Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse 

de Brabander, J. (Justin)

Dekker, E. (Evelien)

Dewint, P. (Pieter)

Eeden, S. (Susanne) van

Eskens, F.A.L.M. (Ferry)

Klümpen, H.J. (Heinz Josef)

Korsse, S.E. (Susanne)

Leerdam, M.E. (Monique) van

de Brabander, J

Eskens, Ferry

Korsse, SE

Dekker, E

Dewint, P

Leerdam, ME

van Eeden, S

Klumpen, HJ

EUR Research Repository

Chemoprevention in Patients with Peutz-Jeghers Syndrome:Lessons LearnedJUSTIN DE BRABANDER,a FERRY A.L.M. ESKENS,b SUSANNE E. KORSSE,c EVELIEN DEKKER,d PIETER DEWINT,g MONIQUE E. VAN LEERDAM,hSUSANNE VAN EEDEN,e HEINZ-JOSEF KLÜMPENfaUniversity of Amsterdam, Amsterdam, The Netherlands; bDepartment of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, TheNetherlands; cDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; dDepartmentof Gastroenterology and Hepatology, eDepartment of Pathology, and fDepartment of Medical Oncology, Cancer Center Amsterdam,Academic Medical Center, Amsterdam, The Netherlands; gDepartment of Gastroenterology and Hepatology, Maria Middelares Hospital,Gent, Belgium; hDepartment of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The NetherlandsTRIAL INFORMATION• ClinicalTrials.gov Identifier: NCT01178151• Sponsor(s): Novartis• Principal Investigator: H.J. Kl€umpen• IRB Approved: YesLESSONS LEARNED• Motivating patients to enroll in chemopreventive studies is challenging.• Chemoprevention with toxic drugs is not feasible.ABSTRACTBackground. LKB1 mutations are the underlying geneticabnormality causing Peutz-Jeghers syndrome (PJS) and are apotential target for everolimus. In this phase II study, the efficacyof everolimus on polyp and tumor growth in PJS patients wasinvestigated.Methods. Adult patients with a proven LKB1 mutation and whowere suitable for everolimus treatment were included in twodifferent PJS cohorts: (a) patients with unresectable malignan-cies and (b) patients with high-risk polyps. Treatment in bothgroups was oral everolimus, 10 mg daily. Response rates wereprimary endpoints for both cohorts.Results. Between October 2011 and April 2016, only twopatients were enrolled, one in each cohort. A 49-year-oldpatient with advanced pancreatic cancer in cohort 1 wasprogressive after 2 months. A 52-year-old male patient incohort 2 experienced severe toxicity and refused treatmentafter 4 months, even though endoscopy suggested stabili-zation of polyps. Adverse events included dental inflamma-tions, mucositis, and rash. In 2016, the trial was abortedfor lack of accrual, despite extensive accrual efforts in anarea where PJS is highly prevalent and care is highlycentralized.Conclusion. Due to accrual problems, no conclusions can bedrawn about the value of everolimus in PJS treatment, ques-tioning the feasibility of this agent for chemoprevention. TheOncologist 2018;23:399–e33DISCUSSIONPeutz-Jeghers syndrome is caused by a mutation in the LKB1gene, a tumor suppressor gene located on chromosome 19.This mutation results in a decreased inhibition of mammaliantarget of rapamycin (mTOR), with uncontrolled cell growth as aresult, manifesting as intestinal polyps (Fig. 1) and malignan-cies. Oral selective mTOR inhibitors such as rapamycin andeverolimus have been successfully used in several exploratorystudies [1, 2]. The report of a successful treatment of a PJSpatient with pancreatic cancer with everolimus was the startingpoint for a more comprehensive study: the EVAMP trial [3].Our hypothesis was that treating PJS patients with everolimuswould result in reduced growth of intestinal polyps and tumors.In 2011, researchers from the University of Utah initiated a sim-ilar study on the role of chemoprevention agents in PJS, whichwas stopped prematurely because of poor accrual [4].Due to the rare nature of the disease, the intent was to startwith a pilot study including 15 patients, executed in the two larg-est PJS centers in The Netherlands (Academic Medical Center,Amsterdam, and Erasmus Medical Center, Rotterdam). To obtainrelevant information about activity of everolimus, we selected ahigh-risk population consisting of patients with either fast-growinggastric or small bowel polyps requiring therapeutic enteroscopy atleast once every 2 years with resection of >4 polyps larger than15mm, or patients suffering from PJS-related malignancies.Correspondence: Dr. Heinz-Josef Kl€umpen, Department of Medical Oncology, Academic Medical Center, Cancer Center Amsterdam, Meibergdreef9, 1105AZ, Amsterdam, The Netherlands. Telephone: 3-120-566-5955; e-mail: h.klumpen@amc.uva.nl Received September 4, 2017; accepted forpublication December 3, 2017; published Online First on January 25, 2018.Oc AlphaMed Press; the data published online to support this summaryis the property of the authors. http://dx.doi.org/10.1634/theoncologist.2017-0682The Oncologist 2018;23:399–e33 www.TheOncologist.com Oc AlphaMed Press 2018Clinical Trial Results by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from Despite the clear study design, the selection of high-riskpatients, and well-targeted medication, our study metsome major obstacles. First, it turned out to be very difficultto find enough relevant patients, and secondly, the chosentreatment turned out to have both poor tolerability and(although in only one patient) a disappointing lack of effi-cacy. Even in two areas where PJS is highly prevalent (TheNetherlands and Utah), researchers were not even close toreaching enough patients to perform a trial. Also, extensiveaccrual efforts, including the provision of additional trialinformation in national medical journals and during twopatient information days in the accrual period, did not leadto increased patient participation. We presume that thecurrently existing intense surveillance programs do alreadydiminish the rate of symptomatic polyps and malignanciesand, therefore, are considered by patients to be efficacious,which probably hampers the willingness of these patientsto enroll in chemoprevention treatment studies. In addi-tion, everolimus often induces cumbersome side effects,which further decreases long-term use in prevention.Furthermore, the need for dose reduction in both TheNetherlands and Utah confirmed the poor tolerability ofeverolimus therapy. Therefore, it is not surprising that bothexperiences raise the question of whether use of this drugfor chemoprevention in PJS patients is feasible. Potentialfuture options are a lower dose of everolimus, or anothertargeted agent.TRIAL INFORMATIONDisease Advanced cancerDisease Peutz-Jeghers syndromeStage of Disease/Treatment PreventionPrior Therapy NoneType of Study - 1 Phase IIType of Study - 2 Single armPrimary Endpoint Overall response rateSecondary Endpoint ToxicityInvestigator’s Analysis Poorly tolerated/not feasibleDRUG INFORMATION FOR PHASE II ADVANCED MALIGNANCIESDrug 1Generic/Working Name EverolimusTrade Name AfinitorCompany Name NovartisDose 10 mg per flat doseRoute p.o.PATIENT CHARACTERISTICS FOR PHASE II ADVANCED MALIGNANCIESNumber of Patients, Male 1Number of Patients, Female 0Age Median (range): 48Number of Prior Systemic Therapies Median (range): 0Performance Status: ECOG 0 — 11 — 02 — 03 — 0Unknown —Figure 1. A Peutz-Jeghers polyp of the small intestine with arboriz-ing smooth muscle fibers and non-neoplastic epithelium.400 EVAMPOc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from PATIENT CHARACTERISTICS FOR PHASE II HIGH-RISK POLYPSNumber of Patients, Male 1Number of Patients, Female 0Age Median (range): 53Number of Prior Systemic Therapies Median (range): 0Performance Status: ECOG 0 — 01 — 12 — 03 — 0Unknown —PRIMARYASSESSMENT METHOD FOR PHASE II ADVANCED MALIGNANCIESTitle Total patient populationNumber of Patients Screened 1Number of Patients Enrolled 1Number of Patients Evaluable for Toxicity 1Number of Patients Evaluated for Efficacy 0Evaluation Method RECIST 1.1Response Assessment PD n 5 1 (100%)(Median) Duration Assessments PFS 7 weeks(Median) Duration Assessments TTP 7 weeks(Median) Duration Assessments OS 6 months(Median) Duration Assessments Duration of Treatment 7 weeksPRIMARYASSESSMENT METHOD FOR PHASE II HIGH-RISK POLYPSTitle Total patient populationNumber of Patients Screened 1Number of Patients Enrolled 1Number of Patients Evaluable for Toxicity 1Number of Patients Evaluated for Efficacy 1Evaluation Method RECIST 1.1Response Assessment SD n 5 1 (100%)(Median) Duration Assessments PFS 8 months(Median) Duration Assessments Response Duration 8 months(Median) Duration Assessments Duration of Treatment 4 monthsAdverse Events: Phase II Advanced Malignancies NoneAdverse Events: Phase II High-Risk Polyps Root cavity inflammation, three timesASSESSMENT, ANALYSIS, AND DISCUSSIONCompletion Study terminated before completionTerminated Reason Did not fully accrueInvestigator’s Assessment Poorly tolerated/not feasibleMutation spectrum: Peutz-Jeghers syndrome (PJS) is anautosomal dominant condition characterized by multiplehamartomatous polyps of the gastrointestinal tract, the pres-ence of mucocutaneous hyperpigmentation, and an elevatedlifetime risk to develop cancer, varying between 37% and 93%[1]. The genetic abnormality responsible for the syndrome is amutation in the LKB1/STK11 gene, which maps to 19p13 [2].This LKB1/STK11 gene activates adenine monophosphate-activated protein kinase, a necessary element in cell metabo-lism that is required for maintaining energy homeostasis, whichin turn activates tumor suppressors tuberous sclerosis complex1 and 2, leading to mammalian target of rapamycin (mTOR)inhibition. Two well-characterized downstream targets of mTORare S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1. In genetic analysis of PJS families, around 150different mutations in the LKB1 gene have been found, rangingde Brabander, Eskens, Korsee et al. e31www.TheOncologist.com Oc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from from truncation to missense mutations [3, 4]. The kind of muta-tion does not clearly correlate with the disease course, althoughloss of heterozygosity is observed more frequently in PJS carcino-mas than in PJS hamartomas. No data on specific LKB1 mutationsand the sensitivity tomTOR inhibition is available.Suitability of everolimus: Elevated levels of phospho-S6(pS6) kinase and pS6 are detected in the polyps from LKB1 1/2 mice, suggesting that hyperactivation of mTOR signalingaccounts for the development of the PJS-characteristic hamar-tomatous lesions. These observations suggested that mTORinhibitors such as rapamycin and its analogues could be usefulfor the treatment of polyps arising from patients with PJS. Weiet al. investigated in 2008 the benefit of mTOR inhibition in thedevelopment of polyps in PJS mice [5]. During this trial, rapamy-cin was given in LKB1 1/2 mice at 9 months of age (after theonset of polyposis) at the dose of 2 mg/kg per day for a 2-month period.The efficacy of rapamycin was assessed by meas-uring polyp sizes and tumor burden. It was found that rapamy-cin effectively suppresses PJS polyposis in a mouse model,suggesting that mTOR inhibitors may represent a new targetedtherapy for the treatment of PJS.Shackelford et al. analyzed 11-month-old LKB1 1/1 andLKB1 1/2 mice by fludeoxyglucose (FDG)-positron emissiontomography (PET) to scan for the presence of gastrointestinal(GI) polyps [6]. Images showed increased FDG uptake in focalmasses located in the LKB1 1/2 mice where the stomach andpylorus are located, whereas the LKB1 1/1 were negative(p 5 .06) for FDG signal in this area. Several of the LKB1 1/2mice were killed after imaging, and it was confirmed that theseanimals had large polyps in the pylorus and stomach corre-sponding exactly to the regions of greatest FDG uptake. Treat-ment of animals with rapamycin for 4 weeks abolished theFDG-PET signal. Immediate autopsy of the animals imaged byFDG-PET revealed that the rapamycin-treated mice had mini-mal detectable GI polyps, whereas the vehicle-treated mice allexhibited the presence of large GI polyps. These results suggestthat rapamycin reverses polyp growth in LKB1 1/2 mice.Our study is based on the observation by Franz et al. thatrapamycin, U.S. Food and Drug Administration approved foruse in orthotopic transplant recipients, was successfully used inan off-label study of five individuals with tuberous sclerosis [7].This disease, which is related to PJS, is caused by germlinemutations in the tuberous sclerosis complex 1 or 2, down-stream of LKB1, also leading to aberrant mTOR activation. All ofthe patients in this study had subependymal giant cell astrocy-tomas, which exhibited regression and necrosis on well-tolerated treatment with oral rapamycin. Faivre et al. suggestedin 2006 the benefit of mTOR inhibitors in the treatment ofpatients with PJS [8]. In a recent case of a patient with PJS suf-fering from advanced pancreatic cancer, we observed animpressive response to oral treatment with everolimus mono-therapy [9]. Therefore, mTOR inhibition might be a potentialanticancer treatment in Peutz-Jeghers-related malignanciesand needs confirmation in a larger patient cohort.Toxicity: Several trials with everolimus have already been per-formed. Yee et al. performed a phase I/II study with everolimus10 mg daily in hematological malignancies and observed the fol-lowing adverse events in more than 15% of the patients, indescending order of frequency: anorexia, oral aphthous ulcers,diarrhea, fatigue, dermatologic, dysgeusia, constipation, andcramps [10]. Blood tests also showed hyperglycemia, hyperlipid-emia, elevated hepatic parameters, hypophosphatemia, hypo-magnesemia, and hypocalcemia in more than 15% of thepatients. Motzer et al. executed a phase III trial in patients withrenal-cell cancer [11]. Stomatitis, rash, fatigue, asthenia, diarrhea,and anorexia occurred in more than 15% of the participants,using 10 mg everolimus per day. Most of the aforementionedadverse events are grade 1 or 2. Toxicities of grade 3 and 4 arerare, with stomatitis and fatigue in less than 10%. In the latterstudy, everolimus toxicity led to treatment discontinuation for10% of the patients. Furthermore, 34% of the patients required adose interruption and 5% had a dose reduction.Chemoprevention: The use of chemoprophylaxis is not anew phenomenon. The ability to prevent cancer has been dem-onstrated before, and some agents are already administratedfor cancer prevention in clinical practice, with aspirin as thebest-known example. Low-dose aspirin is proven to be success-ful in reducing cancer incidence by about 10% in men and 7%in women [12]. Because the side-effect profile is favorable, thebenefits of aspirin treatment outweigh the adverse events inpatients without risk factors for gastrointestinal bleeding.Another chemoprophylactic drug used is tamoxifen, which iseffective against breast cancer [12]. Serious adverse eventssuch as endometrial cancer and venous thromboembolism arerare, making this drug suitable for therapeutic prevention inpatients with an elevated breast cancer risk.In the setting of a preventive intervention with potentialsevere adverse events, the selection of high-risk patients isessential. The presence of a mutation resulting in an enhancedcancer risk might be a suitable target for chemoprevention.Squarize et al. investigated the use of a chemopreventive agenttargeting a directly associated mutation, a situation comparableto the one in our trial [13]. The administration of rapamycin inmice with the Cowden’s disease mutation resulted in adecrease of tumor growth and prolonged survival. A chemopre-vention trial on patients with PJS, executed in 2011, did notlead to statistical analysis due to insufficient polyp burden andpoor accrual [14].DISCLOSURESEvelien Dekker: FujiFilm, Tillots (C/A); FujiFilm (RF); Olympus: Other[endoscopic equipment loan]. The other authors indicated no financialrelationships.(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Experttestimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory boardREFERENCES1. van Lier MG, Wagner A, Mathus-Vliegen EMet al., High cancer risk in Peutz-Jeghers syndrome: Asystematic review and surveillance recommenda-tions. Am J Gastroenterol 2010;105:1258–1264;author reply 1265.2. Jenne DE, Reimann H, Nezu J et al. Peutz-Jeghers syndrome is caused by mutations in anovel serine threonine kinase. Nat Genet 1998;18:38–43.3. Korsse SE, Peppelenbosch MP, van Veelen W.Targeting LKB1 signaling in cancer. Biochim BiophysActa 2013;1835:194–210.4. van Veelen W, Korsse SE, van de Laar Let al. The long and winding road to rationaltreatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 2011;30:2289–2303.5. Wei C, Amos CI, Zhang N et al. Suppression ofPeutz-Jeghers polyposis by targeting mammaliantarget of rapamycin signaling. Clin Cancer Res 2008;14:1167–1171.e32 EVAMPOc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from 6. Shackelford DB, Vasquez DS, Corbeil J et al.mTOR and HIF-1alpha-mediated tumor metabolismin an LKB1mousemodel of Peutz-Jeghers syndrome.Proc Natl Acad Sci U S A 2009;106:11137–11142.7. Franz DN, Leonard J, Tudor C et al.Rapamycin causes regression of astrocytomasin tuberous sclerosis complex. Ann Neurol2006;59:490–498.8. Faivre S, Kroemer G, Raymond E. Current devel-opment of mTOR inhibitors as anticancer agents.Nat Rev Drug Discov 2006;5:671–688.9. Klumpen HJ, Queiroz KC, Spek CA et al. mTORinhibitor treatment of pancreatic cancer in a patientwith Peutz-Jeghers syndrome. J Clin Oncol 2011;29:e150–e153.10. Yee KW, Schittenhelm M, O’Farrell AM et al.Synergistic effect of SU11248 with cytarabine ordaunorubicin on FLT3 ITD-positive leukemic cells.Blood 2004;104:4202–4209.11. Motzer RJ, Escudier B, Oudard S et al.Efficacy of everolimus in advanced renalcell carcinoma: A double-blind, randomised,placebo-controlled phase III trial. Lancet 2008;372:449–456.12. Cuzick J. Preventive therapy for cancer. LancetOncol 2017;18:e472–e482.13. Squarize CH, Castilho RM, Gutkind JS. Chemo-prevention and treatment of experimental Cowden’sdisease by mTOR inhibition with rapamycin. CancerRes 2008;68:7066–7072.14. Kuwada SK, Burt R. A rationale for mTOR inhibi-tors as chemoprevention agents in Peutz-Jegherssyndrome. Fam Cancer 2011;10:469–472.Click here to access other published clinical trials.de Brabander, Eskens, Korsee et al. e33www.TheOncologist.com Oc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from 

English

Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized. Conclusion: Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention

Erasmus University Digital Repository

Chemoprevention in Patients with Peutz-Jeghers Syndrome:Lessons LearnedJUSTIN DE BRABANDER,a FERRY A.L.M. ESKENS,b SUSANNE E. KORSSE,c EVELIEN DEKKER,d PIETER DEWINT,g MONIQUE E. VAN LEERDAM,hSUSANNE VAN EEDEN,e HEINZ-JOSEF KLU¨MPENfaUniversity of Amsterdam, Amsterdam, The Netherlands; bDepartment of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, TheNetherlands; cDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; dDepartmentof Gastroenterology and Hepatology, eDepartment of Pathology, and fDepartment of Medical Oncology, Cancer Center Amsterdam,Academic Medical Center, Amsterdam, The Netherlands; gDepartment of Gastroenterology and Hepatology, Maria Middelares Hospital,Gent, Belgium; hDepartment of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The NetherlandsTRIAL INFORMATION• ClinicalTrials.gov Identifier: NCT01178151• Sponsor(s): Novartis• Principal Investigator: H.J. Kl€umpen• IRB Approved: YesLESSONS LEARNED• Motivating patients to enroll in chemopreventive studies is challenging.• Chemoprevention with toxic drugs is not feasible.ABSTRACTBackground. LKB1 mutations are the underlying geneticabnormality causing Peutz-Jeghers syndrome (PJS) and are apotential target for everolimus. In this phase II study, the efﬁcacyof everolimus on polyp and tumor growth in PJS patients wasinvestigated.Methods. Adult patients with a proven LKB1 mutation and whowere suitable for everolimus treatment were included in twodifferent PJS cohorts: (a) patients with unresectable malignan-cies and (b) patients with high-risk polyps. Treatment in bothgroups was oral everolimus, 10 mg daily. Response rates wereprimary endpoints for both cohorts.Results. Between October 2011 and April 2016, only twopatients were enrolled, one in each cohort. A 49-year-oldpatient with advanced pancreatic cancer in cohort 1 wasprogressive after 2 months. A 52-year-old male patient incohort 2 experienced severe toxicity and refused treatmentafter 4 months, even though endoscopy suggested stabili-zation of polyps. Adverse events included dental inﬂamma-tions, mucositis, and rash. In 2016, the trial was abortedfor lack of accrual, despite extensive accrual efforts in anarea where PJS is highly prevalent and care is highlycentralized.Conclusion. Due to accrual problems, no conclusions can bedrawn about the value of everolimus in PJS treatment, ques-tioning the feasibility of this agent for chemoprevention. TheOncologist 2018;23:399–e33DISCUSSIONPeutz-Jeghers syndrome is caused by a mutation in the LKB1gene, a tumor suppressor gene located on chromosome 19.This mutation results in a decreased inhibition of mammaliantarget of rapamycin (mTOR), with uncontrolled cell growth as aresult, manifesting as intestinal polyps (Fig. 1) and malignan-cies. Oral selective mTOR inhibitors such as rapamycin andeverolimus have been successfully used in several exploratorystudies [1, 2]. The report of a successful treatment of a PJSpatient with pancreatic cancer with everolimus was the startingpoint for a more comprehensive study: the EVAMP trial [3].Our hypothesis was that treating PJS patients with everolimuswould result in reduced growth of intestinal polyps and tumors.In 2011, researchers from the University of Utah initiated a sim-ilar study on the role of chemoprevention agents in PJS, whichwas stopped prematurely because of poor accrual [4].Due to the rare nature of the disease, the intent was to startwith a pilot study including 15 patients, executed in the two larg-est PJS centers in The Netherlands (Academic Medical Center,Amsterdam, and Erasmus Medical Center, Rotterdam). To obtainrelevant information about activity of everolimus, we selected ahigh-risk population consisting of patients with either fast-growinggastric or small bowel polyps requiring therapeutic enteroscopy atleast once every 2 years with resection of >4 polyps larger than15mm, or patients suffering from PJS-related malignancies.Correspondence: Dr. Heinz-Josef Kl€umpen, Department of Medical Oncology, Academic Medical Center, Cancer Center Amsterdam, Meibergdreef9, 1105AZ, Amsterdam, The Netherlands. Telephone: 3-120-566-5955; e-mail: h.klumpen@amc.uva.nl Received September 4, 2017; accepted forpublication December 3, 2017; published Online First on January 25, 2018.Oc AlphaMed Press; the data published online to support this summaryis the property of the authors. http://dx.doi.org/10.1634/theoncologist.2017-0682TheOncologist 2018;23:399–e33 www.TheOncologist.com Oc AlphaMed Press 2018Clinical Trial Results by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from Despite the clear study design, the selection of high-riskpatients, and well-targeted medication, our study metsome major obstacles. First, it turned out to be very difﬁcultto ﬁnd enough relevant patients, and secondly, the chosentreatment turned out to have both poor tolerability and(although in only one patient) a disappointing lack of efﬁ-cacy. Even in two areas where PJS is highly prevalent (TheNetherlands and Utah), researchers were not even close toreaching enough patients to perform a trial. Also, extensiveaccrual efforts, including the provision of additional trialinformation in national medical journals and during twopatient information days in the accrual period, did not leadto increased patient participation. We presume that thecurrently existing intense surveillance programs do alreadydiminish the rate of symptomatic polyps and malignanciesand, therefore, are considered by patients to be efﬁcacious,which probably hampers the willingness of these patientsto enroll in chemoprevention treatment studies. In addi-tion, everolimus often induces cumbersome side effects,which further decreases long-term use in prevention.Furthermore, the need for dose reduction in both TheNetherlands and Utah conﬁrmed the poor tolerability ofeverolimus therapy. Therefore, it is not surprising that bothexperiences raise the question of whether use of this drugfor chemoprevention in PJS patients is feasible. Potentialfuture options are a lower dose of everolimus, or anothertargeted agent.TRIAL INFORMATIONDisease Advanced cancerDisease Peutz-Jeghers syndromeStage of Disease/Treatment PreventionPrior Therapy NoneType of Study - 1 Phase IIType of Study - 2 Single armPrimary Endpoint Overall response rateSecondary Endpoint ToxicityInvestigator’s Analysis Poorly tolerated/not feasibleDRUG INFORMATION FOR PHASE II ADVANCED MALIGNANCIESDrug 1Generic/Working Name EverolimusTrade Name AﬁnitorCompany Name NovartisDose 10 mg per ﬂat doseRoute p.o.PATIENT CHARACTERISTICS FOR PHASE II ADVANCED MALIGNANCIESNumber of Patients, Male 1Number of Patients, Female 0Age Median (range): 48Number of Prior Systemic Therapies Median (range): 0Performance Status: ECOG 0 — 11 — 02 — 03 — 0Unknown —Figure 1. A Peutz-Jeghers polyp of the small intestine with arboriz-ing smooth muscle ﬁbers and non-neoplastic epithelium.400 EVAMPOc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from PATIENT CHARACTERISTICS FOR PHASE II HIGH-RISK POLYPSNumber of Patients, Male 1Number of Patients, Female 0Age Median (range): 53Number of Prior Systemic Therapies Median (range): 0Performance Status: ECOG 0 — 01 — 12 — 03 — 0Unknown —PRIMARYASSESSMENT METHOD FOR PHASE II ADVANCED MALIGNANCIESTitle Total patient populationNumber of Patients Screened 1Number of Patients Enrolled 1Number of Patients Evaluable for Toxicity 1Number of Patients Evaluated for Efﬁcacy 0Evaluation Method RECIST 1.1Response Assessment PD n5 1 (100%)(Median) Duration Assessments PFS 7 weeks(Median) Duration Assessments TTP 7 weeks(Median) Duration Assessments OS 6 months(Median) Duration Assessments Duration of Treatment 7 weeksPRIMARYASSESSMENT METHOD FOR PHASE II HIGH-RISK POLYPSTitle Total patient populationNumber of Patients Screened 1Number of Patients Enrolled 1Number of Patients Evaluable for Toxicity 1Number of Patients Evaluated for Efﬁcacy 1Evaluation Method RECIST 1.1Response Assessment SD n5 1 (100%)(Median) Duration Assessments PFS 8 months(Median) Duration Assessments Response Duration 8 months(Median) Duration Assessments Duration of Treatment 4 monthsAdverse Events: Phase II Advanced Malignancies NoneAdverse Events: Phase II High-Risk Polyps Root cavity inﬂammation, three timesASSESSMENT, ANALYSIS, AND DISCUSSIONCompletion Study terminated before completionTerminated Reason Did not fully accrueInvestigator’s Assessment Poorly tolerated/not feasibleMutation spectrum: Peutz-Jeghers syndrome (PJS) is anautosomal dominant condition characterized by multiplehamartomatous polyps of the gastrointestinal tract, the pres-ence of mucocutaneous hyperpigmentation, and an elevatedlifetime risk to develop cancer, varying between 37% and 93%[1]. The genetic abnormality responsible for the syndrome is amutation in the LKB1/STK11 gene, which maps to 19p13 [2].This LKB1/STK11 gene activates adenine monophosphate-activated protein kinase, a necessary element in cell metabo-lism that is required for maintaining energy homeostasis, whichin turn activates tumor suppressors tuberous sclerosis complex1 and 2, leading to mammalian target of rapamycin (mTOR)inhibition. Two well-characterized downstream targets of mTORare S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1. In genetic analysis of PJS families, around 150different mutations in the LKB1 gene have been found, rangingde Brabander, Eskens, Korsee et al. e31www.TheOncologist.com Oc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from from truncation to missense mutations [3, 4]. The kind of muta-tion does not clearly correlate with the disease course, althoughloss of heterozygosity is observed more frequently in PJS carcino-mas than in PJS hamartomas. No data on speciﬁc LKB1 mutationsand the sensitivity tomTOR inhibition is available.Suitability of everolimus: Elevated levels of phospho-S6(pS6) kinase and pS6 are detected in the polyps from LKB1 1/2 mice, suggesting that hyperactivation of mTOR signalingaccounts for the development of the PJS-characteristic hamar-tomatous lesions. These observations suggested that mTORinhibitors such as rapamycin and its analogues could be usefulfor the treatment of polyps arising from patients with PJS. Weiet al. investigated in 2008 the beneﬁt of mTOR inhibition in thedevelopment of polyps in PJS mice [5]. During this trial, rapamy-cin was given in LKB1 1/2 mice at 9 months of age (after theonset of polyposis) at the dose of 2 mg/kg per day for a 2-month period.The efﬁcacy of rapamycin was assessed by meas-uring polyp sizes and tumor burden. It was found that rapamy-cin effectively suppresses PJS polyposis in a mouse model,suggesting that mTOR inhibitors may represent a new targetedtherapy for the treatment of PJS.Shackelford et al. analyzed 11-month-old LKB1 1/1 andLKB1 1/2 mice by ﬂudeoxyglucose (FDG)-positron emissiontomography (PET) to scan for the presence of gastrointestinal(GI) polyps [6]. Images showed increased FDG uptake in focalmasses located in the LKB11/2 mice where the stomach andpylorus are located, whereas the LKB1 1/1 were negative(p5 .06) for FDG signal in this area. Several of the LKB1 1/2mice were killed after imaging, and it was conﬁrmed that theseanimals had large polyps in the pylorus and stomach corre-sponding exactly to the regions of greatest FDG uptake. Treat-ment of animals with rapamycin for 4 weeks abolished theFDG-PET signal. Immediate autopsy of the animals imaged byFDG-PET revealed that the rapamycin-treated mice had mini-mal detectable GI polyps, whereas the vehicle-treated mice allexhibited the presence of large GI polyps. These results suggestthat rapamycin reverses polyp growth in LKB11/2mice.Our study is based on the observation by Franz et al. thatrapamycin, U.S. Food and Drug Administration approved foruse in orthotopic transplant recipients, was successfully used inan off-label study of ﬁve individuals with tuberous sclerosis [7].This disease, which is related to PJS, is caused by germlinemutations in the tuberous sclerosis complex 1 or 2, down-stream of LKB1, also leading to aberrant mTOR activation. All ofthe patients in this study had subependymal giant cell astrocy-tomas, which exhibited regression and necrosis on well-tolerated treatment with oral rapamycin. Faivre et al. suggestedin 2006 the beneﬁt of mTOR inhibitors in the treatment ofpatients with PJS [8]. In a recent case of a patient with PJS suf-fering from advanced pancreatic cancer, we observed animpressive response to oral treatment with everolimus mono-therapy [9]. Therefore, mTOR inhibition might be a potentialanticancer treatment in Peutz-Jeghers-related malignanciesand needs conﬁrmation in a larger patient cohort.Toxicity: Several trials with everolimus have already been per-formed. Yee et al. performed a phase I/II study with everolimus10 mg daily in hematological malignancies and observed the fol-lowing adverse events in more than 15% of the patients, indescending order of frequency: anorexia, oral aphthous ulcers,diarrhea, fatigue, dermatologic, dysgeusia, constipation, andcramps [10]. Blood tests also showed hyperglycemia, hyperlipid-emia, elevated hepatic parameters, hypophosphatemia, hypo-magnesemia, and hypocalcemia in more than 15% of thepatients. Motzer et al. executed a phase III trial in patients withrenal-cell cancer [11]. Stomatitis, rash, fatigue, asthenia, diarrhea,and anorexia occurred in more than 15% of the participants,using 10 mg everolimus per day. Most of the aforementionedadverse events are grade 1 or 2. Toxicities of grade 3 and 4 arerare, with stomatitis and fatigue in less than 10%. In the latterstudy, everolimus toxicity led to treatment discontinuation for10% of the patients. Furthermore, 34% of the patients required adose interruption and 5% had a dose reduction.Chemoprevention: The use of chemoprophylaxis is not anew phenomenon. The ability to prevent cancer has been dem-onstrated before, and some agents are already administratedfor cancer prevention in clinical practice, with aspirin as thebest-known example. Low-dose aspirin is proven to be success-ful in reducing cancer incidence by about 10% in men and 7%in women [12]. Because the side-effect proﬁle is favorable, thebeneﬁts of aspirin treatment outweigh the adverse events inpatients without risk factors for gastrointestinal bleeding.Another chemoprophylactic drug used is tamoxifen, which iseffective against breast cancer [12]. Serious adverse eventssuch as endometrial cancer and venous thromboembolism arerare, making this drug suitable for therapeutic prevention inpatients with an elevated breast cancer risk.In the setting of a preventive intervention with potentialsevere adverse events, the selection of high-risk patients isessential. The presence of a mutation resulting in an enhancedcancer risk might be a suitable target for chemoprevention.Squarize et al. investigated the use of a chemopreventive agenttargeting a directly associated mutation, a situation comparableto the one in our trial [13]. The administration of rapamycin inmice with the Cowden’s disease mutation resulted in adecrease of tumor growth and prolonged survival. A chemopre-vention trial on patients with PJS, executed in 2011, did notlead to statistical analysis due to insufﬁcient polyp burden andpoor accrual [14].DISCLOSURESEvelien Dekker: FujiFilm, Tillots (C/A); FujiFilm (RF); Olympus: Other[endoscopic equipment loan]. The other authors indicated no ﬁnancialrelationships.(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Experttestimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientiﬁc advisory boardREFERENCES1. van Lier MG, Wagner A, Mathus-Vliegen EMet al., High cancer risk in Peutz-Jeghers syndrome: Asystematic review and surveillance recommenda-tions. Am J Gastroenterol 2010;105:1258–1264;author reply 1265.2. Jenne DE, Reimann H, Nezu J et al. Peutz-Jeghers syndrome is caused by mutations in anovel serine threonine kinase. Nat Genet 1998;18:38–43.3. Korsse SE, Peppelenbosch MP, van Veelen W.Targeting LKB1 signaling in cancer. Biochim BiophysActa 2013;1835:194–210.4. van Veelen W, Korsse SE, van de Laar Let al. The long and winding road to rationaltreatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 2011;30:2289–2303.5. Wei C, Amos CI, Zhang N et al. Suppression ofPeutz-Jeghers polyposis by targeting mammaliantarget of rapamycin signaling. Clin Cancer Res 2008;14:1167–1171.e32 EVAMPOc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from 6. Shackelford DB, Vasquez DS, Corbeil J et al.mTOR and HIF-1alpha-mediated tumor metabolismin an LKB1mousemodel of Peutz-Jeghers syndrome.Proc Natl Acad Sci U S A 2009;106:11137–11142.7. Franz DN, Leonard J, Tudor C et al.Rapamycin causes regression of astrocytomasin tuberous sclerosis complex. Ann Neurol2006;59:490–498.8. Faivre S, Kroemer G, Raymond E. Current devel-opment of mTOR inhibitors as anticancer agents.Nat Rev Drug Discov 2006;5:671–688.9. Klumpen HJ, Queiroz KC, Spek CA et al. mTORinhibitor treatment of pancreatic cancer in a patientwith Peutz-Jeghers syndrome. J Clin Oncol 2011;29:e150–e153.10. Yee KW, Schittenhelm M, O’Farrell AM et al.Synergistic effect of SU11248 with cytarabine ordaunorubicin on FLT3 ITD-positive leukemic cells.Blood 2004;104:4202–4209.11. Motzer RJ, Escudier B, Oudard S et al.Efﬁcacy of everolimus in advanced renalcell carcinoma: A double-blind, randomised,placebo-controlled phase III trial. Lancet 2008;372:449–456.12. Cuzick J. Preventive therapy for cancer. LancetOncol 2017;18:e472–e482.13. Squarize CH, Castilho RM, Gutkind JS. Chemo-prevention and treatment of experimental Cowden’sdisease by mTOR inhibition with rapamycin. CancerRes 2008;68:7066–7072.14. Kuwada SK, Burt R. A rationale for mTOR inhibi-tors as chemoprevention agents in Peutz-Jegherssyndrome. Fam Cancer 2011;10:469–472.Click here to access other published clinical trials.de Brabander, Eskens, Korsee et al. e33www.TheOncologist.com Oc AlphaMed Press 2018 by guest on May 29, 2019http://theoncologist.alphamedpress.org/Downloaded from 

Abstract
               
                  Lessons Learned
                  Motivating patients to enroll in chemopreventive studies is challenging. Chemoprevention with toxic drugs is not feasible.
               
               
                  Background
                  LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated.
               
               
                  Methods
                  Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts.
               
               
                  Results
                  Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized.
               
               
                  Conclusion
                  Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.
               </jats:sec

Justin de Brabander

Ferry A.L.M. Eskens

Susanne E. Korsse

Evelien Dekker

Pieter Dewint

Monique E. van Leerdam

Susanne van Eeden

Heinz-Josef Klümpen

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The Oncologist

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Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible. LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized. Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemopreventio

Omineca Herald, May, 23, 1924

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