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1.
Geoffrey I. Shapiro Robert Wesolowski Craig Devoe Simon Lord John Pollard Bart S. Hendriks Martin Falk Ivan Diaz-Padilla Ruth Plummer Timothy A. Yap 《British journal of cancer》2021,125(4):520
Background Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin.Methods Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W).Results Thirty-one patients received berzosertib (90–210 mg/m2) and cisplatin (40–75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy.Conclusions Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting.Clinical Trials Identifier .Subject terms: NCT02157792Medical research, Cancer 相似文献
2.
Baek-Yeol Ryoo Ann-Li Cheng Zhenggang Ren Tae-You Kim Hongming Pan Kun-Ming Rau Hye Jin Choi Joong-Won Park Jee Hyun Kim Chia Jui Yen Ho Yeong Lim Dongli Zhou Josef Straub Juergen Scheele Karin Berghoff Shukui Qin 《British journal of cancer》2021,125(2):200
Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression.Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).Results In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.Trial registration ClinicalTrials.gov .Subject terms: NCT01988493Hepatocellular carcinoma, Molecularly targeted therapy 相似文献
3.
Sangeetha Venugopal Koichi Takahashi Naval Daver Abhishek Maiti Gautam Borthakur Sanam Loghavi Nicholas. J. Short Maro Ohanian Lucia Masarova Ghayas Issa Xuemei Wang Bueso-Ramos Carlos Musa Yilmaz Tapan Kadia Michael Andreeff Farhad Ravandi Marina Konopleva Hagop M. Kantarjian Courtney D. DiNardo 《Blood cancer journal》2022,12(1)
Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed ().Twenty-six pts received ENA + AZA (median 68 years, range, 24–88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07–0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML.Clinical trial registration information: https://clinicaltrials.gov/. NCT03683433Subject terms: NCT03683433Acute myeloid leukaemia, Drug development 相似文献
4.
J-L Lee J-H Ahn M K Choi Y Kim S-W Hong K-H Lee I-G Jeong C Song B-S Hong J H Hong H Ahn 《British journal of cancer》2014,110(10):2472-2478
Background:
There has been no previous study on the activity of gemcitabine in combination with oxaliplatin (GemOx) for castration-resistant prostate cancer (CRPC).Methods:
The GemOx was preclinically tested for cytotoxic activity in human prostate cancer cell lines. Clinically, patients with CRPC who failed prior docetaxel were treated with gemcitabine 1000 mg m−2 and oxaliplatin 100 mg m−2 intravenously every 2 weeks and prednisolone 5 mg orally twice daily. The primary end point was the prostate-specific antigen (PSA) response rate.Results:
The GemOx displayed synergistic effects based on Chou and Talalay analysis. In the phase II study, 33 patients were accrued. The median dose of docetaxel exposure was 518 mg m−2. A total of 270 cycles were administered with a median of eight cycles per patient. A PSA response rate was 55% (95% CI, 38–72) and radiologic response rate was 82% (9 out of 11). With a median follow-up duration of 20.5 months, the median time to PSA progression was 5.8 months (95% CI, 4.4–7.2) and the median overall survival was 17.6 months (95% CI, 12.6–22.6). The most frequently observed grade 3 or 4 toxicities were neutropenia (13%) and thrombocytopenia (13%).Conclusions:
The GemOx is active and tolerable in patients with metastatic CRPC after docetaxel failure (). NCT 01487720相似文献5.
Robin Kate Kelley Rebecca Miksad Irfan Cicin YenHsun Chen Heinz-Josef Klümpen Stefano Kim Zhong-Zhe Lin Jillian Youkstetter Saswati Hazra Suvajit Sen Ann-Lii Cheng Anthony B. El-Khoueiry Tim Meyer Ghassan K. Abou-Alfa 《British journal of cancer》2022,126(4):569
Background Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC.Methods Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as ≤ −2.60 score and a grade of 2 as a score of > −2.60 to ≤ −1.39.Results Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46–0.86] and 0.42 [0.32–0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66–1.06] and 0.46 [0.37–0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup.Discussion These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2.Trial registration number ClinicalTrials.gov number, NCT01908426.Subject terms: NCT01908426Drug development, Hepatocellular carcinoma 相似文献
6.
Takayuki Ikezoe Kiyoshi Ando Masahiro Onozawa Takahisa Yamane Naoko Hosono Yasuyoshi Morita Toru Kiguchi Hiromi Iwasaki Toshihiro Miyamoto Keisuke Matsubara Saori Sugimoto Yasushi Miyazaki Masahiro Kizaki Koichi Akashi 《Cancer science》2022,113(12):4258
Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment‐refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP‐2033), a potent cyclin‐dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open‐label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30‐min intravenous (i.v.) bolus (30 mg/m2/d), followed by a continuous i.v. infusion over 4 h on days 1–3 (60 mg/m2/d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose‐limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, . NCT03563560相似文献
7.
Yuankai Shi Qingyuan Zhang Xiaohong Han Yan Qin Xiaoyan Ke Hang Su Li Liu Jinxiang Fu Jie Jin Jifeng Feng Xiaonan Hong Xiaohong Zhang Depei Wu Bin Jiang Xiaodong Dong 《中国癌症研究》2021,33(3):405-416
ObjectiveThis study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01 (a rituximab biosimilar) and reference rituximab sourced from China (MabThera®; rituximab-CN). MethodsHere we report the results of two phase 1 studies. In the phase 1a, open-label, dose-escalation study (, CTR20140400), eligible patients received 250, 375 and 500 mg/m2 HLX01 sequentially at 7-day intervals, after confirming no dose-limiting toxicity (DLT). In the phase 1b, double-blind study ( NCT03218072, CTR20140764), eligible patients were given a single dose of 375 mg/m2 HLX01 or rituximab-CN. The primary endpoints included safety and tolerability parameters for the phase 1a and the area under the plasma concentration-time curve from time zero to day 91 (AUC0−91 d) for the phase 1b study. Equivalence was concluded if 90% confidence interval (90% CI) for the geometric least squares mean ratio (GLSMR) fell in the pre-specified equivalence criteria (80%−125%). ResultsBetween June 20, 2014 and January 5, 2015, 12 patients were enrolled in the phase 1a study. The pharmacokinetics of HLX01 showed dose proportionality and accumulation to steady state. HLX01 was well tolerated, with no serious adverse events (AEs), discontinuations or DLTs. Between November 8, 2014 and August 13, 2015, 87 eligible patients were enrolled in the phase 1b study, including 43 who received HLX01 and 44 who were treated with rituximab-CN. The equivalence endpoint was met with GLSMR for AUC0−91 d being 89.6% (90% CI: 80.4%−99.8%). AEs, anti-drug antibodies, and CD19+ and CD20+ B lymphocyte counts were similar between the HLX01 and rituximab-CN treatment groups. ConclusionsTreatment with HLX01 was safe and well tolerated in Chinese patients with B-cell lymphoma. HLX01 and rituximab-CN have similar pharmacokinetic, pharmacodynamic and safety profiles. NCT02584920相似文献
8.
Jason D. Lickliter Mark Voskoboynik Linda Mileshkin Hui K. Gan Ganessan Kichenadasse Kathy Zhang Maggie Zhang Zhiyu Tang Michael Millward 《British journal of cancer》2022,126(4):576
Background Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models.Methods This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects.Results Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7–38.6%). Median duration of response was 14.9 months (95% CI, 8.7–26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6–55.8%).Conclusions Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC.ClinicalTrials.gov Identifier .Subject terms: NCT02361723Ovarian cancer, Drug development 相似文献
9.
Zhihuang Hu Si Sun Xinmin Zhao Hui Yu Xianghua Wu Jialei Wang Jianhua Chang Huijie Wang 《The oncologist》2022,27(4):253
BackgroundThis open-label, phase II study aimed to investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) plus irinotecan/cisplatin as second-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC).MethodsEligible patients received 15mg/m2 Rh-endostatin as a continuous intravenous pump infusion (7 continuous days), 60mg/m2 irinotecan (days 1 and 8), and 60mg/m2 cisplatin (day 1) every 3 weeks. The primary endpoint was progression-free survival (PFS).ResultsA total of 50 patients were assessable for efficacy and safety analysis. The median follow-up was 10.97 months (95%CI: 7.03-19.42) as the data cutoff. Median PFS was 4.01 months (95% CI: 3.19-5.49), and median overall survival (OS) was 12.32 months (95% CI: 8.21-17.45); 13 (26%; 95% CI: 15.87-39.55) of 50 patients had an objective response, and 31 (62%; 95% CI: 48.15-74.14) had disease control. Grade 3 or greater treatment-related adverse events (AEs) occurred in 12 (24.0%) patients, and no deaths were reported. The common grade 3 or greater AEs were leucopenia (18.0%) and neutropenia (16.0%). Five (10%) patients discontinued treatment because of AEs.ConclusionRh-endostatin plus irinotecan/cisplatin showed promising anti-tumor activity in advanced ESCC patients with a good safety profile in the second-line setting, which warrants further study in this population. (ClinicalTrials.gov identifier: ). NCT03797625相似文献
10.
E. Van Cutsem I. Danielewicz M. P. Saunders P. Pfeiffer G. Argils C. Borg R. Glynne-Jones C. J. A. Punt A. J. Van de Wouw M. Fedyanin D. Stroyakovskiy H. Kroening P. Garcia-Alfonso H. Wasan A. Falcone R. Fougeray A. Egorov N. Amellal V. Moiseyenko 《British journal of cancer》2022,126(11):1548
Background Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results.Methods TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS.Results At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings.Conclusions TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy.Clinical trial information (clinicaltrials.gov)Subject terms: NCT02743221Colorectal cancer, Colorectal cancer 相似文献
11.
Angus G Dalgleish Justin Stebbing Douglas JA Adamson Seema Safia Arif Paolo Bidoli David Chang Sue Cheeseman Robert Diaz-Beveridge Carlos Fernandez-Martos Rob Glynne-Jones Cristina Granetto Bartomeu Massuti Karen McAdam Raymond McDermott Andrés J Mu?oz Martín Demetris Papamichael Roberto Pazo-Cid Jose M Vieitez Alberto Zaniboni Kevin J Carroll Shama Wagle Andrew Gaya Satvinder S Mudan 《British journal of cancer》2016,115(7):789-796
Background:
Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. NCT01303172Methods:
Patients were randomised (2 : 1) to IMM-101 (10 mg ml−l intradermally)+GEM (1000 mg m−2 intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected.Results:
IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01).Conclusions:
IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study. 相似文献12.
G L Ceresoli P A Zucali M Mencoboni M Botta F Grossi D Cortinovis N Zilembo C Ripa M Tiseo A G Favaretto H Soto-Parra F De Vincenzo A Bruzzone E Lorenzi L Gianoncelli B Ercoli L Giordano A Santoro 《British journal of cancer》2013,109(3):552-558
Background:
The aim of this open label phase II study () was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM). NCT00407459Methods:
Eligible patients received pemetrexed 500 mg m−2, carboplatin area under the plasma concentration–time curve (AUC) 5 mg ml−1 per minute and bevacizumab 15 mg kg−1, administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.Results:
Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7–46.0%). Forty-four (57.9%, 95% CI 46.0–69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3–4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.Conclusion:
The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM. 相似文献13.
Thomas Ollila James Butera Pamela Egan John Reagan Anthony Thomas Inna Yakirevich Kelsey MacKinnon Jeannine Margolis Jessica McMahon Valerie Rosati Adam J Olszewski 《The oncologist》2022,27(7):532
BackgroundWe conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma.MethodsParticipants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph−) acute lymphoblastic leukemia (ALL).ResultsAmong 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died.ConclusionVincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.Clinical Trials Registration Number: ClinicalTrials.gov identifier . NCT02257242相似文献
14.
Keith T Schmidt Fatima Karzai Marijo Bilusic Lisa M Cordes Cindy H Chau Cody J Peer Susan Wroblewski Alwin D R Huitema Jan H M Schellens James L Gulley William L Dahut William D Figg Ravi A Madan 《The oncologist》2022,27(9):718
BackgroundDespite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207, a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor camptothecin, in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on enzalutamide.MethodsThis was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide. A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily.ResultsBetween March 2019 and June 2021, four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression, the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients.ConclusionNLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy.ClinicalTrials.gov Identifier. NCT03531827相似文献
15.
Bi-Yun Wang Jian Zhang Jia-Lei Wang Si Sun Zhong-Hua Wang Lei-Ping Wang Qun-Ling Zhang Fang-Fang Lv En-Ying Cao Zhi-Min Shao Stefano Fais Xi-Chun Hu 《Journal of experimental & clinical cancer research : CR》2015,34(1)
Background
Acidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC).Methods
Patients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m2 followed by cisplatin 75 mg/m2 on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate.Results
Ninety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (46.9 % vs. 67.7 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045). Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI.Conclusions
The results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.Trial registration
Clinicaltrials.gov identifier: . NCT01069081Electronic supplementary material
The online version of this article (doi:10.1186/s13046-015-0194-x) contains supplementary material, which is available to authorized users. 相似文献16.
Steve Nicholson Holly Tovey Tony Elliott Stephanie M. Burnett Clare Cruickshank Amit Bahl Peter Kirkbride Anita V. Mitra Alastair H. Thomson Naveen Vasudev Balaji Venugopal Rachel Slade Lucy Tregellas Bruno Morgan Alison Hassall Emma Hall Lisa M. Pickering 《British journal of cancer》2022,126(1):34
Background We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit.Methods Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming–A’Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable.Results Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression.Conclusions Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease.Trial registration .Subject terms: NCT02057913Penile cancer, Penile cancer, Chemotherapy 相似文献
17.
Thomas Decaens Carlo Barone Eric Assenat Martin Wermke Angelica Fasolo Philippe Merle Jean-Frdric Blanc Vronique Grando Angelo Iacobellis Erica Villa Joerg Trojan Josef Straub Rolf Bruns Karin Berghoff Juergen Scheele Eric Raymond Sandrine Faivre 《British journal of cancer》2021,125(2):190
Background This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.Methods Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).Results In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).Conclusions Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenib pretreated aHCC with MET overexpression.Trial Registration ClinicalTrials.gov: .Subject terms: NCT02115373Hepatocellular carcinoma, Molecularly targeted therapy 相似文献
18.
Andrew H. Wei Panayiotis Panayiotidis Pau Montesinos Kamel Laribi Vladimir Ivanov Inho Kim Jan Novak Don A. Stevens Walter Fiedler Maria Pagoni Julie Bergeron Stephen B. Ting Jing-Zhou Hou Achilles Anagnostopoulos Andrew McDonald Vidhya Murthy Takahiro Yamauchi Jianxiang Wang Brenda Chyla Yan Sun Qi Jiang Wellington Mendes John Hayslip Courtney D. DiNardo 《Blood cancer journal》2021,11(10)
VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #.Subject terms: NCT03069352Targeted therapies, Acute myeloid leukaemia 相似文献
19.
J K Lee M Capanu E M O'Reilly J Ma J F Chou J Shia S S Katz B Gansukh D Reidy-Lagunes N H Segal K H Yu K-Y Chung L B Saltz G K Abou-Alfa 《British journal of cancer》2013,109(4):915-919
Background:
This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy.Methods:
Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m−2 and cisplatin 25 mg m−2 on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand–foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m−2, cisplatin 20 mg m−2 and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57–77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome.Results:
A total of 39 patients were accrued. The most common grade 3–4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34–66%). Median PFS and overall survival were 6.5 (95% CI: 3.5–8.3) and 14.4 months (95% CI: 11.6–19.2 months), respectively. No correlation was observed between pERK and outcomes.Conclusion:
The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased. 相似文献20.
Enrique Grande Cristina RodriguezAntona Carlos Lpez Teresa AlonsoGordoa Marta Benavent Jaume Capdevila Alex Teul Ana Custodio Isabel Sevilla Jorge Hernando Pablo Gajate Javier MolinaCerrillo Juan Jos Díez María Santos Javier Lanillos Rocío GarcíaCarbonero 《The oncologist》2021,26(11):941
BackgroundSunitinib (SUN)‐induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo‐isophosphoramide mustard. SUNEVO, a phase II, open‐label, single‐arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs).MethodsSystemic treatment‐naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1.ResultsFrom 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow‐up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression‐free survival was 10.4 months (95% confidence interval, 2.6–18.0). Treatment‐related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations.ConclusionSUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: )Implications for PracticeAddition of hypoxia‐activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression‐free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs'' resistance to antiangiogenic agents with other therapies with a safer profile. NCT02402062相似文献