GLORIA

GEOMAR Library Ocean Research Information Access

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    In: British Journal of Cancer, Springer Science and Business Media LLC, Vol. 122, No. 8 ( 2020-04-14), p. 1166-1174
    Abstract: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS -mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER). Methods In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS -mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336). Results Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC. Conclusions Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS -mutant patients due to its negative safety profile.
    Type of Medium: Online Resource
    ISSN: 0007-0920 , 1532-1827
    RVK:
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2002452-6
    detail.hit.zdb_id: 80075-2
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 2
    In: Cancer Reports, Wiley, Vol. 4, No. 4 ( 2021-08)
    Abstract: ModraDoc006 is an oral formulation of docetaxel, which is co‐administered with the cytochrome P450 3A4 and P‐glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration‐resistant prostate cancer (mCRPC). Aim We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC. Methods mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose‐escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate‐specific antigen (PSA) and radiological evaluation. Results Cohort 1 ( n  = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30‐20/100‐100). The mean docetaxel area under the plasma concentration‐time curve (mAUC0‐inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 ( n  = 6, ModraDoc006/r 30‐20/200‐200), the mAUC0‐inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A ( n  = 6, ModraDoc006/r 30‐20/200‐100), the mAUC0‐inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B ( n  = 3, ModraDoc006/r 20‐20/200‐100), the mAUC0‐inf was 558 ng/mL × h without DLTs. The mAUC0‐inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of 〉 50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed. Conclusion The RP2D was established at weekly ModraDoc006/r 30‐20/200‐100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3‐weekly IV docetaxel in patients with mCRPC.
    Type of Medium: Online Resource
    ISSN: 2573-8348 , 2573-8348
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2920367-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 3
    Online Resource
    Online Resource
    Elsevier BV ; 2022
    In:  European Journal of Cancer Vol. 174 ( 2022-10), p. 99-101
    In: European Journal of Cancer, Elsevier BV, Vol. 174 ( 2022-10), p. 99-101
    Type of Medium: Online Resource
    ISSN: 0959-8049
    RVK:
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1120460-6
    detail.hit.zdb_id: 1468190-0
    detail.hit.zdb_id: 82061-1
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 9507-9507
    Abstract: 9507 Background: Standard of care for locally advanced cutaneous SCC (CSCC) consists of extensive and mutilating surgery often with adjuvant radiotherapy (RT). To improve clinical prospects of these patients (pts), we tested efficacy of neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (COMBO) in pts with CSCC with an indication for extensive surgery with or without adjuvant RT. Methods: 40 pts with T1-4N0-3M0 or TxN1-3M0 CSCC and an indication for extensive and/or mutilating surgery were needed to reach the primary objective of this trial. Pts were randomized for ARM A: NIVO (3 mg/kg, weeks 0 & 2, N = 26) or ARM B: NIVO (3 mg/kg, weeks 0 & 2) + IPI (1mg/kg, week 0, N = 24) prior to surgery (week 4). Primary objective was pathological response at time of surgery. A major pathological response (MPR) was defined as ≤10% residual viable cancer cells in the surgical resection specimen. Secondary endpoints were tolerability (CTCAE v.5.0), survival, and quality of life (QOL). Key exploratory aim for the trial was the serial collection of pre- and on-treatment tumor samples to investigate immunogenomic features correlating with immunotherapy response. Preliminary results: 50 pts were enrolled at median age 76, of whom 32% with TxN1-3M0 disease. Grade 3-4 irAEs occurred in 6 (12%) pts and were well manageable. 40 pts underwent standard of care surgery w/wo adjuvant RT, of whom 40% and 53% reached an MPR upon NIVO and COMBO, respectively. However, 10 pts withdrew consent to undergo surgery and RT, of whom nine pts declined because of self-reported substantial clinical remission upon neoadjuvant immunotherapy. These clinical responses were confirmed via FDG-PET evaluation in week 4. All these 9 pts are currently cancer free at median FU of 12 months (range 4 to 27) with superior QOL compared to MATISSE pts undergoing standard of care. Overall, we found deep clinical responses in 13/26 (50%) and 14/23 (61%) of pts upon NIVO and COMBO, respectively, being either a MPR at time of surgery or a clinical CR in patients declining surgery. Preliminary conclusions: The MATISSE trial shows deep responses of 50% and 61% upon neoadjuvant NIVO and COMBO, respectively, with well manageable toxicity in this elderly CSCC population. Nine MATISSE patients have proven the concept that organ preservation and durable complete remissions can be achieved after two infusions of neoadjuvant immunotherapy only, without extensive or mutilating curative surgery and/or RT. Clinical trial information: NCT04620200 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 22 ( 2020-08-01), p. 2476-2487
    Abstract: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti–PD-1 in the neoadjuvant setting for resectable MCC. METHODS In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 6
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 9, No. 7 ( 2019-07-01), p. 852-871
    Abstract: Previous studies have described that tumor organoids can capture the diversity of defined human carcinoma types. Here, we describe conditions for long-term culture of human mucosal organoids. Using this protocol, a panel of 31 head and neck squamous cell carcinoma (HNSCC)–derived organoid lines was established. This panel recapitulates genetic and molecular characteristics previously described for HNSCC. Organoids retain their tumorigenic potential upon xenotransplantation. We observe differential responses to a panel of drugs including cisplatin, carboplatin, cetuximab, and radiotherapy in vitro. Additionally, drug screens reveal selective sensitivity to targeted drugs that are not normally used in the treatment of patients with HNSCC. These observations may inspire a personalized approach to the management of HNSCC and expand the repertoire of HNSCC drugs. Significance: This work describes the culture of organoids derived from HNSCC and corresponding normal epithelium. These tumoroids recapitulate the disease genetically, histologically, and functionally. In vitro drug screening of tumoroids reveals responses to therapies both currently used in the treatment of HNSCC and those not (yet) used in clinical practice. See related commentary by Hill and D'Andrea, p. 828. This article is highlighted in the In This Issue feature, p. 813
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2607892-2
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 7
    In: Journal of Cachexia, Sarcopenia and Muscle, Wiley, Vol. 13, No. 3 ( 2022-06), p. 1554-1564
    Abstract: Chemotherapy‐induced toxicities frequently occur in non‐small cell lung cancer (NSCLC) patients treated with platinum‐based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy‐induced toxicity in a large cohort of NSCLC patients. Methods A multicentre prospective follow‐up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II–IV) treated with first‐line platinum‐based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m 2 ) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy‐induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non‐haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose‐limiting toxicity (DLT) (treatment switch, delay, de‐escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI). Results In total, 297 patients (male n  = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% ( n  = 108) of the patients, 24.6% ( n  = 73) experienced any non‐haematological toxicity grade ≥2, and 55.6% ( n  = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31–4.45, P  = 0.005) and age at diagnosis 〉 65 years (ORadj 1.76, 95% CI 1.07–2.90, P  = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non‐haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23–4.04, P  = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23–0.74, P  = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT. Conclusions Non‐small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy.
    Type of Medium: Online Resource
    ISSN: 2190-5991 , 2190-6009
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2586864-0
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 8
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 80, No. 2 ( 2015-08), p. 253-266
    Abstract: The aim of the study was to determine the effect of renal impairment and prior platinum‐based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum‐based (PB) chemotherapy. Methods A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CL cr)  = 50–79 ml min −1 ], moderate [CL cr  = 30–49 ml min −1 ], severe [CL cr 〈 30 ml min −1 ]). Results Fifty‐nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration–time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non‐Asian patients with the same degree of renal impairment. Thirteen dose‐limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m −2 day −1 , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m −2 day −1 for patients with moderate renal impairment (suggested dose 1.9 mg m −2 day −1 for non‐Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m −2 day −1 in this cohort. Conclusions Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1498142-7
    SSG: 15,3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 9
    In: British Journal of Cancer, Springer Science and Business Media LLC, Vol. 124, No. 7 ( 2021-03-30), p. 1199-1206
    Abstract: Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands. Methods A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands. Results In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5–22.6) for laBCC, 11.7 (95% CI, 5.2–17.5) for mBCC and 19.1 (95% CI, 7.4–20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p  = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses. Conclusions Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.
    Type of Medium: Online Resource
    ISSN: 0007-0920 , 1532-1827
    RVK:
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2002452-6
    detail.hit.zdb_id: 80075-2
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 2536-2536
    Abstract: 2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC 0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and C max increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC 0-24 and C max ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC 0-∞ ) and 1.78-fold (C max ). Clinical trial information: NCT00732420.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...