Clinical Trial Of Metformin Research Articles

Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

Trial in Progress: Phase I Open-Label Study of Metformin and Nelfinavir in Combination with Bortezomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Background:GLUT4 inhibition is an attractive therapeutic option in multiple myeloma (MM) given the dependence of MM cells on glucose transport. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor in MM cells to counter the possibility of therapeutic resistance to GLUT4 inhibition has demonstrated synergistic promise (Dalva-Aydemir et al, Clin Can Res 2015). Using a GLUT4 inhibitor such as the HIV protease inhibitor nelfinavir is an attractive choice since it not only inhibits the transport function of GLUT4, but it also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (Driessen et al, Blood 2018). Thus, in summary the FDA-approved oral HIV-PI nelfinavir, long used for the treatment of HIV disease, can bind to glucose transporters (GLUT4) on MM cells and reversibly inhibit glucose uptake, thus disrupting the Warburg effect. Nelfinavir can also enhance the activity of PIs such as bortezomib overcome its resistance in MM cells. Metformin, an oral FDA-approved drug for the treatment of Type II Diabetes has the ability to disrupt the electron transport chain of defective mitochondria within MM cells, thus blocking the ability of such mitochondria to generate energy and anabolic substrates as compensatory mechanisms required for proliferation in the setting of GLUT4 inhibition. Thus, this study will look at the safety and tolerability of repurposing the existing FDA-approved drugs for Type II diabetes and HIV in combination with bortezomib for the treatment of relapsed and/or refractory myeloma.Methods:This study is a phase 1 clinical trial of metformin and nelfinavir in combination with bortezomib for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design with 3 dose levels planned. Part B is a dose expansion cohort at the Maximal Tolerated Dose (MTD) determined in Part A. Up to a maximum of 36 patients will be enrolled and treated for a maximum of six 21-day cycles. Bortezomib is administered in its usual weekly subcutaneous dosing schedule of days 1, 8 and 15 of a 21-day cycle at a dose level of 1.3 mg/m2. Metformin will be administered for 14 days of a 21-day cycle and started at a dose level of 500 mg twice daily and will be investigated to a maximum dose of 1000 mg twice daily. Nelfinavir will also be administered for 14 days of a 21-day cycle and started at a dose level of 1250 mg twice daily and will be investigated to a maximum dose of 2500 mg twice daily. Key inclusion criteria include having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, adequate hematologic reserve, kidney function and liver function. This trial especially allows patients with non-secretory disease yet measurable by bone marrow assessments or cross-sectional imaging of plasmacytomas to be enrolled which constitutes an unmet need in the real-world MM population. Finally, this allows patients to be treated with a dexamethasone-free regimen. The primary objective of this trial is to determine the MTD of metformin and nelfinavir in combination with bortezomib. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated with this combination. Potential predictive biomarkers as well as resistance mechanisms using genomic RNA, immunohistochemistry and metabolomics-based assessment platforms will be evaluated in this study. Recruitment is ongoing with no safety concerns. This trial is registered on clinicaltrials.gov: NCT03829020. This investigator-initiated trial was funded by the generous gift of the Helen Diller Family Foundation. DisclosuresKumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Study protocol of a phase II clinical trial of oral metformin for the intravesical treatment of non-muscle invasive bladder cancer

BackgroundNon-muscle-invasive bladder cancer (NMIBC) is the most common neoplasm of the urinary tract and requires life-long invasive surveillance to detect disease recurrence. Currently, there are no effective oral therapies that delay disease recurrence or progression. We recently demonstrated that in mice, metformin accumulates unchanged in the urine. Urothelial cells are exposed to metformin concentrations ~ 240-fold higher than in serum. This was effective in the treatment of mouse bladder cancer models.MethodsWe describe the protocol of a multi-centre, open-label, phase II clinical trial of metformin in up to 49 evaluable patients with intermediate-risk NMIBC with the aim to determine the overall response to administration of oral metformin for 3 months on a marker tumour deliberately left following transurethral resection of multiple, papillary NMIBC tumours. All patients will receive metformin orally at doses up to 3000 mg per day. Metformin treatment will start within 2 weeks following transurethral resection of all tumours except one marker lesion. After 3 months of metformin treatment, the effect of metformin on the marker lesion is evaluated by cystoscopy and biopsy under anaesthesia. Residual tumour, if present at this evaluation, will be resected. In case of complete disappearance of the marker lesion, the former tumour area will be biopsied. The primary outcome is the complete response rate of the marker lesion, as determined by decentralised scoring of pre- and post-treatment cystoscopy images by expert independent urologists. Secondary outcomes are the partial response rate, overall safety of metformin and the duration of the time to recurrence.DiscussionPreclinical studies show the potential role of oral metformin treatment in the management of NMIBC. It could offer an alternative to current adjuvant intravesical treatment. If positive, the reported results of this study could warrant further phase III trials to compare the efficacy of metformin against current treatments of intravesical installations with chemotherapy or Bacillus Calmette-Guérin (BCG).Trial registrationThis trial is registered in ClinicalTrials.gov under NCT03379909.

Regulation of Fetal Hemoglobin through the Insulin Signaling Pathway

Background: HbF induction is a key therapeutic strategy for sickle cell disease (SCD). Analysis of whole exome sequencing (WES) data from patients with SCD identified variants in two components of the insulin signaling pathway, FOXO3 and its activator, AMPK, to be associated with HbF levels; the association was confirmed by functional studies in hematopoietic stem and progenitor cells (HSPC) (Zhang, Blood 2018). This work has led to a clinical trial of metformin, an activator of FOXO3, as a novel HbF inducing agent in patients with SCA (NCT02981329). We then performed whole genome sequencing (WGS) on 567 samples from patients with SCA, and identified an association between another component of the insulin signaling pathway, IGFBP3, and HbF levels (p<1x10-6). Of note, IGFBP-3 expression is upregulated by several drugs also reported to increase HbF, including decitabine, metformin, and vitamin D. Methods: Plasma levels of IGFBP3 relative to IGF1 in patients with and without IGFBP3 variants were measured by ELISA. Three unique SCD patient-derived HSPC cultures were treated with metformin (100 µM), piceatannol (12.5 µM) compound C (1 µM), and exogenous IGFBP3 (1µg/ml); their effect on HbF, gamma-globin, known modifiers of HbF, protein levels and phosphorylation status of members of the FOXO3-AMPK pathway were assessed by HPLC, RT-qPCR and western blot at day 14 and 21 of culture. Results In vitro: Plasma IGFBP3 levels were higher in patients heterozygous for an IGFBP3 variant (p=0.01). Treatment of HSPCs with recombinant IGFBP3 resulted in a significant increase in %HbF (p=0.008). Adding IGFBP3 to erythroid culture altered the insulin signaling pathway; both total protein and activated phosphorylated (Ser 413) levels of FOXO3 increased (p=0.01 and p=0.03, respectively). Piceatannol induces HbF (Zhang, Blood 2018), however, this effect was abolished when AMPK specific inhibitor compound C was added (p=0.01). Neither IGFBP3 nor metformin altered erythroid maturation or expression of known gamma-globin regulators BCL11A, KLF1, and MYB; however, addition of IGFBP3 increased total NRF2 protein levels and Ser40 NRF2 phosphorylation. In vivo: In Table 1, we show the HbF response to metformin from our prospective clinical trial. Patients who demonstrated compliance with metformin showed an average 4 percentage point rise in HbF. Furthermore, retrospective chart review of HbF and vitamin D levels in patients with SCD indicate that HbF levels correlate strongly with vitamin D levels (R2=0.404), and that vitamin D supplementation increases HbF in patients with SCD (Figure 1). Conclusions: In vitro: We have shown that elevation or activation of IGFBP3, FOXO3, and AMPK induces HbF in HSPCs in vitro, without altering erythroid maturation or levels of BCL11A, KLF1, or MYB. These results show that manipulation of the insulin signaling pathway at several levels can induce HbF in vitro in HSPCs. We hypothesize that circulating IGFBP3 induces HbF via the insulin signaling pathway, by binding IGF1, preventing activation of the IGF1 receptor (IGF1R), a negative regulator of FOXO3. Thus, IGFBP3 may promote HbF production by inhibiting aFOXO3 inhibitor (Figure 2), and by activating a known positive regulator of HbF, NRF2. In vivo: Preliminary results from our clinical trial of metformin in patients with SCA shows a rise in HbF in adherent patients, providing in vivo support for the role of the insulin signaling pathway in HbF regulation. Correlations between HbF and vitamin D levels in patients with SCD suggest that agents that increase IGFBP3 like vitamin D, may increase HbF in patients with SCD. Our in vitro and in vivo data in combination indicates a role for the insulin signaling pathway in HbF regulation. We propose that the insulin signaling pathway can be pharmacologically targeted with safe, well-studied agents like metformin and Vitamin D along with other HbF inducers to maximize clinical benefit. Disclosures Weiss: Cellarity INC: Consultancy; Rubius INC: Consultancy; GlaxoSmithKline: Consultancy; Esperian: Consultancy; Beam Therapeutics: Consultancy.

Metformin Clinical Trial in HPV+ and HPV- Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate.

Background: Metformin, an oral anti-hyperglycemic drug which inhibits mitochondrial complex I and oxidative phosphorylation has been reported to correlate with improved outcomes in head and neck squamous cell carcinoma (HNSCC) and other cancers. This effect is postulated to occur through disruption of tumor-driven metabolic and immune dysregulation in the tumor microenvironment (TME). We report new findings on the impact of metformin on the tumor and immune elements of the TME from a clinical trial of metformin in HNSCC.Methods: Human papilloma virus—(HPV–) tobacco+ mucosal HNSCC samples (n = 12) were compared to HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples (n = 17) from patients enrolled in a clinical trial. Apoptosis in tumor samples pre- and post-treatment with metformin was compared by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Metastatic lymph nodes with extra-capsular extension (ECE) in metformin-treated patients (n = 7) were compared to archival lymph node samples with ECE (n = 11) for differences in immune markers quantified by digital image analysis using co-localization and nuclear algorithms (PD-L1, FoxP3, CD163, CD8).Results: HPV–, tobacco + HNSCC (mean Δ 13.7/high power field) specimens had a significantly higher increase in apoptosis compared to HPV+ OPSCC specimens (mean Δ 5.7/high power field) (p < 0.001). Analysis of the stroma at the invasive front in ECE nodal specimens from both HPV—HNSCC and HPV+ OPSCC metformin treated specimens showed increased CD8+ effector T cell infiltrate (mean 22.8%) compared to archival specimens (mean 10.7%) (p = 0.006). Similarly, metformin treated specimens showed an increased FoxP3+ regulatory T cell infiltrate (mean 9%) compared to non-treated archival specimens (mean 5%) (p = 0.019).Conclusions: This study presents novel data demonstrating that metformin differentially impacts HNSCC subtypes with greater apoptosis in HPV—HNSCC compared to HPV+ OPSCC. Moreover, we present the first in vivo human evidence that metformin may also trigger increased CD8+ Teff and FoxP3+ Tregs in the TME, suggesting an immunomodulatory effect in HNSCC. Further research is necessary to assess the effect of metformin on the TME of HNSCC.

200. Clinical trial of metformin to treat preterm preeclampsia: pharmacokinetics and biomarker studies

Introduction Metformin is a potential therapeutic for preeclampsia as it decreases sFlt-1 and soluble endoglin and rescues endothelial dysfunction. Metformin pharmacokinetics in preeclampsia, where there is increased renal clearance and proteinuria, has not been established. Objective/Hypothesis To evaluate metformin XR (extended release) pharmacokinetics in preterm preeclampsia, obtain data on pregnancy prolongation and circulating levels of biomarkers associated with endothelial dysfunction. Methods 15 women with preterm preeclampsia were treated with 1.5 g metformin XR twice daily. Pharmacokinetic sampling was performed on day 1 at 2,4,5,6,7,8,24 h, and concentrations measured using liquid chromatography-tandem mass spectrometry. Given steady state is reached at 24–48 h, trough concentrations were measured at day 1 and 5 to assess the increase in Cmin over time. Plasma was taken twice weekly and biomarkers of endothelial dysfunction measured. Results Gestation at recruitment ranged from 27 to 31 weeks, and median prolongation was 11.5 days [IQR 5.8–23.8]. Pharmacokinetic studies confirmed excellent circulating levels at 0–12 h exposure, with Cmax [median (IQR)] 1.6 (1.3–1.9) mg/l, AUC 0–12 11.7 (8.9–13.5) mg.h/l and AUC 0-infinity 17.0 (10.7–36.6) mg.h/l. Day 1 and 5 trough concentrations were 0.55 (0.34–1.22) mg/l and 0.01 (0.01–0.70) mg/l suggesting steady state exposure is similar to day 1. Umbilical cord blood:plasma ratios taken 4 (3–9.5) hours after dosing were 0.67 (0.2–0.86). None of the following circulating biomarkers increased across pregnancy among those who remain undelivered: sFlt1, soluble endoglin, Vascular Cell Adhesion Molecule 1, Endothelin-1 and placental growth factor. Discussion 1.5 g of metformin XL twice daily in preterm preeclampsia resulted in at least the same exposure as 2 g daily in healthy controls, despite pregnancy and preeclampsia related changes. Metformin potentially stabilised levels of circulating biomarkers of endothelial dysfunction. Randomised trials to treat preterm preeclampsia should be performed.

Metformin prolonged the survival of diffuse large B-cell lymphoma and grade 3b follicular lymphoma patients responding to first-line treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone: a prospective phase II clinical trial

Background: With the addition of rituximab to chemotherapy, the response rates of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3b (FL3b) have been significantly improved. However, recurrence remains to be the hinder of long survival of the patients. Metformin is a widely used anti-diabetic agent and has an anti-lymphoma effect through adenosine monophosphate (AMP)-activated protein kinase activation in vitro and in vivo. Methods: We conducted a single center, prospective, single-arm phase II clinical trial of metformin for maintenance therapy in patients with DLBCL or FL3b who achieved complete remission after the first-line treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and analyzed the efficacies of metformin maintenance. Results: The patients received metformin maintenance had significantly better overall survival (OS) than those without metformin maintenance, especially for the diabetic patients. Patients with age >60, elevated serum lactate dehydrogenase (LDH), or International Prognostic Index (IPI) score ≥2 were benefit from metformin maintenance, as well as those with tumor cell expressing Ki67 ≥80%, or with non-germinal center B-cell-like (non-GCB) subtype. In multivariate analysis, age >60, elevated serum LDH and diabetic patients without metformin maintenance were the three independent unfavorable prognostic factors for OS. Conclusions: Metformin could thus be a safe and economic maintenance agent for elderly and high-risk patients not suitable for transplantation.

Abstract 058: Efficacy and Mechanisms of Metformin Therapy in Established Experimental Abdominal Aortic Aneurysms

Objective: Diabetes reduces the risk for abdominal aortic aneurysm (AAA) disease. In prior work in rodent models, pre-treatment with metformin was protective against experimental AAA initiation and progression. This study examined the influence of metformin therapy on progression of existing experimental AAAs. Methods: AAAs were created in 10-12 week old male C57BL/6J mice via transient intra-aortic infusion of porcine pancreatic elastase (PPE). Mice were treated with metformin (250 mg/kg via oral gavage), metformin plus AMPK inhibitor Compound C (the later via 10 mg/kg intraperitoneal injection) or vehicle alone for 10 days starting on day 4 following AAA creation. Outcomes were assessed by serial transabdominal ultrasonographic assessment of aortic diameter during treatment, as well as histological examination at sacrifice. Results: The principal findings are summarized in the Figure. Vehicle-treated mice experienced progressive, time-dependent aortic enlargement from day 3 to 14 following PPE infusion. Metformin treatment substantially attenuated further enlargement of existing AAAs. Treatment with Compound C partially rescued the AAA phenotype in metformin-treated mice. Histologically, characteristic aneurysmal pathologic changes, including medial elastin degradation, smooth muscle cell (SMC) depletion, mural leukocyte accumulation and neoangiogenesis (assessed by CD31 staining), present in PPE-infused, vehicle-treated mice, were substantially attenuated with metformin treatment. Co-treatment with Compound C abrogated the effects of metformin on media elastin degradation, SMC depletion and mural macrophage infiltration, with less influence on mural angiogenesis. Conclusion: Metformin therapy suppresses further expansion of existing experimental AAAs. This effect is abrogated by co-treatment with Compound C. These findings further justify performance of a clinical trial of metformin for medical management of AAA disease.

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

IntroductionHigh-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...

High accumulation of metformin in colonic tissue of subjects with diabetes or metabolic syndrome.

1557 Background: Epidemiological studies consistently observed an association between metformin use in diabetic patients and decreased colon cancer incidence and mortality at clinical doses (1500-2250 mg day), corresponding to plasma levels of 0.003-0.045 mM. Preclinical models report much higher doses of metformin, ranging between 1 and 40 mM for in vitro and 0.006-0.145 mM for in vivo studies. A recent trial using a low dose of metformin (250 mg/day, Higurashi T et al. Lancet 2016;17:475) showed a 40% reduction of colorectal adenoma recurrence. We performed a pilot study to measure metformin in plasma and colonic tissue of subjects with diabetes or metabolic syndrome and to explore their correlation with different tissue biomarkers, including Ki-67, pS6k, a mTOR effector protein, and EGFR expression. Methods: We used LC-MS/MS to quantify metformin in plasma and colonic tissues from 13 volunteers with diabetes or metabolic syndrome undergoing screening colonoscopy. All patients had received metformin at 1000-1850 mg/day for a median of 6.5 yrs (range 2-15), except for one who served as untreated control. Tissue quantifications were performed on specimens derived from right and left colon biopsies with or without washing to exclude a potential contamination due to lumen accumulation by the drug. Biomarker assessment was performed by standard IHC assay. Results: The mean plasma metformin was 0.025 mM/L (range 5x10-5-0.017), whereas the colonic tissue was ~100 fold higher in right [0.39 mM/Kg (range 0.034-1.75)] and left colon [0.46 mM/Kg (range 5x10-3-1.86)]. There was no significant difference between washed and unwashed biopsies. No significant correlations were detected between metformin levels in plasma/tissue and tissue biomarkers. Conclusions: Metformin can attain ~100 fold higher colonic tissue levels than in plasma. These levels are in the range of a direct antitumor effect observed in in vivo preclinical models. A two-by-two clinical trial of metformin and aspirin in colon cancer patients is underway by our group to further elucidate independent and synergistic antitumor effects.

A phase II clinical trial of metformin as a cancer stem cell targeting agent in stage IIc/III/IV ovarian, fallopian tube, and primary peritoneal cancer.

5556 Background: Epidemiologic and preclinical studies suggest that Metformin has antitumor effects which may be due to an impact on cancer stem-like cells (CSC). We present a phase II trial of metformin administered in combination with chemotherapy for patients with advanced stage epithelial ovarian cancer (EOC). Primary endpoints were 18 month progression free survival (PFS) and CSC number in Metformin treated tumors. Methods: Thirty-eight patients with confirmed stage IIC(n=1)/III(n=25)/IV(n=12) EOC were treated with either neoadjuvant metformin followed primary debulking surgery and adjuvant Metformin+chemotherapy, or neo-adjuvant metformin+chemotherapy, followed by interval debulking and adjuvant chemotherapy+Metformin. Patients were evaluated for side effects, PFS and overall survival (OS). Metformin treated tumors were evaluated for the presence of CSC via FACS and sphere assays. Results: Thirty-two patients (84%) completed at least six cycles of metformin+chemotherapy. Metformin was well tolerated with only one grade III/IV treatment-related adverse event (3%) noted. Common adverse effects were diarrhea (18%) and nausea (16%). Eighteen month PFS was 65.4% (95% confidence interval 47.9-78.3), Median PFS was 21.7 months (CI-17-26.7). Estimated three year OS was 73.5% (CI-54.7-84.3) with median OS not reached after a media follow-up of 33 months. Finally, tumors treated with metformin were noted to have a 3-fold decrease in ALDH+ CSC at baseline, increased sensitivity to Cisplatin in vitro, and a reduced ability to amplify ALDH+ CSC with passage in vitro. Conclusions: This is the first prospective study of Metformin in EOC patients. Translational studies confirm an impact of metformin on CSC. Metformin was well tolerated and outcome results were favorable, supporting the use of Metformin in phase-III studies. Clinical trial information: NCT01579812.

Telemedicine-enabled clinical trial of metformin in patients (pts) with biochemically-recurrent prostate cancer (PCa).

243 Background: Clinical trials are critical to informing cancer care but are hampered by slow accrual and suboptimal generalizability, both contributed to by poor geographic accessibility. We previously reported that &gt; 50% of the US population resides &gt; 1 hour from the nearest PCa clinical trial site (Galsky, JAMA Int Med, 2015). We sought to test the feasibility of replacing on-site study visits with telemedicine visits in a prospective clinical trial. Methods: Castration-naïve non-metastatic pts with PCa and a rising PSA after local therapy were eligible. Pts required a single on-site visit for enrollment. Treatment consisted of metformin 850 mg QD x 1 month followed by 850 mg BID x 5 months. Telemedicine visits were conducted monthly using a HIPAA-compliant smartphone application. The primary objective was to determine feasibility defined as completion of all eligible telemedicine visits by &gt; 2/3 enrolled pts; pts were ineligible for future telemedicine visits if treatment discontinued early for toxicity or disease progression. Secondary objectives included safety, % patients with ≤ 20% PSA rise at 6 months, quality of life, and patient satisfaction. Results: 15 pts were enrolled, median age 68 (range, 57, 83), one-way driving time 1.3 hours (range, 0.2-2.8), Gleason score 7 (range, 6, 9), and pre-study PSA 4.1 (range, 0.52, 31.7). The 6 month course of metformin was completed by 11/15 (73%) pts; 2 discontinued early due to rising PSA, 1 due to adverse event (AE), and 1 remains on study. Excluding 1 pt still on study, 14/14 (100%; 95% CI 76, 100) pts completed all 78 eligible telemedicine visits. The most common AEs were diarrhea (grade 1 = 60%) and fatigue (grade 1 = 20%); 1 pt experienced grade ≥ 3 AE (dehydration). The 6-month PSA was ≤ 20% baseline in 1 pt; median % PSA change at last televisit was +52.8% (range, -3.0, +318.8). Quality of life and pt satisfaction will be reported at the meeting. Conclusions: To our knowledge, this is the first ever interventional oncology clinical trial conducted via telemedicine. Telemedicine-enabled trials are feasible and may overcome barriers to trial participation. Metformin was generally well tolerated but associated with minimal anti-PCa activity as measured by PSA. Clinical trial information: NCT02376166.

Molecular and metabolic differences of treatment responders versus nonresponders in a phase 0 clinical trial of metformin in endometrial cancer

Objectives: In a phase 0 clinical trial of metformin in endometrial cancer (EC) patients, we previously reported that metformin decreased proliferation in the tumors of the majority of patients enrolled. We aimed to determine molecular and metabolic differences between responders and nonresponders to metformin treatment. Methods: Obese women with endometrioid EC were enrolled. Patients took metformin (850 mg QD) for 1 to 4 weeks before surgical staging. Tissue microarrays (triplicate cores) were constructed from formalin-fixed, paraffin-embedded endometrial biopsy and hysterectomy specimens before and after metformin treatment. Expression of the metformin transporters (OCT1, OCT3, PMAT, MATE1, MATE2), phosphorylated (p)-insulinlike growth factor 1 receptor (IGF1R), p-insulin receptor substrate-1 (IRS1), LKB1, and PTEN were evaluated using immunohistochemistry. Global, untargeted metabolomics was performed on serum samples of EC patients before metformin treatment, using combined GC-MS and LC-MS/MS techniques. Results: Of 20 patients enrolled, 13 (65%) responded to metformin as defined by a significant decrease in Ki-67 staining. In responders, metformin decreased the expression of OCT1 (46%, P = .003), OCT3 (40%, P = .036), PMAT (66%, P = .0019), MATE2 (26%, P = .0017), p-IGF1R (24%, P = .035), LKB1 (36%, P = 0.0015), and PTEN (80%, P = .033) but was not associated with changes in MATE1 or p-IRS1. In nonresponders, metformin treatment was not associated with any changes in these molecular targets. Pretreatment MATE2 expression approached significance in predicting response to metformin (P = .0625). Metabolomic profiling revealed that responders had higher premetformin treatment levels of amino acids, dipeptides, glycolytic intermediates, arachidonic acid, monohydroxy fatty acids and lysolipids compared with nonresponders (P < .05). Conclusions: Treatment response to metformin was associated with decreased expression of OCT1, OCT3, PMAT, and MATE2 transporters as well as metabolically relevant proteins associated with obesity and EC. Baseline metabolic differences were found between responders and nonresponders to metformin that may serve as biomarkers for ongoing clinical trials of metformin in this obesity-driven disease.

Molecular and metabolic differences of treatment responders versus nonresponders in a phase 0 clinical trial of metformin in endometrial cancer

Molecular and metabolic differences of treatment responders versus nonresponders in a phase 0 clinical trial of metformin in endometrial cancer

Abstract POSTER-TECH-1123: Advancing metformin as therapeutic for ovarian cancer: metabolomic profiling of mouse ovarian tumors identifies metformin-induced global metabolic changes

Abstract Background: Epidemiologic and preclinical studies indicate that use of metformin, a widely prescribed anti-diabetic drug, has protective effects in ovarian cancer (OvCa). One of the current challenges in the field is understanding which patients are most likely to benefit from metformin treatment. The aim of this study was to test the hypothesis that metformin would prevent OvCa progression in a mouse model and to identify metabolic changes induced in tumors by metformin. The long-term goal of these studies is to use the findings to inform the analysis of biospecimens in an ongoing prospective clinical trial of metformin in OvCa. Methods: To test the effect of metformin on ovarian tumorigenesis, HeyA8 xenograft mice were treated with metformin (250 mg/kg/day) or control. At the time of sacrifice, mean tumor weight was determined and tumors were stained by immunohistochemistry for Cyclin D1. Metabolomic analysis was performed on serum and tumor samples from mice treated with metformin and compared to mice treated with control. Here, after precipitation in 80% methanol and reconstitution in LC/MS grade water/HPLC grade acetonitrile samples were analyzed using a Q-Exactive Mass Spectrometer coupled to HILIC chromatography that was able to quantify over 300 polar metabolites and over 5000 molecular features in each sample. Results: The results indicate that in a mouse model metformin inhibits OvCa progression and induces global metabolic alterations. Metformin-treated mice had 68% lower mean tumor weight than controls (p=0.003). To understand how metformin inhibited tumor growth we stained tumors for Cyclin D1 to test whether metformin induced cell cycle arrest, a finding demonstrated in our prior studies (unpublished results). We found lower Cyclin D1 levels in tumors from metformin-treated mice than controls. Next, we measured the level of metformin in both the serum and tumors using mass-spectrometry. In serum, the results showed metformin levels in mice ranging from 1-5 nM; this was comparable to reports of serum levels of patients taking 1 gm of metformin daily. In tumors, there was trend toward smaller tumors having higher levels of metformin (Spearman, one-tailed R= -0.60, p=0.16). Finally, we used metabolomic profiling for a more global and unbiased assessment of metformin’s effect in OvCa. This analysis revealed two novel findings. First, an unbiased hierarchical clustering approach revealed metabolome profiles that could clearly predict the mice that had been treated with metformin. Second, global metabolic changes were noted in tumors from metformin treated mice. Metabolic pathways altered in metformin-treated mice included: alterations in glycolytic intermediates, induction of oxidative stress, decreased biosynthetic components of nucleotides, and changes in lipid metabolism. Conclusion: These findings of decreased tumor burden in metformin-treated mice add to the growing body of evidence supporting repurposing metformin as a metabolic therapeutic for OvCa. In addition, the metabolic changes in tumors induced by metformin indicate that it might be possible to establish a metabolomic signature in ovarian tumors that is predictive of metformin response. Citation Format: Iris L. Romero, Xiaojing Liu, Anirban K Mitra, Ernst Lengyel, Jason W. Locasale. Advancing metformin as therapeutic for ovarian cancer: metabolomic profiling of mouse ovarian tumors identifies metformin-induced global metabolic changes [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1123.

Molecular and metabolic differences of treatment responders versus non-responders in a phase 0 clinical trial of metformin in endometrial cancer.

e22259 Background: In a phase 0 clinical trial of metformin in endometrial cancer (EC) patients, we previously reported that metformin decreased proliferation in the tumors of the majority of patie...

Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder

Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder

Utilizing metformin as a radiosensitizing agent in the treatment of prostate cancer.

89 Background: External beam radiation therapy (EBRT) is a well recognized curative prostate cancer (PCa) treatment modality utilizing ionizing radiation (IR). In addition to mediating DNA damage, IR upregulates several intracellular pro-survival pathways including the insulin- like growth factor (IGR) signaling network. This may contribute to the intrinsic radioresistance exhibited by certain tumors. Diabetic patients with PCa experience poorer outcomes following EBRT than their non-diabetic counterparts. Some attribute this to diabetes-induced chronic hyperinsulinemia with consequent upregulation of pro-survival insulin/IGF signalling. Previous work by our group showed diet-induced hyperinsulinemia to enhance PCa tumor growth in vivo. Metformin, a diabetic treatment, alleviates hyperinsulinemia, and also exhibits anti-neoplastic properties. We postulate that pre-treatment with metformin to correct hyperinsulinemia may protect cells from radiation-mediated pro-survival insulin/IGF signaling. Thus we assessed the radiosensitizing potential of metformin using in vitro and in vivo PCa models. Methods: The effect of IR and/or metformin on colony formation rates was assessed in LNCaP, PC3, DU145 and PC3AR2 PCa cell lines using clonogenic assay. The combination treatment regimen was assessed in vivo using a murine xenograft model. Western blot and cell cycle analyses are ongoing to try and elucidate any mechanisms of interaction between metformin and IR. Results: Monotherapy with IR (1-8Gy) or metformin (0.01-10.0mM) caused significant dose-dependent reduction in colony formation rates (p&lt;0.001). Combination treatment further significantly reduced colony formation rates (p&lt;0.03). Preliminary results from our in vivo study show diminished tumor growth in response to combination treatment (p&lt;0.0001), and are currently subject to ongoing statistical analyses. Conclusions: Our in vitro findings confirm combining metformin with IR significantly reduces PCa cell colony formation rates further than either monotherapy. Recapitulation of these results in vivo would provide justification for translating this work into a phase II clinical trial of metformin as a radiosensitizing agent. No significant financial relationships to disclose.

A phase 2 clinical trial of metformin as a treatment for non‐diabetic paediatric non‐alcoholic steatohepatitis

Children with non-alcoholic steatohepatitis are insulin-resistant and metformin has been proposed as a potential therapy. However, paediatric safety and efficacy data are absent. To test the hypothesis that metformin therapy will safely improve markers of liver disease in paediatric non-alcoholic steatohepatitis. Single-arm open-label pilot study of metformin 500 mg twice daily for 24 weeks in non-diabetic children with biopsy-proven non-alcoholic steatohepatitis. Ten obese children (mean body mass index 30.4) enrolled and completed the trial. Mean alanine aminotransferase and aspartate aminotransferase (AST) improved significantly (P < 0.01) from baseline (184, 114 U/L) to end of treatment (98, 68 U/L). Alanine aminotransferase normalized in 40% and AST normalized in 50% of subjects. Children demonstrated significant improvements in liver fat measured by magnetic resonance spectroscopy (30-23%, P < 0.01); insulin sensitivity measured by quantitative insulin sensitivity check index (0.294-0.310, P < 0.05); and quality of life measured by pediatric quality of life inventory 4.0 (69-81, P < 0.01). Open-label treatment with metformin for 24 weeks was notable for improvement in liver chemistry, liver fat, insulin sensitivity and quality of life. A large randomized-controlled trial is needed to definitively determine the efficacy of metformin for paediatric non-alcoholic steatohepatitis.