Johanna W. Wilmink

Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial

BACKGROUND In preclinical work and retrospective population studies, the anti-diabetic drug metformin has been associated with antineoplastic activity and decreased burden of many cancers, including pancreatic cancer. There is therefore interest in the hypothesis that this drug might be repurposed for indications in oncology. We aimed to assess the efficacy of the addition of metformin to a standard systemic therapy in patients with advanced pancreatic cancer, and provide the first report of a clinical trial with a survival endpoint of metformin for an oncological indication. METHODS We did this double-blind, randomised, placebo-controlled phase 2 trial at four centres in the Netherlands. Patients aged 18 years or older with advanced pancreatic cancer were randomly assigned (1:1), via a permutated computer-generated block allocation scheme (block size of six) to receive intravenous gemcitabine (1000 mg/m(2)) on days 1, 8, and 15 every 4 weeks and oral erlotinib (100mg) once daily in combination with either oral metformin or placebo twice daily. Metformin dose was escalated from 500 mg (in the first week) to 1000 mg twice daily in the second week. Randomisation was stratified by hospital, diabetes status, and tumour stage. The primary endpoint was overall survival at 6 months in the intention-to-treat population. This trial is complete and is registered with ClinicalTrials.gov, number NCT01210911. FINDINGS Between May 31, 2010, and Jan 3, 2014, we randomly assigned 121 patients to receive gemcitabine and erlotinib with either placebo (n=61) or metformin (n=60). Overall survival at 6 months was 63·9% (95% CI 51·9-75·9) in the placebo group and 56·7% (44·1-69·2) in the metformin group (p=0·41). There was no difference in overall survival between groups (median 7·6 months [95% CI 6·1-9·1] vs 6·8 months [95% CI 5·1-8·5] in the metformin group; hazard ratio [HR] 1·056 [95% CI 0·72-1·55]; log-rank p=0·78). The most frequent grade 3-4 toxic effects were neutropenia (15 [25%] patients in placebo group vs 15 [25%] in metformin group), skin rash (six [10%] vs four [7%]), diarrhoea (three [5%] vs six [10%]), and fatigue (two [3%] vs six [10%]). INTERPRETATION Addition of a conventional anti-diabetic dose of metformin does not improve outcome in patients with advanced pancreatic cancer treated with gemcitabine and erlotinib. Future research should include studies of more potent biguanides, and should focus on patients with hyperinsulinaemia and patients with tumours showing markers of sensitivity to energetic stress, such as loss of function of AMP kinase, a key regulator of cellular energy homoeostasis. FUNDING Academic Medical Centre, Amsterdam, and The Terry Fox Foundation, Vancouver, Canada.

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1(R132H), a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1(R132H) that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1(R132H) mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1(R132H) inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1(R132H) inhibitors in these patients may limit irradiation efficacy in this setting.

Feasibility and repeatability of PET with the hypoxia tracer [18F]HX4 in oesophageal and pancreatic cancer

BACKGROUND AND PURPOSE To investigate the feasibility and to determine the repeatability of recurrent [(18)F]HX4 PET scans in patients with oesophageal (EC) and pancreatic (PC) cancer. MATERIALS AND METHODS 32 patients were scanned in total; seven patients (4 EC/3 PC) were scanned 2, 3 and 4h post injection (PI) of [(18)F]HX4 and 25 patients (15 EC/10 PC) were scanned twice 3.5h PI, on two separate days (median 4, range 1-9days). Maximum tumour to background ratio (TBRmax) and the tumour hypoxic volume (HV) (TBR>1.0) were calculated. Repeatability was assessed using Bland-Altman analysis. Agreement in localization was calculated as the distance between the centres of mass in the HVs. RESULTS For EC, the TBRmax in the tumour (mean±SD) was 1.87±0.46 with a coefficient of repeatability (CoR) of 0.53 (28% of mean). The HV ranged from 3.4 to 98.8ml with a CoR of 5.1ml. For PC, the TBRmax was 1.72±0.23 with a CoR of 0.27 (16% of mean). The HV ranged from 4.6 to 104.0ml with a CoR of 7.8ml. The distance between the centres of mass in the HV was 2.2±1.3mm for EC and 2.1±1.5mm for PC. CONCLUSIONS PET scanning with [(18)F]HX4 was feasible in both EC and PC patients. Amount and location of elevated [(18)F]HX4 uptake showed good repeatability, suggesting [(18)F]HX4 PET could be a promising tool for radiation therapy planning and treatment response monitoring in EC and PC patients.

Preoperative chemoradiation therapy in combination with panitumumab for patients with resectable esophageal cancer: the PACT study

PURPOSE Preoperative chemoradiation therapy (CRT) has become the standard treatment strategy for patients with resectable esophageal cancer. This multicenter phase 2 study investigated the efficacy of the addition of the epidermal growth factor receptor (EGFR) inhibitor panitumumab to a preoperative CRT regimen with carboplatin, paclitaxel, and radiation therapy in patients with resectable esophageal cancer. METHODS AND MATERIALS Patients with resectable cT1N1M0 or cT2-3N0 to -2M0 tumors received preoperative CRT consisting of panitumumab (6 mg/kg) on days 1, 15, and 29, weekly administrations of carboplatin (area under the curve [AUC] = 2), and paclitaxel (50 mg/m(2)) for 5 weeks and concurrent radiation therapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. Primary endpoint was pathologic complete response (pCR) rate. We aimed at a pCR rate of more than 40%. Furthermore, we explored the predictive value of biomarkers (EGFR, HER 2, and P53) for pCR. RESULTS From January 2010 until December 2011, 90 patients were enrolled. Patients were diagnosed predominantly with adenocarcinoma (AC) (80%), T3 disease (89%), and were node positive (81%). Three patients were not resected due to progressive disease. The primary aim was unmet, with a pCR rate of 22%. Patients with AC and squamous cell carcinoma reached a pCR of 14% and 47%, respectively. R0 resection was achieved in 95% of the patients. Main grade 3 toxicities were rash (12%), fatigue (11%), and nonfebrile neutropenia (11%). None of the biomarkers was predictive for response. CONCLUSIONS The addition of panitumumab to CRT with carboplatin and paclitaxel was safe and well tolerated but could not improve pCR rate to the preset criterion of 40%.

Protease‐activated receptor‐1 drives pancreatic cancer progression and chemoresistance

Protease activated receptor (PAR)‐1 expression in tumor cells is associated with disease progression and overall survival in a variety of cancers of epithelial origin; however, the importance of PAR‐1 in the tumor microenvironment remains unexplored. Utilizing an orthotopic pancreatic cancer model in which tumor cells are PAR‐1 positive whereas stromal cells are PAR‐1 negative, we show that PAR‐1 expression in the microenvironment drives progression and induces chemoresistance of pancreatic cancer. PAR‐1 enhances monocyte recruitment into the tumor microenvironment by regulating monocyte migration and fibroblast dependent chemokine production thereby inducing chemoresistance. Overall, our data identify a novel role of PAR‐1 in the pancreatic tumor microenvironment and suggest that PAR‐1 may be an attractive target to reduce drug resistance in pancreatic cancer.

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours

Introduction High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine. Methods and analysis We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications. Ethics and dissemination This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal. Trial registration number This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.

IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors

Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known. Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT, and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors. Results: IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells. Conclusions: IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML. Clin Cancer Res; 24(7); 1705–15. ©2018 AACR.

Phase I clinical trial to determine the feasibility and maximum tolerated dose of panitumumab to standard gemcitabine-based chemoradiation in locally advanced pancreatic cancer

Purpose: Epidermal growth factor receptor (EGFR) inhibitors may improve both the therapeutic efficacy of radiotherapy and the radiosensitizing activity of gemcitabine. Based on this rationale and the nonoverlapping toxicity profiles of gemcitabine and the monoclonal EGFR antibody panitumumab, we designed a phase I trial to investigate the maximum-tolerated dose (MTD), safety, and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC). Experimental Design: Patients with LAPC and WHO performance status 0 to 1 were treated with weekly panitumumab at four dose levels (1–2.5 mg/kg), combined with weekly gemcitabine 300 mg/m2 and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m2 weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity. Each cohort was monitored during the combination therapy to establish dose limiting toxicity. Tumor evaluation was performed after CRT and during gemcitabine monotherapy. Results: Fourteen patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg. Three of the 6 patients, treated at MTD, experienced grade 3 adverse events during the combination therapy; neutropenia (n = 2; 33%), fatigue (n = 1; 17%), nausea (n = 1; 17%), and vomiting (n = 1; 17%). Partial response was achieved by 3 patients (23%), 1 in each dose cohort. Median progression free survival of the three cohorts together was 8.9 months. Conclusions: The addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC has manageable toxicity and potential clinical efficacy. Clin Cancer Res; 21(20); 4569–75. ©2015 AACR.

Neoadjuvant chemoradiotherapy followed by esophagectomy does not increase morbidity in patients over 70

Esophagectomy in elderly esophageal carcinoma patients is correlated with a high morbidity and even mortality. Studies on neoadjuvant chemoradiotherapy (NT) in elderly patients are scarce. The aim of this study was to evaluate the effect of advanced age in combination with NT in esophageal carcinoma patients who underwent an esophagectomy. Patients who underwent NT prior to esophagectomy between 1993 and 2010 were divided into three groups: <70, 70-74, and ≥75 years. Toxicity of NT and postoperative morbidity were compared between groups. Primary endpoints were toxicity, complication rate, and survival. Two hundred thirteen patients underwent NT during the study period, 26 were aged 70-74 years, and 17 were ≥70 years. Toxicity of NT was comparable for younger and elderly patients (46% vs. 54% vs. 47%, P = 0.263). Overall complications occurred in 62% of younger patients versus 73% and 71% among patients aged 70-74 years and ≥75 years, respectively (P = 0.836). Cardiac complications occurred in 14% of younger patients versus 27% and 41% of elderly patients (P = 0.021). Three-year survival rates were 59% versus 44% versus 31% among patients aged <70, 70-74, and ≥75 years, respectively (P = 0.237). Higher age (odds ratio 1.750, P < 0.001) was an independent risk factor for development of cardiac complications. Toxicity of NT and postoperative complications are comparable for patients aged <70, 70-74, and ≥75 years, with the exception of cardiac complications. Therefore, we consider NT followed by esophagectomy in elderly patients a safe treatment modality in our center.

Wild-type and mutated IDH1/2 enzymes and therapy responses

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are key enzymes in cellular metabolism, epigenetic regulation, redox states, and DNA repair. IDH1/2 mutations are causal in the development and/or progression of various types of cancer due to supraphysiological production of d-2-hydroxyglutarate. In various tumor types, IDH1/2-mutated cancers predict for improved responses to treatment with irradiation or chemotherapy. The present review discusses the molecular basis of the sensitivity of IDH1/2-mutated cancers with respect to the function of mutated IDH1/2 in cellular processes and their interactions with novel IDH1/2-mutant inhibitors. Finally, lessons learned from IDH1/2 mutations for future clinical applications in IDH1/2 wild-type cancers are discussed.