlimab and were included in the analyses. Median duration of tx was 169 d (range, 1–442). The efficacy cut-off for the primary analysis occurred once all pts had been followed for at least 6 mo from the time of initial tx. Confirmed RECIST v1.1 responses were observed in all tumor types (Table) and were consistent with published ORR for other CPIs; median DOR was not reached for any tumor cohort and tx was ongoing at the time of data cutoff for 17, 11, 9, and 15 pts with melanoma, NSCLC, UC, and RCC, respectively. The most common tx-emergent AEs (TEAEs, >10% incidence) were asthenia (17.4%), arthralgia (14.9%), decreased appetite (14.0%), pruritus (12.4%), rash (10.7%), and urinary tract infection (10.7%); majority of TEAEs were low grade (≤ grade 2) and none led to tx discontinuation. Immune-related AEs occurred in 23 pts (19.0%), most common (>1% incidence) were hypothyroidism (7.4%), rash (4.1%), hyperthyroidism (2.5%), and pruritus (1.7%). Immune-related AEs led to dose delay in 5 pts (4.1%), but none led to tx discontinuation and/or dose interruption. Conclusions: Retifanlimab demonstrated antitumor activity and was generally well-tolerated in pts with melanoma, NSCLC, UC, or RCC comparable with approved CPIs for these tumor types. These results support ongoing further development of retifanlimab. Clinical trial information: NCT03679767. [Table: see text]

Phase (Ph) 1b/2 evaluation of olaratumab in combination with gemcitabine and docetaxel in advanced soft tissue sarcoma (STS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11517-11517
Author(s):  
Steven Attia ◽  
Victor Manuel Villalobos ◽  
Nadia Hindi ◽  
Brian Andrew Van Tine ◽  
Andrew J. Wagner ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Parameter Estimates ◽  
Second Line ◽  
Line Therapy ◽  
Significant Difference ◽  
Ecog Ps

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m2, d1 and d8) and D (75 mg/m2, d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]

A phase II, randomized study of nivolumab (nivo) or nivo plus BMS-986205 with or without intravesical Bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC): CheckMate 9UT.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS493-TPS493 ◽  
Author(s):  
Noah M. Hahn ◽  
Sam S. Chang ◽  
Maxwell Meng ◽  
Neal D. Shore ◽  
Badrinath R. Konety ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Unmet Need ◽  
Clinical Activity ◽  
Free Survival ◽  
Bcg Therapy ◽  
Intravesical Bcg

TPS493 Background: Immune checkpoint inhibitors, including nivo (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. BMS-986205, a selective, potent, once-daily IDO1 inhibitor that works early in the IDO1 pathway, has demonstrated clinical activity in combination with nivo in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). These findings provide a rationale for investigation of nivo + BMS-986205 ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of nivo ± BMS-986205 ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC. Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component (>50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with nivo ± BMS-986205 ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR), duration of CR in pts with CIS, and event-free survival for all pts without CIS. Secondary endpoints are progression-free survival and safety. This global study in 13 countries is underway, with a target enrollment of 436 pts. ( Clinical trial information: NCT03519256.

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 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS541-TPS541
Author(s):  
Neeraj Agarwal ◽  
Ulka N. Vaishampayan ◽  
Bradley Alexander McGregor ◽  
Marjorie C. Green ◽  
Nehal Mohamed ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Phase 1B

TPS541 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.

A phase II, randomized study of nivolumab (NIVO), NIVO plus linrodostat mesylate, or NIVO plus intravesical bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, nonmuscle invasive bladder cancer (NMIBC): CheckMate 9UT.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5090-TPS5090
Author(s):  
Noah M. Hahn ◽  
Sam Chang ◽  
Maxwell Meng ◽  
Neal D. Shore ◽  
Badrinath R. Konety ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Checkpoint Inhibitors ◽  
Randomized Study ◽  
Objective Response ◽  
Locally Advanced ◽  
Unmet Need ◽  
Clinical Activity ◽  
Bcg Therapy ◽  
Intravesical Bcg

TPS5090 Background: Immune checkpoint inhibitors, including NIVO (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. Linrodostat mesylate, a selective, potent, once-daily IDO1 inhibitor, has demonstrated clinical activity in combination with NIVO in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). Furthermore, high levels of PD-L1 expression have been reported in patients not responding to BCG tx. These findings provide a rationale for investigation of NIVO ± linrodostat ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of NIVO ± linrodostat ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC (NCT03519256). Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component ( > 50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with NIVO ± linrodostat ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR) and duration of CR in pts with CIS. Secondary endpoints are progression-free survival and safety. This global study in 14 countries is underway, with a target enrollment of 436 pts. Clinical trial information: NCT03519256 .

Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 440-440 ◽  
Author(s):  
Petros Grivas ◽  
Yohann Loriot ◽  
Susan Feyerabend ◽  
Rafael Morales-Barrera ◽  
Min Yuen Teo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS42-TPS42 ◽  
Author(s):  
Manuel C. Maia ◽  
Neeraj Agarwal ◽  
Bradley Alexander McGregor ◽  
Ulka N. Vaishampayan ◽  
Toni K. Choueiri ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Phase 1B

TPS42 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.

A phase II study of rh-endostatin combined with paclitaxel and nedaplatin in treating patients with recurrent or metastatic esophageal squamous cell carcinoma (ESCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4522-4522
Author(s):  
Zhiqiang Wang ◽  
Yu-Hong Li ◽  
De-Shen Wang ◽  
Fenghua Wang ◽  
Chao Ren ◽  
...  
Keyword(s):  
Clinical Stage ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Complete Response ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Karnofsky Score ◽  
Best Response ◽  
Metastatic Sites

4522 Background: For patients (pts) with metastatic ESCC, the prognosis is poor. Rh-endostatin (endostar), a potent inhibitor of angiogenesis, has shown clinical activity when combined with chemoradiotherapy in treating locally advanced ESCC. This single-arm phase 2 study was designed to assess the efficacy and safety of endostar combined with paclitaxel and nedaplatin in treating pts with recurrent or metastatic ESCC. Methods: Eligible pts had recurrent or metastatic ESCC and Karnofsky score ≥70. Endostar (30 mg/day, continuous infusion, day 1-14) plus paclitaxel (150 mg/m2, day 4) and nedaplatin (80 mg/m2, day 4) were administered every 3 weeks for 6 cycles followed by maintenance therapy with endostar. Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Results: From January 2015 to August 2019, 53 pts were enrolled. 44 (83%) pts were male. The median age was 59 years. 43 (81%) pts had pathology of poor or moderate differentiated ESCC. The middle and lower thirds of the esophagus (81%) were the most common primary tumor sites. 11 (21%) patients had undergone esophagectomy. At the time of treatment, 49 (93%) pts were diagnosed with clinical stage IVB. The most common metastatic sites were lymph node (91%), lung (32%) and liver (26%). 50 pts were assessable for response. No complete response was observed. 21 pts achieved a best response of partial response and 14 pts had stable disease. ORR was 42% and DCR was 70%. The median PFS and OS was 5.1 months (95% CI 3.7-6.6 months) and 13.2 months (95% CI 8.0-18.4 months) respectively. The most common AEs observed during this study were anemia (49.1%), neutropenia (34%), fatigue (28.3%) and anorexia (26.4%). The most common Grade 3/4 AE observed was neutropenia (17%). Conclusions: The combination of endostar plus paclitaxel and nedaplatin is a well tolerated treatment modality with promising activity in previously untreated recurrent or metastatic ESCC. Its efficacy and safety could be further studied in randomized trials. Clinical trial information: NCT02350517 .

A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3007-3007
Author(s):  
Sang Joon Shin ◽  
Jeeyun Lee ◽  
Tae Min Kim ◽  
Jin-Soo Kim ◽  
Yu Jung Kim ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Locally Advanced ◽  
Tumor Xenograft ◽  
Clinical Activity ◽  
Expansion Stage ◽  
Specific Expansion ◽  
Melanoma Patients

3007 Background: Belvarafenib, a potent, selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant (NRASm) melanoma patients. The combination of belvarafenib and cobimetinib more potently and durably suppressed MAPK pathway output and tumor growth than currently approved BRAF/MEK inhibitors in RAS- or RAF-mutant tumor xenograft models. This interim results of phase 1b trial evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of belvarafenib in combination with cobimetinib in dose-escalation and NRASm melanoma patients among the 9 indication-specific expansion cohorts. Methods: Patients with locally advanced or metastatic solid tumors harboring RAS or RAF mutation were enrolled in the dose-escalation stage, and the recommended doses were explored in the indication-specific expansion stage. Patients in the dose-escalation stage were given belvarafenib (100–300mg BID) in combination with cobimetinib (20–40mg QD) and the dose of subsequent cohorts was decided by a traditional 3+3 design and safety profile. Primary objectives were to evaluate the safety and tolerability, to estimate the maximum tolerable dose, and to identify the RP2D of the combination. Results: A total of 32 patients enrolled were evaluated for safety analysis; 19 were enrolled in 4 cohorts in the dose-escalation stage and 13 NRASm melanoma patients were enrolled in the indication-specific expansion stage (cut-off date: 2020-7-24). There were 3 DLTs (G3 colitis, G3 diarrhoea, G3 nausea) in 2 patients at the starting dose of belvarafenib 200mg BID continuously and cobimetinib 40mg QD 21/7 schedule. Belvarafenib dose was escalated to 300mg BID with cobimetinib 20mg QD, which did not result in DLTs. The most common treatment-emergent adverse events that occurred in ≥30% of 32 patients were dermatitis acneiform, diarrhoea, constipation, and increase in blood creatine phosphokinase. Two combination doses were explored in the indication-specific expansion stage. Out of the 9 indication-specific expansion cohorts, NRASm melanoma patients exhibited promising efficacy signal; 5 patients reached partial responses (PRs) out of 13, giving a response rate of 38.5%. Among them, 11 had been previously treated with checkpoint inhibitors (CPIs), including 5 (45.5%) who achieved PR. The median PFS was 7.3 months and 5 patients remained on the treatment at the cut-off date. Conclusions: Belvarafenib in combination with cobimetinib showed acceptable tolerability and encouraging efficacy in NRASm melanoma, and in those with prior CPI treatment. Further research is ongoing in other cohorts (Clinicaltrial.gov, NCT03284502) and in NRASm melanoma (reference GO42273 by clinicaltrials.gov ID number). *S.J.S and J.L contributed equally to this work. Clinical trial information: NCT03284502.

Sign in / Sign up

Export Citation Format

Share Document