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.

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.

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 .

scholarly journals Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Cornelis M. van Tilburg ◽  
Till Milde ◽  
Ruth Witt ◽  
Jonas Ecker ◽  
Thomas Hielscher ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Single Agent ◽  
Patient Dose ◽  
Weekly Dose ◽  
Significant Activity ◽  
Dose Escalation Study ◽  
Plasma Cytokine

Abstract Background Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3–18 years) with relapsed or therapy-refractory malignancies. Results A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m2/day with weekly dose escalations of 50 mg/m2 until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m2/day was determined (maximum, 580 mg/m2/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher Cmax. Five patients achieved prolonged disease control (> 12 months) and showed a higher Cmax (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion An SDR of 130 mg/m2/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker. Trial registration ClinicalTrials.gov, NCT01422499. Registered 24 August 2011,

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.

Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma

2009 ◽  
Vol 27 (7) ◽  
pp. 1075-1081 ◽  
Author(s):  
Luis H. Camacho ◽  
Scott Antonia ◽  
Jeffrey Sosman ◽  
John M. Kirkwood ◽  
Thomas F. Gajewski ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Cytotoxic T Lymphocyte ◽  
Single Agent ◽  
Objective Response ◽  
Complete Response ◽  
Dosing Regimen ◽  
Grade 3

PurposeCytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development.Patients and MethodsTwenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months.ResultsNo dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and three partial responses in each dosing regimen. Most responses were durable (range, 3 to 30+ months). Most frequent treatment-related adverse events (AEs) were diarrhea, rash, and pruritus. Frequency of grade 3/4 AEs was 13% in the 15 mg/kg every 3 months arm and 27% in the 10 mg/kg once every month. Serious AEs were also less frequent in the 15 mg/kg once every 3 months cohort (9% v 23% in 10 mg/kg arm).ConclusionMultiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.

scholarly journals Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002057
Author(s):  
Yousef Zakharia ◽  
Robert R McWilliams ◽  
Olivier Rixe ◽  
Joseph Drabick ◽  
Montaser F Shaheen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Programmed Death ◽  
Evaluable Population

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

1246 POSTER A Phase I Dose-escalation Study of EMD 1214063, an Oral Selective C-Met Inhibitor, in Patients With Advanced Solid Tumours

2011 ◽  
Vol 47 ◽  
pp. S158
Author(s):  
G.S. Falchook ◽  
S. Fu ◽  
H.M. Amin ◽  
S.A. Piha-Paul ◽  
D.S. Hong ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Solid Tumours ◽  
Dose Escalation Study ◽  
Met Inhibitor

Single-arm phase II study of low-dose paclitaxel and pembrolizumab in platinum-refractory metastatic urothelial carcinoma (UC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 433-433
Author(s):  
Rhonda L. Bitting ◽  
Donald Charles Vile ◽  
Janet A. Tooze ◽  
Christopher Y. Thomas ◽  
Morgan Neve ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Immune Cell ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Intention To Treat ◽  
Definitive Therapy ◽  
Platinum Refractory

433 Background: Single agent checkpoint inhibition is effective in a small proportion of platinum-refractory UC patients but improvements are needed. UC is highly inflammatory, and low-dose chemotherapy may enhance the response to immunotherapy. We evaluated whether combination therapy with low-dose paclitaxel and pembrolizumab is more efficacious than single-agent pembrolizumab which had an objective response rate (ORR) of 21% in a similar patient population in the KEYNOTE-045 study. We also incorporated multiple novel biomarker studies to explore immune regulatory mechanisms in UC. Methods: This is a prospective, single-arm phase II trial (NCT02581982) of pembrolizumab combined with low-dose paclitaxel in patients with platinum-refractory metastatic UC. Key inclusion criteria included measurable progression of disease within 12 months of platinum therapy and ECOG ≤1. Patients received pembrolizumab 200mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21 day cycle for up to 8 cycles unless clinical or radiographic disease progression or unacceptable adverse events (AEs) were observed. Responding patients could remain on pembrolizumab maintenance for up to 2 years. The primary endpoint was ORR; key secondary endpoints included overall survival (OS), 6-month progression free survival (PFS), and safety. Results: Twenty-seven patients were treated between 4/2016 - 6/2020, with a median follow up of 9.9 months. At baseline, the median age was 68 years (range 49-80), with 81% men and 78% non-Hispanic white. The majority (59%) were ECOG 1. Twenty-one of 27 (78%) received prior definitive therapy: chemoradiation in 24% and surgery in 76%. The majority (78%) of patients received prior cisplatin. 70% progressed on a cisplatin-based regimen while 30% progressed on carboplatin-based regimen within 12 months of study entry. The ORR by intention to treat was 9 of 27 patients (33%) and in patients evaluable for response by imaging was 9 of 25 (36%), including 3 with complete response. Disease control rate in evaluable patients was 72%. Six-month PFS was 46.8% (95% CI: 27.2%, 64.2%) and median OS was 11.7 months (95% CI: 8.7 mo, NR). Common ≥ grade 2 AEs were anemia (44%), lymphopenia (37%), hyperglycemia (33%), and fatigue (33%). Possible treatment-related at least grade 3 or 4 AEs occurred in 56% of subjects, including 2 immune-mediated AEs (pneumonitis and nephritis) resulting in therapy cessation but a durable partial response. There were no grade 5 events. Conclusions: This study illustrates that the addition of low-dose paclitaxel to pembrolizumab improves outcomes in patients with platinum-refractory UC, relative to single-agent pembrolizumab. No unanticipated safety signals emerged. Exploratory analyses including PDL1 status, tumor mutational burden, and change in circulating microRNAs and in immune cell populations are ongoing. Clinical trial information: NCT02581982.

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