Olaparib plus bevacizumab as maintenance therapy in patients with newly diagnosed,advanced ovarian cancer: Japan subset from the PAOLA-1/ENGOT-ov25 trial

ObjectiveThe addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial ({"type":"clinical-trial","attrs":{"text":"NCT02477644","term_id":"NCT02477644"}}NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1.MethodsPAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint).ResultsOf 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11–1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16–2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab.ConclusionResults in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477644","term_id":"NCT02477644"}}NCT02477644     

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive,HER2-negative advanced breast cancer

Background This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients.Methods In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction.Results Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72–96% (60th percentile) and 97–100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis.Conclusions This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs.Trial registration MONALEESA-2 ({"type":"clinical-trial","attrs":{"text":"NCT01958021","term_id":"NCT01958021"}}NCT01958021) first posted October 8, 2013; MONALEESA-3 ({"type":"clinical-trial","attrs":{"text":"NCT02422615","term_id":"NCT02422615"}}NCT02422615) first posted April 21, 2015; MONALEESA-7 ({"type":"clinical-trial","attrs":{"text":"NCT02278120","term_id":"NCT02278120"}}NCT02278120) first posted October 29, 2014.Subject terms: Breast cancer, Cancer     

A Phase Ib Study of Lucitanib (AL3810) in a Cohort of Patients with Recurrent and Metastatic Nasopharyngeal Carcinoma

BackgroundLucitanib is a novel multi-target inhibitor of FGFR1-3, VEGFR 1-3, and PDGFR α/β. Here, we evaluated the safety, tolerability, and preliminary efficacy of lucitanib in recurrent and metastatic nasopharyngeal carcinoma (RM-NPC).MethodsPatients with pretreated RM-NPC were randomly divided into two treatment arms: continuous or intermittent treatment. The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).ResultsOne hundred percent of patients in the continuous arm and 90% of patients in the intermittent arm had at least one treatment-related AE (TRAE). Grade ≥3 related TRAEs occurred in 5 patients in the continuous arm (5/10, 50%). No TRAEs grade >3 occurred in the intermittent arm. The ORR and DCR of the continuous arm was 20% and 90%, and the intermittent arm was 10% and 60%, respectively. All responses were observed by the first evaluation. The duration of response was more than 1 year, with two patients still on treatment with sustained response at more than 3 years.ConclusionLucitanib has promising clinical activity and tolerable safety profile in heavily pretreated patients with NPC. Patients who responded to lucitanib treatment generally achieved a long DoR. Lucitanib is now being evaluated in phase II/III studies.ClinicalTrials.gov identifier{"type":"clinical-trial","attrs":{"text":"NCT03260179","term_id":"NCT03260179"}}NCT03260179     

Phase 1 studies comparing safety,tolerability, pharmacokinetics and pharmacodynamics of HLX01 (a rituximab biosimilar) to reference rituximab in Chinese patients with CD20-positive B-cell lymphoma

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 ({"type":"clinical-trial","attrs":{"text":"NCT03218072","term_id":"NCT03218072"}}NCT03218072, 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 ({"type":"clinical-trial","attrs":{"text":"NCT02584920","term_id":"NCT02584920"}}NCT02584920, 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 (AUC_{0−91 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 AUC_{0−91 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.     

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

BackgroundLarotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors.MethodsPatients with TRK fusion-positive primary CNS tumors from two clinical trials ({"type":"clinical-trial","attrs":{"text":"NCT02637687","term_id":"NCT02637687"}}NCT02637687, {"type":"clinical-trial","attrs":{"text":"NCT02576431","term_id":"NCT02576431"}}NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR).ResultsAs of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. The 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45–100), 56% (95% CI: 38–74), and 85% (95% CI: 71–99), respectively. Median time to response was 1.9 months (range 1.0–3.8 months). Duration of treatment ranged from 1.2–31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3–4 in 3 patients. No new safety signals were identified.ConclusionsIn patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.     

Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade

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 ({"type":"clinical-trial","attrs":{"text":"NCT01908426","term_id":"NCT01908426"}}NCT01908426). 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, {"type":"clinical-trial","attrs":{"text":"NCT01908426","term_id":"NCT01908426"}}NCT01908426.Subject terms: Drug development, Hepatocellular carcinoma     

Apatinib plus S-1 for previously treated,advanced gastric or gastro-oesophageal junction adenocarcinoma: a phase 2, single-arm,prospective study

BackgroundThe current management of advanced gastric or gastro-oesophageal junction adenocarcinoma remains unsatisfactory. We investigated the efficacy and safety of the combination therapy of apatinib and S-1, considering the potential advantage of home-based treatment without hospital admission, in patients with platinum-refractory gastric or gastro-oesophageal junction adenocarcinoma.MethodsIn this open-label, single-arm, phase 2 trial, in each 21-day cycle, eligible patients received apatinib at an initial dose of 500 mg once daily continuously and S-1 at a dose of 40–60 mg twice daily on days 1–14 until the trail was discontinued disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoints were progression-free survival. The secondary endpoints were objective response rates, disease control rates, and safety, and overall survival. This study was registered at ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT04338438","term_id":"NCT04338438"}}NCT04338438.ResultsBetween April 2015 and May 2019, we included 37 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma refractory to first-line platinum-containing therapy. At the data cutoff, the 6-month progression-free survival was 31.5%, the median progression-free survival and overall survival were 4.2 (95% CI: 3.50–4.90) months and 8.2 (95% CI: 4.69–11.71) months, respectively. Of 37 eligible patients, 8 (21.6%) patients reached objective responses, 31 (83.8%) patients reached disease control. Grade 3 or 4 adverse events occurred in 8 (21.6%) patients, including hand-foot syndrome, hypertension, and diarrhea, etc.ConclusionsThe combination of Apatinib and S-1 showed promising efficacy and manageable toxicity as a home-based, second-line therapy in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, especially for the elder patients with poor performance status.Trial Registration{"type":"clinical-trial","attrs":{"text":"NCT04338438","term_id":"NCT04338438"}}NCT04338438.     

Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer

Background Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance.Methods We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples.Results Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes.Conclusions We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy.ClinicalTrials.gov EORTC 10994/BIG 1-00 Trial registration number {"type":"clinical-trial","attrs":{"text":"NCT00017095","term_id":"NCT00017095"}}NCT00017095.Subject terms: Cancer genomics, Breast cancer     

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours

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 {"type":"clinical-trial","attrs":{"text":"NCT02157792","term_id":"NCT02157792"}}NCT02157792.Subject terms: Medical research, Cancer     

Biomarker-guided targeted therapy in platinum-resistant ovarian cancer (AMBITION; KGOG 3045): a multicentre,open-label,five-arm,uncontrolled, umbrella trial

ObjectiveManagement of heavily pre-treated platinum-resistant ovarian cancer remains a therapeutic challenge. Outcomes are poor with non-platinum, single-agent chemotherapy (CT); however, molecularly targeted anticancer therapies provide new options.MethodsThis open-label, investigator-initiated, phase 2 umbrella trial ({"type":"clinical-trial","attrs":{"text":"NCT03699449","term_id":"NCT03699449"}}NCT03699449) enrolled patients with platinum-resistant ovarian cancer (at least 2 prior lines of CT and Eastern Cooperative Oncology Group 0/1) to receive combination therapy based on homologous recombination deficiency (HRD) and programmed death ligand 1 (PD-L1) status determined by archival tumour sample assessment. HRD-positive patients were randomised to either olaparib 200mg bid tablet + cediranib 30mg qd (arm 1) or olaparib 300mg bid tablet + durvalumab 1,500mg q4w (arm 2). HRD-negative patients were allocated to either durvalumab 1,500 mg q4w + pegylated liposomal doxorubicin (PLD) or topotecan or weekly paclitaxel (6 cycles; arm 3, those with PD-L1 expression) or durvalumab 1,500 mg q4w + tremelimumab 75mg q4w (4 doses) + PLD or topotecan or weekly paclitaxel (4 cycles; arm 4, those without PD-L1 expression). Arm 5 (durvalumab 1,500 mg q4w + tremelimumab 300mg [1 dose] + weekly paclitaxel [60 mg/m² D1,8,15 q4w for 4 cycles] was initiated after arm 4 completed. The primary endpoint was objective response rate (ORR; Response Evaluation Criteria in Solid Tumours 1.1).ResultsBetween Dec 2018 and Oct 2020, 70 patients (median 57 years; median 3 prior treatment lines [range 2–10]) were treated (n=16, 14, 5, 18, and 17, respectively). Overall ORR was 37.1% (26/70, 95% confidence interval=25.9, 49.5); 2 achieved complete response. ORR was 50%, 42.9%, 20%, 33.3%, and 29.4%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients, respectively. No TRAEs leading to treatment discontinuation and no grade 5 TRAEs were observed.ConclusionThis study, the first biomarker-driven umbrella trial in platinum-resistant recurrent ovarian cancer, suggests clinical utility with biomarker-driven targeted therapy. All treatment combinations were manageable, and without unexpected toxicities.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03699449","term_id":"NCT03699449"}}NCT03699449     

Quality of life outcomes from the randomized trial of hyperthermic intraperitoneal chemotherapy following cytoreductive surgery for primary ovarian cancer (KOV-HIPEC-01)

ObjectiveTo investigate the health-related quality of life (HRQOL) related to hyperthermic intraperitoneal chemotherapy (HIPEC) following primary or interval cytoreductive surgery for primary ovarian cancer.MethodsBetween 2010 and 2016, a total of 184 patients were randomly assigned to receive cytoreductive surgery with HIPEC (n=92) or without HIPEC (n=92). Quality of life (QOL) assessment was evaluated at baseline (before surgery); on postoperative day 7; after the 3rd and 6th cycle of adjuvant chemotherapy; and at 3, 6, 9, and 12 months after randomization. Patient-reported QOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (EORTC-QLQ-C30), ovarian cancer questionnaire modules (QLQ-OV28), and the MD Anderson Symptoms Inventory (MDASI).ResultsOf the 184 patients enrolled, 165 (83/92 in the HIPEC group and 82/92 in the control group) participated in the baseline QOL assessment. There were no statistically significant differences in functional scales and symptom scales in QLQ-C30; symptom scales, including gastrointestinal symptoms QLQ-OV28; and severity and impact score in MDASI between the 2 treatment groups until 12 months after randomization.ConclusionHIPEC with cytoreductive surgery showed no statistically significant difference in HRQOL outcomes. Thus, implementation of HIPEC during either primary or interval cytoreductive surgery does not impair HRQOL.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01091636","term_id":"NCT01091636"}}NCT01091636     

Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma

BackgroundTreatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting.MethodsThis was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.gov number: {"type":"clinical-trial","attrs":{"text":"NCT01215136","term_id":"NCT01215136"}}NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m² on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts.ResultsA total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing.ConclusionEverolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT01215136","term_id":"NCT01215136"}}NCT01215136).     

Efficacy and Safety of Apatinib in Patients with Recurrent or Refractory Melanoma

BackgroundThe prognosis of patients with metastatic malignant melanoma is very poor and partly due to resistance to conventional chemotherapies. The study’s objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma.MethodsThis was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients had received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily.ResultsFifteen patients (V660E BRAF status: 2 mutation, 2 unknown, 11 wild type) were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.3% response rate. Eleven patients had stable disease, with a DCR of 86.7%. The median OS was 12.0 months. The most common treatment-related adverse events of any grade were hypertension (80.0%), mucositis oral (33.3%), hand-foot skin reaction (26.7%), and liver function abnormalities, hemorrhage, diarrhea (each 20%). The only grade ≥3 treatment-related adverse effects that occurred in 2 patients was hypertension (6.7%) and mucositis (6.7%). No treatment-related deaths occurred.ConclusionApatinib showed antitumor activity as a second- or above-line therapy in patients with malignant melanoma. The toxicity was manageable.ClinicalTrials.gov Identifier{"type":"clinical-trial","attrs":{"text":"NCT03383237","term_id":"NCT03383237"}}NCT03383237     

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors

BackgroundLiquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy.MethodsNine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma ({"type":"clinical-trial","attrs":{"text":"NCT03616860","term_id":"NCT03616860"}}NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone ({"type":"clinical-trial","attrs":{"text":"NCT03739905","term_id":"NCT03739905"}}NCT03739905).ResultsBrain regions averaging 7.8 ± 6.0 cm³ (range 0.8-23.1 cm³) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation.ConclusionsThis first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.     

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer

Background The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses.Methods In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0–N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT.Results Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt. Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17–0.88) P = 0.0091.Conclusion TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect.Trial registration ISRCTN34086741 (21/7/2004), {"type":"clinical-trial","attrs":{"text":"NCT00983684","term_id":"NCT00983684"}}NCT00983684 (24/9/2009).Subject terms: Breast cancer, Radiotherapy, Surgical oncology     

Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation

BackgroundPatients with KRAS-mutant cancers have limited treatment options. Here we present a phase I study of JNJ-74699157, an oral, selective, covalent inhibitor of the KRAS G12C isoform, in patients with advanced cancer harboring the KRAS G12C mutation.MethodsEligible patients (aged ≥18 years) who had previously received or were ineligible for standard treatment received JNJ-74699157 once daily on a 21-day cycle. Dose escalation was guided by a modified continual reassessment method.ResultsTen patients (100 mg: 9 and 200 mg: 1) were enrolled. Tumor types included non–small cell lung cancer (n = 5), colorectal cancer (n = 4), and carcinoma of unknown primary site (n = 1). The median age was 65 (range: 36-74) years and median treatment duration was 2.91 (range: 0.5-7.5) months. Dose-limiting toxicities of grades 3–4 increased blood creatinine phosphokinase (CPK) were observed in 100 mg and 200 mg dose levels. The most common adverse event was increased blood CPK (6 patients). No significant clinical benefit was observed; the best response was stable disease in 4 patients (40%).ConclusionBased on dose-limiting skeletal muscle toxicities and the lack of efficacy at the 100 mg dose, further enrollment was stopped. The safety profile of JNJ-74699157 was not considered favorable for further clinical development.ClinicalTrials.gov Identifier{"type":"clinical-trial","attrs":{"text":"NCT04006301","term_id":"NCT04006301"}}NCT04006301     

Imaging Protocol and Criteria for Evaluation of Axillary Lymph Nodes in the NAUTILUS Trial

Axillary ultrasonography (US) is the most commonly used imaging modality for nodal evaluation in patients with breast cancer. No Axillary Surgical Treatment in Clinically Lymph Node-Negative Patients after Ultrasonography (NAUTILUS) is a prospective, multicenter, randomized controlled trial investigating whether sentinel lymph node biopsy (SLNB) can be safely omitted in patients with clinically and sonographically node-negative T1–2 breast cancer treated with breast-conserving therapy. In this trial, a standardized imaging protocol and criteria were established for the evaluation of axillary lymph nodes. Women lacking palpable lymph nodes underwent axillary US to dismiss suspicious nodal involvement. Patients with a round hypoechoic node with effaced hilum or indistinct margins were excluded. Patients with T1 tumors and a single node with a cortical thickness ≥ 3 mm underwent US-guided biopsy. Finally, patients with negative axillary US findings were included. The NAUTILUS axillary US nodal assessment criteria facilitate the proper selection of candidates who can omit SLNB.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT04303715","term_id":"NCT04303715"}}NCT04303715     

Intra-tumor AvidinOX allows efficacy of low dose systemic biotinylated Cetuximab in a model of head and neck cancer

For locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC), the current clinical use of Cetuximab in chemo/radiotherapy protocols is often associated to severe systemic toxicity. Here we report in vitro data in human FaDu pharynx SCC cells, showing that inactive concentrations of biotinylated Cetuximab (bCet) become active upon anchorage to AvidinOX on the surface of tumor cells. AvidinOX-anchored bCet induces apoptosis and DNA damage as well as specific inhibition of signaling, degradation and abrogation of nuclear translocation of EGFR. In the mouse model of FaDu cancer, we show that intra-tumor injection of AvidinOX allows anti-tumor activity of an otherwise inactive, intraperitoneally delivered, low dose bCet. Consistently with in vitro data, in vivo tumor inhibition is associated to induction of apoptosis, DNA damage and reduced angiogenesis. AvidinOX is under clinical investigation for delivering radioactive biotin to inoperable tumors (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02053324","term_id":"NCT02053324"}}NCT02053324) and present data support its use for the local treatment of HNSCC in combination with systemic administration of low dose bCet.     

Rh-Endostatin Plus Irinotecan/Cisplatin as Second-Line Therapy for Advanced Esophageal Squamous Cell Carcinoma: An Open-Label,Phase II Study

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: {"type":"clinical-trial","attrs":{"text":"NCT03797625","term_id":"NCT03797625"}}NCT03797625).     

Outcomes of children exposed in utero to chemotherapy for breast cancer

IntroductionThe incidence of breast cancer diagnosed during pregnancy is expected to increase as more women delay childbearing in the United States. Treatment of cancer in pregnant women requires prudent judgment to balance the benefit to the cancer patient and the risks to the fetus. Prospective data on the outcomes of children exposed to chemotherapy in utero are limited for the breast cancer population.MethodsBetween 1992 and 2010, 81 pregnant patients with breast cancer were treated in a single-arm, institutional review board–approved study with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in the adjuvant or neoadjuvant setting. Labor and delivery records were reviewed for each patient and neonate. In addition, the parents or guardians were surveyed regarding the health outcomes of the children exposed to chemotherapy in utero.ResultsIn total, 78% of the women (or next of kin) answered a follow-up survey. At a median age of 7 years, most of the children exposed to chemotherapy in utero were growing normally without any significant exposure-related toxicity or health problems. Three children were born with congenital abnormalities: one each with Down syndrome, ureteral reflux or clubfoot. The rate of congenital abnormalities in the cohort was similar to the national average of 3%.ConclusionsDuring the second and third trimesters, pregnant women with breast cancer can be treated with FAC safely without concerns for serious complications or short-term health concerns for their offspring who are exposed to chemotherapy in utero. Continued long-term follow-up of the children in this cohort is required.

Trial registration

ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00510367","term_id":"NCT00510367"}}NCT00510367. Other Study ID numbers: ID01-193, NCI-2012-01578. Registration date: 31 July 2007.