Results of phase II randomized study of intermittent versus continuous schedule of vemurafenib plus cobimetinib in BRAF-mutated advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9528-9528
Author(s):  
Maria Gonzalez-Cao ◽  
Clara Mayo de las Casas ◽  
Juana Oramas ◽  
Miguel-Angel Berciano-Guerrero ◽  
Luis De la Cruz ◽  
...  
Keyword(s):  
Randomized Study ◽  
Objective Response ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Advanced Melanoma ◽  
Treatment Schedule ◽  
Intermittent Schedule ◽  
Clinical Value ◽  
Drug Pressure

9528 Background: Combination of vemurafenib plus cobimetinib is approved for the treatment of BRAF-mutated advanced melanoma. Although patients initially respond to treatment, resistance emerges before 18 months in most cases. One of the key pre-clinical observations that supported an intermittent schedule was that resistant tumors suffer a fitness deficit in the absence of the drug, so modulation of the drug pressure through an intermittent dosing could delay the emergence of resistance. Methods: GEM1501 is a randomized phase 2 study comparing the activity of the combination of vemurafenib 960 mg every 12 h/d plus cobimetinib 60 mg/d in a standard (arm A) versus intermittent schedule (arm B). Arm A: four-week (w) cycles of daily vemurafenib for 4w plus cobimetinib for 3w-on and 1w-off-treatment. Arm B: first three cycles according to the standard schedule, followed by 6w-cycle with 2w-off vemurafenib & 3w-off cobimetinib. Primary endpoint was progression free survival (PFS) and secondary were objective response (OR) and treatment-related adverse events (TAEs). Results: 70 treatment-naïve patients were included. Results in arms A and B: median PFS 16.2 (95%CI 9.5, 24.1) vs 6.9 months (95%CI 5.2, 9.3) (p = 0.079); OR in 25 (71.4%) (8 complete -23%-) vs 21 (60%) patients (5 complete -14%-); G3-4 TAEs 42.8% vs 40.0%, respectively. Analysis of BRAFV600 mutation in tumoral cell free DNA (cfDNA) was performed in serial plasma samples in 41 patients. Twenty-one (51%) patients had detectable BRAFV600 mutation in pretreatment cfDNA (preBRAF+). Significant differences in PFS were found according to preBRAF V600: 8.2 months (95%CI 5.2, 13.6) in preBRAF+ vs non-reached (NR) (95%CI 2.8, NR) in preBRAF- (p = 0.017). In arm A, median PFS was 13.3 months (95% CI 4.6, NR) in preBRAF+ vs NR (95% CI 2.3, NR) in preBRAF-. In arm B, median PFS was 6.2 months (95% CI 0.3-8.3) in preBRAF+ vs NR (95%CI 2.8, NR) in preBRAF- (p = 0.003). BRAFV600 mutation became undetectable in cfDNA after treatment initiation in all preBRAF+ patients. Different kinetic of BRAFV600 mutation in cfDNA was found according to treatment arm. At progression, BRAFV600 reappeared in cfDNA in all (5/5) cases treated in arm B, but only in 50% (3/6) of cases in arm A. NGS analysis of cfDNA at progression suggested different resistance mechanisms. Conclusions: The results of this study do not support the use of an intermittent schedule of vemurafenib plus cobimetinib in advanced melanoma. BRAFV600 detection in pretreatment cfDNA is a prognostic factor of poor survival that it is independent of treatment schedule, although most striking differences favoring continuous arm vs intermittent arm were found in patients with detectable BRAFV600 mutation on pretreatment cfDNA. Further research is required to determine the clinical value of the analysis of resistance mechanisms in cfDNA. Clinical trial information: 2014-005277-36.

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.

scholarly journals Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma

2018 ◽  
Vol 36 (35) ◽  
pp. 3450-3458 ◽  
Author(s):  
Diwakar Davar ◽  
Hong Wang ◽  
Joe-Marc Chauvin ◽  
Ornella Pagliano ◽  
Julien J. Fourcade ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Pegylated Interferon ◽  
Gene Signature ◽  
Advanced Melanoma ◽  
Phase Ib

Purpose Objective responses are reported in 34% to 37% of patients with programmed death-1 (PD-1)–naïve advanced melanoma treated with PD-1 inhibitors. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature correlate with response to PD-1 blockade. Here, we report a phase Ib/II study of pembrolizumab/pegylated (PEG)-IFN combination in PD-1–naïve advanced melanoma. Patients and Methods PEG-IFN (1, 2, and 3 μg/kg per week) was dose escalated using a modified toxicity probability interval design in three cohorts of four patients each, whereas pembrolizumab was dosed at 2 mg/kg every 3 weeks in the phase Ib portion. Thirty-one patients were enrolled in the phase II portion. Primary objectives were safety and incidence of dose-limiting toxicities. Secondary objectives included objective response rate, progression-free survival (PFS), and overall survival. Results Forty-three patients with stage IV melanoma were enrolled in the phase Ib and II portions of the study and included in the analysis. At the data cutoff date (December 31, 2017), median follow-up duration was 25 months (range, 1 to 38 months). All 43 patients experienced at least one adverse event; grade 3/4 treatment-related adverse events occurred in 21 of 43 patients (48.8%). Objective responses were seen at all three dose levels among 43 evaluable patients. The objective response rate was 60.5%, with 46.5% of patients exhibiting ongoing response. Median PFS was 11.0 months in all patients and unreached in responders, whereas median overall survival remained unreached in all patients. The 2-year PFS rate was 46%. Conclusion Pembrolizumab/PEG-IFN demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in PD-1–naïve metastatic melanoma. These results support the rationale to further investigate this pembrolizumab/PEG-IFN combination in this disease.

Phase II randomized study of gefitinib alone or plus vinorelbine every 2 weeks’ treatment in patients with adenocarcinoma of the lung who failed at least two regimens

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17095-17095
Author(s):  
Y. Chen ◽  
R. Perng ◽  
C. Tsai ◽  
J. Whang-Peng
Keyword(s):  
Disease Progression ◽  
Low Dose ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Chinese Patients ◽  
Lung Cancer Patients ◽  
Ethnic Chinese ◽  
Adenocarcinoma Of The Lung ◽  
Treatment Objective

17095 Background: To assess the feasibility and the efficacy of adding chronic intermittent low-dose vinorelbine to gefitinib (Iressa) treatment for lung cancer patients with adenocarcinoma who failed 2 previous regimens of chemotherapy. Methods: Patients who had adenocarcinoma and failed at least 2 regimens, including taxanes and platinum, were enrolled and randomized into 2 arms: oral Iressa 250 mg daily (I) or vinorelbine 15 mg/m2 intravenous infusion day 1 and oral Iressa 250 mg daily from day 2 to 14, every 2 weeks (IV). From August 2004 to October 2005, 48 patients were enrolled. Results: Twenty-four patients were randomized into Iressa plus vinorelbine treatment. However, 3 patients refused vinorelbine treatment and received Iressa treatment only. Thus, 27 patients received I treatment and 21 patients received IV treatment. Objective response rates were 55.6% in I and 57.1% in IV. Any grade of leukopenia, neutropenia, and fatigue sensation was significantly higher in the IV arm (p=0.035, 0.001, 0.012, respectively). All the toxicities in both arms were generally mild and no toxic death occurred. However, many patients in the IV arm stopped V treatment before disease progression, including port-A occlusion in 4 patients (after 2, 5, 20, and 23 injections, respectively), mucositis in 1 (after 4 injections), and fatigue sensation in 1 (after 7 injections). After a median follow-up of 8 months, median time to disease progression was higher in IV than I (longer than 12 months vs. 7.1 months, p = 0.0271), more than half of the patients in each arm were still alive (p = 0.2269), and more than 9 patients in each arm survived longer than 1 year. Conclusions: Iressa is highly effective in ethnic Chinese patients with adenocarcinoma of the lung who have failed previous platinum and taxane treatment. The addition of low-dose V every 2 weeks produced a signiificantly better progression-free survival. Replacement of intravenous V with oral V should be considered to prevent the early termination of V treatment. No significant financial relationships to disclose.

Phase II randomized, open-label study of YM155 (sepantronium bromide) plus docetaxel versus docetaxel alone as first-line treatment for HER2 negative metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 548-548
Author(s):  
Michael R. Clemens ◽  
Anne Therese Keating ◽  
Oleg Gladkov ◽  
Fei Jie ◽  
Joyce Steinberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Randomized Study ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Open Label ◽  
Eligibility Criteria ◽  
Prior Therapy

548 Background: YM155 (YM) is a small molecule survivin suppressant. In a phase I/II study of YM plus docetaxel (D) in solid tumors evidence of anti-tumor activity was observed in women with human epidermal growth factor 2 non-overexpressing (HER2 negative) metastatic breast cancer (mBC). Methods: This was a randomized study of YM plus D versus D as 1st line treatment in subjects with HER2 negative mBC. Eligibility criteria were: ECOG < 1, no prior chemotherapy for mBC, and at least one measurable lesion. Primary endpoint was progression free survival (PFS); secondary endpoints were: objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR) and safety. YM was administered at 5 mg/m2/day as a 168 hr continuous infusion followed by 14 Day (d) observation and D was administered at 75 mg/m2over 1 hr on d1 every 21d. In the control arm, D was dosed per investigator choice q 21d. Results: 101 subjects were randomized (50 YM + D; 51 D). Median (m) age 55 (range: 25 – 79), 25% had triple negative disease, > 60% had bone and lymph mets, 86% had prior therapy for BC. mPFS (days) was 251 (95%CI: 176 – 333) YM + D vs 252 (95%CI: 202-433) D (p=0.34). ORR, CBR and TTR (YM+D; D): 26% vs. 25.5%; 82% vs. 84.3% and 45 vs 59 d. OS data are immature but showed no difference (p=0.911). Adverse events [AEs (> 25%)] [YM + D% vs D %]: neutropenia 83 vs 84, alopecia 62.5 vs 53, fatigue 50 vs 41.2, nausea 35.4 vs 41.2, leucopenia 27 vs 33 and dyspnoea 33 vs 14. Common (>10%) serious AEs [YM + D% vs D%]: febrile neutropenia 21 vs 8 and neutropenia 10 vs 8. Conclusions: Preclinical and clinical evidence suggested the combination of YM + D may offer additional benefit to D alone in subjects with mBC. This study showed no difference in efficacy, but the combination appeared to be well tolerated. Clinical trial information: NCT01038804.

Phase Ib/II trial of lenvatinib plus pembrolizumab in advanced melanoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 15-15
Author(s):  
Matthew H. Taylor ◽  
Nicholas J. Vogelzang ◽  
Allen Lee Cohn ◽  
Daniel E. Stepan ◽  
Robert Charles Shumaker ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
T Cell Infiltration ◽  
Rational Combination ◽  
Macrophage Populations ◽  
Ecog Ps

15 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for first-line treatment of advanced melanoma (objective response rates [ORR], 21–34%). In preclinical studies, LEN decreased tumor-associated macrophage populations, increased CD8+ T cell infiltration, and augmented PD-1 inhibitor activity; thus, LEN is a rational combination partner for PEM. We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in solid tumors, focusing on advanced melanoma. Methods: In this multicenter, open-label study, patients (pts) with measurable, confirmed, metastatic melanoma and ECOG PS ≤1 received oral LEN (20 mg/day) + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. Tumor assessments were by investigator per immune-related RECIST (irRECIST). Phase 2 primary end point was ORR at 24 weeks (ORRWK24). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 14 (67%) were PD-L1+, 4 (19%) were PD-L1-; 3 (14%) not tested. 38% had ≥1 prior anticancer therapy. ORRWK24 was 47.6% (95% CI, 25.7–70.2). All pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 13 (62%) and 1 (5%; adrenal insufficiency) pts respectively. There were no fatal TRAEs. Most common any-grade TRAEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension (48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to TRAEs occurred in 13 (62%) and 10 (48%) pts, respectively. Conclusions: LEN + PEM was well-tolerated and had encouraging clinical activity. The combination may potentially improve on the antitumor activity of anti-PD-1 monotherapies, supporting further evaluation in advanced melanoma. Clinical trial information: NCT02501096. [Table: see text]

Olaparib treatment in patients (pts) with platinum-sensitive relapsed (PSR) ovarian cancer (OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: Phase II LIGHT study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6013-6013 ◽  
Author(s):  
Karen Anne Cadoo ◽  
Fiona Simpkins ◽  
Cara Amanda Mathews ◽  
Nashwa Kabil ◽  
James Bennett ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Primary Analysis ◽  
Open Label ◽  
Platinum Sensitive ◽  
Grade 3 ◽  
Platinum Chemotherapy

6013 Background: In Study 19 (NCT00753545), olaparib capsules demonstrated improvement in progression-free survival (PFS) vs placebo in the PSR OC maintenance setting, irrespective of BRCAm status (Ledermann et al. Lancet Oncol 2014). LIGHT is the first prospective study to evaluate olaparib tablet treatment in PSR OC pts by BRCAm and HRD status. Methods: This is an open-label, non-randomized study (NCT02983799) that assessed efficacy and safety of olaparib monotherapy (300 mg BID) in pts with PSR, high-grade serous/endometrioid epithelial OC and ≥1 prior line of platinum chemotherapy. Pts were assigned to one of four cohorts: germline (g) BRCAm; somatic (s) BRCAm; HRD+ve (non-BRCAm); HRD–ve; by Myriad BRACAnalysis CDx and myChoice tests. HRD+ve was a score ≥42. Primary endpoint was objective response rate (ORR). Secondary endpoints included: disease control rate (DCR) and investigator-assessed PFS (RECIST v1.1). Primary analysis was to be ~6 months (mo) after the last pt was enrolled. Results: Data cut off was 8/27/19. Of 271 pts treated (median of 31.7 weeks [2.1–96.0]), 270 had measurable disease at baseline and were included in efficacy analyses (Table). The most common treatment-emergent adverse events (AEs) were nausea (66%) and fatigue (62%).Serious AEs and Grade ≥3 AEs were experienced by 25% and 44% of pts, respectively. AEs leading to olaparib dose interruptions, reductions and discontinuations occurred in 33%, 24% and 4% of pts, respectively. Conclusions: Olaparib treatment demonstrated activity across all cohorts. As observed in the maintenance setting, similar efficacy was seen in the gBRCAm and sBRCAm cohorts. For non-BRCAm pts, longer median PFS and higher ORR were observed in the HRD+ve cohort. Olaparib treatment was well tolerated with no new safety signals identified and a safety profile consistent with that seen in the PSR and first-line settings. Clinical trial information: NCT02983799. [Table: see text]

Updated results from a phase Ib trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 135-135
Author(s):  
Kohei Shitara ◽  
Hiroki Hara ◽  
Naoki Takahashi ◽  
Takashi Kojima ◽  
Akihito Kawazoe ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase 1 ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Significant Difference ◽  
One Year ◽  
Anti Tumor Activity

135 Background: In the phase 1 REGONIVO study, regorafenib of 80 mg/day plus nivolumab showed manageable safety profiles and encouraging anti-tumor activity for advanced colorectal cancer (CRC) or gastric cancer (GC) with objective response rate (ORR) of 36% in CRC and 44% in GC (Fukuoka, et al. ASCO 2019). Updated efficacy results are presented. Methods: Enrolled patients (pts) received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one to estimate the MTD and the recommended dose. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 28-8 antibody. Tumor mutation burden (TMB) was measured using Oncomine tumor mutation load assay. Results: Fifty pts were enrolled (25 CRC; 25 GC) until October 2018 with median prior treatment line of 3. Efficacy results were updated as of September 1st 2019. One CRC pt was with MSI-high but all other pts were with MSS or MMR-proficient. Among the 20 pts (9 CRC and 11 GC) with objective response (40%), responses are still ongoing in 13 pts (7 CRC and 6 GC) and the median duration of response was not reached (NR). Median progression free survival (PFS) was 7.8 months in CRC (95% CI, 2.8- NR) and 5.5 months (95% CI, 2.6-10.2 months) in GC. One-year PFS rate was 41.7% in CRC and 22.4% in GC. Median overall survival (OS) was not reached in CRC (95% CI, 9.7-NR) and 12.1 months (95% CI, 5.2-NR) in GC. One-year OS rate was 68% in CRC and 55.3% in GC. No significant difference of PFS and ORR was observed in CRC according to PD-L1 and TMB. Conclusions: Encouraging anti-tumor activity of the combination of regorafenib plus nivolumab had been maintained with long-term follow-up. A randomized study for MSS CRC is under planning. Clinical trial information: NCT03406871.

Phase II study of apatinib combined with temozolomide in advanced melanoma patients after failure of anti-PD-1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22043-e22043
Author(s):  
Li Zhou ◽  
Chuanliang Cui ◽  
Lu Si ◽  
Zhihong Chi ◽  
Xinan Sheng ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Lactate Dehydrogenase Level ◽  
Advanced Melanoma ◽  
First Line Therapy ◽  
Hand Foot Syndrome ◽  
Melanoma Patients

e22043 Background: Immunotherapy is first-line therapy in advanced melanoma. Because of different subtypes and gene alterations, the efficacy of immunotherapy in Asians, mostly comprised of acral and mucosal melanoma, is lower than Caucasians. There are no standard treatment strategies after immunotherapy failure. Chemotherapy and anti-angiogenesis combination showed emerging evidence of activity in mucosal and acral melanoma. This study was to evaluate the efficacy of apatinib combined with temozolomide in advanced immunotherapy refractory melanoma patients (pts). Methods: This prospective, single-arm, phase II study recruited unresectable or metastatic melanoma pts after failure of anti-PD-1 therapy. Other treatment including targeted therapy, chemotherapy, and clinical trials were allowed. Primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). According to the dose recommended from previous phase I study, pts were given apatinib 500 mg every day and temozolomide 300mg day 1-5, 28 days for one cycle. Results: 31 pts were enrolled between Feb 2018 and Dec 2018, with 8 males, average age 55 yrs (range 24 – 69 yrs). 13 pts (41.9%) were from mucosal primaries, 9 (29.0%) acral, 5 (16.1%) cutaneous (non-acral), and 4 (12.9%) unknown primaries. One had BRAF mutation, 1 CKIT, and 3 NRAS mutations. 9 pts (29.0%) were classified as IIIc/M1a, 9 (29.0%) M1b, and 13 (41.9%) M1c. 18 pts (58.1%) had elevated lactate dehydrogenase level. All pts progressed after anti-PD-1 therapy. In addition, 29.0% pts received dacarbazine based chemotherapy, 29.0% paclitaxel or albumin-bound paclitaxel, and 3.2% had dabrafenib with trametinib. Up to Dec 2019, 30 pts can be evaluated for efficacy. Median follow-up time was 10.2 mos (2.0-23.1 mos). There were 5 confirmed PRs and 20 SDs. ORR was 16.7%, DCR 83.3%, and median PFS was 5.0 mos (95%CI 1.9-8.1 mos). Median overall survival was 10.1 mos (95%CI 4.7-15.5 mos). Common AEs were hypertension (51.6%), proteinuria (41.9%), elevated transaminase (25.8%), thrombocytopenia (16.1%), and hand-foot syndrome (16.1%). Most were grade 1-2. Grade 3-4 AEs included proteinuria (12.9%), hypertension (6.4%), and thrombocytopenia (6.4%); 10 pts required a dose reduction, and 1 had to discontinue. No treatment-related deaths were observed. Conclusions: In pts progressed after anti-PD-1 therapy, apatinib in combination with temozolomide demonstrated promising efficacy and favorable safety profile. Clinical trial information: NCT03422445.

scholarly journals Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Advanced Melanoma

2014 ◽  
Vol 32 (32) ◽  
pp. 3659-3666 ◽  
Author(s):  
Patrick A. Ott ◽  
Omid Hamid ◽  
Anna C. Pavlick ◽  
Harriet Kluger ◽  
Kevin B. Kim ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Advanced Melanoma ◽  
Weekly Schedule ◽  
Antibody Drug Conjugate ◽  
End Points ◽  
Drug Conjugate ◽  
Antibody Drug

Purpose The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB (gpNMB) to the potent cytotoxin monomethyl auristatin E. This study evaluated the safety and activity of glembatumumab vedotin in patients with advanced melanoma. Patients and Methods Patients received glembatumumab vedotin every 3 weeks (schedule 1) in a dose escalation and phase II expansion at the maximum-tolerated dose (MTD). Dosing during 2 of 3 weeks (schedule 2) and weekly (schedule 3) was also assessed. The primary end points were safety and pharmacokinetics. The secondary end points included antitumor activity, gpNMB expression, and immunogenicity. Results One hundred seventeen patients were treated using schedule 1 (n = 79), schedule 2 (n = 15), or schedule 3 (n = 23). The MTDs were 1.88, 1.5, and 1.0 mg/kg for schedules 1, 2, and 3, respectively. Grade 3/4 treatment-related toxicities that occurred in two or more patients included rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea. Three treatment-related deaths (resulting from pneumococcal sepsis, toxic epidermal necrolysis, and renal failure) occurred at doses exceeding the MTDs. In the schedule 1 phase II expansion cohort (n = 34), five patients (15%) had a partial response and eight patients (24%) had stable disease for ≥ 6 months. The objective response rate (ORR) was 2 of 6 (33%) for the schedule 2 MTD and 3 of 12 (25%) for the schedule 3 MTD. Rash was correlated with a greater ORR and improved progression-free survival. Conclusion Glembatumumab vedotin is active in advanced melanoma. The schedule 1 MTD (1.88 mg/kg once every 3 weeks) was associated with a promising ORR and was generally well tolerated. More frequent dosing was potentially associated with a greater ORR but increased toxicity.

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