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Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

ABSTRACT: BACKGROUND:Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. METHODS: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.

SUBMITTER: Dalgleish AG

PROVIDER: S-EPMC5046215 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

Dalgleish Angus G AG Stebbing Justin J Adamson Douglas Ja DJ Arif Seema Safia SS Bidoli Paolo P Chang David D Cheeseman Sue S Diaz-Beveridge Robert R Fernandez-Martos Carlos C Glynne-Jones Rob R Granetto Cristina C Massuti Bartomeu B McAdam Karen K McDermott Raymond R Martín Andrés J Muñoz AJ Papamichael Demetris D Pazo-Cid Roberto R Vieitez Jose M JM Zaniboni Alberto A Carroll Kevin J KJ Wagle Shama S Gaya Andrew A Mudan Satvinder S SS

British journal of cancer 20160906 7

<h4>Background</h4>Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma.<h4>Methods</h4>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 ...[more]

PMID: 27599039

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Project description:BackgroundGemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers.MethodsIn this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m(2)) and oxaliplatin (100 mg/m(2)) with or without cetuximab (500 mg/m(2)), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149.FindingsBetween Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52-74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43-65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1-7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7-6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1-13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6-16·0) in the chemotherapy alone group. The most common grade 3-4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group.InterpretationThe addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option.FundingInstitut National du Cancer, Merck Serono.

Project description:PurposeAs a novel small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (VEGFR2-TKI), Methylsulfonic apatinib (apatinib) exhibits a specific antitumor effect in various solid tumors via inhibition of angiogenesis. The present study was performed to evaluate the clinical efficacy and safety of apatinib in the treatment of advanced cholangiocarcinoma after failed gemcitabine-based chemotherapy.Patients and methodsThis was a prospective open-label phase II trial (NCT03521219). A total of 32 patients, in whom gemcitabine-based first-line chemotherapy for advanced intrahepatic cholangiocarcinoma had failed, were consecutively enrolled in a prospective, open, exploratory, and single-center clinical trial from November 2017 to November 2018. They were treated with apatinib mesylate second-line monotherapy (orally, 500 mg per day for a cycle of 28 days) until progressive disease or unacceptable toxicity. Using Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) and the Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE 4.0), the efficacy and adverse were evaluated, respectively. Kaplan-Meier method was used for survival analysis.ResultsTwenty-six patients were enrolled in full analysis set. At the end of follow-up, two patients were lost to follow-up, 24 of 26 patients in FAS were included in efficacy analyses. For the efficacy analysis set, the objective response rate (ORR) was 20.8% [95% confidence interval (CI): 9.24-40.47%] and the disease control rate (DCR) was 62.5% (95% CI: 112.86-387.14 days). One patient (4%) showed complete response (CR), 4 patients (17%) showed partial response (PR), 10 patients (41.7%) stable disease (SD), and 9 patients (37.5%) had progressive disease (PD). Meanwhile, apatinib therapy achieved the median progression-free survival PFS was 95 days (95% CI: 79.70-154.34 days), and the median OS was 250 days (95% CI: 112.86-387.14 days). Furthermore, univariate analysis revealed that age and tumor's anatomic location significantly affected PFS (P < 0.05). The most common clinically adverse events (AEs) included myelosuppression (69.2%), hypertension (57.7%), proteinuria (46.2%). The AEs were mild, mainly in grade 1 or 2, and no toxicity-induced death occurred.ConclusionApatinib monotherapy is an effective and promising regimen for treating patients with advanced cholangiocarcinoma who experienced failure of gemcitabine-based chemotherapy.

Project description:BackgroundImmune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer (BTC). The aim of this study was to assess the efficacy and safety of camrelizumab, plus gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC and explored the potential biomarkers associated with response.MethodsIn this single-arm, open-label, phase II study, we enrolled stage IV BTC patients. Participants received camrelizumab (3 mg/kg) plus gemcitabine (800 mg/m2) and oxaliplatin (85 mg/m2). Primary endpoints were 6-month progression-free survival (PFS) rate and safety. Secondary endpoints were objective response rate (ORR), PFS and overall survival (OS). Exploratory endpoints included association between response and tumor mutational burden (TMB), blood TMB, dynamic change of ctDNA and immune microenvironment.Results54 patients with advanced BTC were screened, of whom 38 eligible patients were enrolled. One patient withdrew informed consent before first dose treatment. Median follow-up was 11.8 months. The 6-month PFS rate was 50% (95% CI 33 to 65). Twenty (54%) out of 37 patients had an objective response. The median PFS was 6.1 months and median OS was 11.8 months. The most common treatment-related adverse events (TRAEs) were fatigue (27 (73%)) and fever (27 (73%)). The most frequent grade 3 or worse TRAEs were hypokalemia (7 (19%)) and fatigue (6 (16%)). The ORR was 80% in patients with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥1% versus 53.8% in PD-L1 TPS <1%. There was no association between response and TMB, blood TMB, immune proportion score or immune cells (p>0.05), except that PFS was associated with blood TMB. Patients with positive post-treatment ctDNA had shorter PFS (p=0.007; HR, 2.83; 95% CI 1.27 to 6.28).ConclusionCamrelizumab plus GEMOX showed a promising antitumor activity and acceptable safety profile as first-line treatment in advanced BTC patients. Potential biomarkers are needed to identify patients who might respond to camrelizumab plus GEMOX.Trial registration numberNCT03486678.

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Dataset Information

Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

Publications

Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

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