First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus

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2 Modified Practice Guideline: Systemic Therapy Summary First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus (GENU-Temsirolimus) Effective: January 2009 Required Update: February 2014 Annual Review: February 2013 CCMB Electronic Posting Date:

3 Systemic Therapy Summary 2 ACKNOWLEDGEMENT AND SPONSORSHIP DISCLAIMERS Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 2

4 Systemic Therapy Summary 3 Introduction This document has been prepared by the Winnipeg Regional Health Authority/CancerCare Manitoba (WRHA/CCMB) Oncology Pharmacotherapeutic (P&T) Subcommittee s Systemic Therapy Summaries Working Group, as a means of disseminating drug information and formulary decisions made by the Subcommittee. The CCMB Provincial Pharmacy Program, Provincial Oncology Drug Program (PODP), and Clinical Practice Guidelines Initiative (CPGI) have contributed to the development of this summary. Systemic Therapy Summaries (STS) are being developed for drugs/or indications where clinical benefit has been accepted by the P&T Subcommittee, based on scientific data. All STS documents are approved by the P&T Subcommittee Chair and the CPGI Lead/Advisory Panel Chair. The content of this STS was in large part adapted from the Formulary Addition Request submitted to the P&T Subcommittee by the CCMB Gastro Intestinal (GI) Disease Site Group, May, This document will be reviewed, and updated as necessary, once in every twelve month period; unless emerging evidence from scientific research dictates otherwise. Purpose This document is intended as a guide to facilitate the safe and effective clinical use of temsirolimus in the firstline treatment of advanced renal cell carcinoma. For this purpose, it may be used by qualified and licensed healthcare practitioners involved with the care of oncology patients, which may include (but is not limited to): physicians, nurses, and pharmacists at CancerCare Manitoba, Community Cancer Programs Network (CCPN) sites, and WRHA Community Oncology Program sites. Disclaimer Use of this document should not preclude the practitioner s independent clinical judgment, nor should it replace consultation with the oncologist. It is the responsibility of the practitioner to develop an individualized treatment plan for each patient under his/her care, and ideally this should take place within the context of a multidisciplinary team. The unique needs and preferences of the patient and the family should always be reflected in the plan of care. This document is not a comprehensive drug monograph. Practitioners must refer to other sources for complete drug information. Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 3

5 Systemic Therapy Summary 4 First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus Protocol Code: GENU-Temsirolimus Developed by: Genitourinary (GENU) Systemic Therapy Group Date of Presentation to P&T Subcommittee: January 2009 Treatment Recommendation Temsirolimus is an option for the first line treatment of advanced renal cell carcinoma for patients who meet the inclusion criteria stated below. Treatment Intent Non curative Prolongation of overall survival and progression free survival Rationale Most cases of metastatic renal cell carcinoma cannot be cured. Interferon alfa and interleukin 2 have been the main treatments for metastatic renal cell carcinoma. These cytokines have limited efficacy, substantial toxicity, and minimal benefit in patients with extensive tumor burden and adverse prognostic factors. Temsirolimus, an mtor (mammalian target of rapamycin) inhibitor, has demonstrated a survival advantage in this high risk patient population. Clinical Benefit (Level 1 Evidence see Appendix I) Support for the use of temsirolimus in newly diagnosed advanced renal cell carcinoma comes from the Phase III Global Advanced Renal Cell Carcinoma (ARCC) trial (Hudes G, et al. 2007). The trial compared three arms of treatment in a patient population with poor prognosis disease (n= 626): temsirolimus alone, temsirolimus and interferon alfa, and interferon alfa alone. Eligibility criteria were restricted to patients with at least three of the following six predictors of short survival: a corrected serum calcium level of more than 2.5 mmol/l; a time from initial diagnosis to randomization of less than 1 year; a Karnofsky performance status score of 60 or 70; metastases in multiple organs; a serum lactate dehydrogenase (LDH) level of more than 1.5 times the upper limit Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 4

6 Systemic Therapy Summary 5 of the normal range; a hemoglobin level below the lower limit of the normal range. The primary endpoint of the study was overall survival. Patients who received temsirolimus alone had a longer median overall survival than interferon alone (10.9 months vs. 7.3 months; statistically significant). Progression free survival was also longer in the temsirolimus alone arm. The study results showed that the combination of temsirolimus and interferon did not improve survival. Patient Population and Selection Criteria Inclusion criteria (January 2009) This treatment may be offered to patients with advanced or metastatic renal cell carcinoma (both clear cell and non clear cell histology) with poor prognosis, defined as having at least 3 of the following 6 criteria (Hudes G, et al 2007): Serum LDH of more than 1.5 times the upper limit of normal range Corrected serum calcium level above the upper limit of normal range (greater than 2.6 mmol/l) Time from initial diagnosis of renal cell carcinoma to treatment of less than 1 year ECOG performance status score of 2 or lower (see Appendix II) Metastases in multiple organs Hemoglobin level below the lower limit of normal range Exclusion criteria (January 2009) Major surgery within the last 4 weeks Active brain metastases Fasting cholesterol level greater than 9.1 mmol/l Fasting triglyceride level greater than 4.5 mmol/l ECOG performance status 3 or greater Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 5

7 Systemic Therapy Summary 6 CCMB Formulary Status 1. Formulary definition Non Formulary* P&T Subcommittee Drug Approval Process Step 2a** * Case by case approval by the P&T Subcommittee Chair is required. A Non Formulary Drug Request Form must be completed. ** Clinical benefit accepted by the P&T Subcommittee based on scientific evidence. Cost effectiveness analysis demonstrates a potentially unacceptable cost effectiveness and/or budget impact. 2. Adjudication process Request form to use: Non Formulary Request Form 2008 update (J:\Forms\Pharmacy) Approval required by: P&T Subcommittee Chair 3. Restrictions Prescribing of temsirolimus should be first approved by the Genitourinary (GENU) Systemic Therapy Group. Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 6

8 Systemic Therapy Summary 7 Treatment Regimen GENU Temsirolimus 1 cycle = 4 weeks (planned treatment 6 cycles) Drug Dose CCMB Administrative Guideline Temsirolimus 25 mg once weekly IV in 250mL NS (non PVC bag) over 30 to 60 minutes (use non PVC tubing with in line filter) Supportive Care Medications Drug Dose CCMB Administrative Guideline Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 7

9 Systemic Therapy Summary 8 Clinical Monitoring and Follow-Up Recommendations Hematology and chemistry laboratory tests Before each dose: CBC (including platelets) At baseline and prior to each 4 week cycle: CBC, platelets, electrolytes, creatinine, BUN, serum glucose, calcium, phosphorus, AST, LDH, total bilirubin, alkaline phosphatase, total cholesterol, triglycerides Clinical toxicity assessment (Use CTCAE v.4.0, see Appendix III) Prior to each cycle: assess patient for signs and symptoms of hyperglycemia, bleeding, fluid retention, skin toxicity, infections, nausea & vomiting, mucositis, diarrhea Assessment of treatment response Clinical follow up with diagnostic imaging every 2 months. Treatment should continue until the patient is no longer benefiting clinically from therapy or unacceptable toxicity occurs. Common or Clinically Important Adverse Events* (Refer to individual drug monographs for full details of adverse events) Hyperglycemia Hyperglycemia was reported on at least one occasion, in over 82% of patients receiving temsirolimus. Approximately 16% of patients have a serum glucose level of greater than 13.9 mmol/l reported on one occasion. Hyperglycemia may necessitate dose modification and treatment with insulin. Hyperlipidemia Hypercholesterolemia and/or hypertriglyceridemia (total cholesterol greater than mmol/l and/or triglycerides greater than 5 times upper limit of normal) were present in approximately 45% of patients. Hematological toxicity Grade 3 or 4 anemia was reported in 20% of patients receiving temsirolimus weekly. Grade 3 or 4 leukopenia, neutropenia, and thrombocytopenia occurred in 1%, 5%, and 1% of patients respectively. Bleeding Bleeding events were observed in 25% of patients who received temsirolimus. The most common bleeding event was epistaxis (12% of patients). Most bleeding events were grade 1 or 2 and only 3% were grade 3 or 4. Other adverse effects Edema/peripheral (28%, severe 3%) Hematuria (31%, severe 1%) Proteinuria (36%, severe less than 1%) * See Appendix III CTCAE v.4.0 Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 8

10 Systemic Therapy Summary 9 Precautions Respiratory Cases of interstitial lung disease have occurred in patients who received temsirolimus. Patients should be followed closely for clinical respiratory symptoms. Caution is advised for the use of this drug in patients with significant lung dysfunction. Hypersensitivity reactions Hypersensitivity reactions, including anaphylactic reactions, have occurred with the administration of temsirolimus. Most reactions have occurred with initial dosing. Infections Temsirolimus may be immunosuppressive. Patients should be observed for Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 9

11 Systemic Therapy Summary 10 Dose Modifications Hepatic dysfunction Temsirolimus is mainly metabolized and excreted through the liver. Caution should be exercised and dose modifications considered in patients with moderate to severe hepatic impairment. Renal dysfunction A very small percentage of temsirolimus and its metabolites are excreted by the kidney. No data exist for temsirolimus in patients with moderate to severe kidney failure. Hematological toxicity Day 1 Blood Counts ANC greater than or equal to 1.0 x 10 9 /L and Platelets greater than or equal to 75 x 10 9 /L Dose 100% ANC less than 1.0 x 10 9 /L or Platelets less than 75 x 10 9 /L Hold until ANC greater than or equal to 1.0 x 10 9 /L and Platelets greater than or equal to 75 x 10 9 /L Reduce by 5 mg/week Non Hematological toxicity Grade of Temsirolimus related adverse events Grade % Dose Adjustments Intolerable Grade 2 Reduce by 5 mg/week Grade 3 or 4 Hold until recovered to grade 2 or lower AND Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 10

12 Systemic Therapy Summary 11 Drug Interactions Temsirolimus is metabolized primarily by cytochrome P450 3A4. Potential drug interactions with inducers or inhibitors must be considered. CYP3A4 inducers may decrease exposure of temsirolimus and its metabolite, sirolimus. CYP3A4 inhibitors may increase blood concentrations of temsirolimus and sirolimus. Temsirolimus in combination with sunitinib, gemcitabine or fluorouracil has been associated with serious adverse drug reactions. Fatal events have been seen when temsirolimus was combined with fluorouracil. Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 11

13 Systemic Therapy Summary 12 References 1. Hudes G., Carducci M., Tomczak P., et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal Cell Carcinoma. The New England Journal of Medicine. 356; 22 (May 31, 2007): Torisel (Temsirolimus) product monograph. Wyeth Canada. 19 July 2007 edition. Ministry of Health and Long Term Care. Government of Ontario. Joint Oncology Drug Review and CED Recommendations. 3. BCCA Cancer Agency. BCCA Protocol Summary for Therapy for Advanced Renal Cancer Using Temsirolimus. Accessed from website January 31, CancerCare Ontario. CCO Regimen Code: Temsirolimus and CCO Drug Monograph for Temirolimus. Accessed from website January 31, Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 12

14 Systemic Therapy Summary 13 CCMB Contributors Dr. Piotr Czaykowski, Medical Oncologist, Genitourinary Systemic Therapy Group Mr. Marc Geirnaert, BSc (Pharm), Genitourinary Systemic Therapy Group Ms. Kimberly Watkinson, BSc (Pharm), Provincial Oncology Drug Program Ms. Kristi Hofer, BSc (Pharm), Community Cancer Programs Network Contact Physician Dr. Piotr Czaykowski, Medical Oncologist, Genitourinary Systemic Therapy Group Approved By Dr. Sri Navaratnam, Medical Oncologist Chair, WRHA/CCMB Oncology Pharmacotherapeutic Subcommittee Dr. Piotr Czaykowski, Medical Oncologist Lead and Advisory Panel Chair, CCMB Clinical Practice Guidelines Initiative We gratefully acknowledge the support of CancerCare Manitoba, and the CancerCare Manitoba Foundation. The Provincial Oncology Clinical Practice Guidelines Initiative Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 13

15 Systemic Therapy Summary 14 Appendix I Levels of Evidence Ia Evidence obtained from meta analysis of randomised controlled trials Ib Evidence obtained from at least one randomised controlled trial IIa Evidence obtained from at least one well designed controlled study without randomisation IIb Evidence obtained from at least one other type of well designed, quasi experimental study III Evidence obtained from well designed, non experimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities British Committee for Standards in Haematology Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 14

16 Systemic Therapy Summary 15 Appendix II ECOG Performance Status Scale 0 Fully active, able to carry on all pre disease activities without restriction (Karnofsky ) 1 Restricted in physical strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework or office work (Karnofsky 70 80) 2 Ambulatory and capable of all self care but unable to carry out any work activities. Up and about greater than or equal to 50% of waking hours (Karnofsky 50 60) 3 Capable of only limited self care, confined to bed or chair greater than or equal to 50% of waking hours (Karnofsky 30 40) 4 Completely disabled, cannot carry on any self care, totally confined to bed or chair (Karnofsky 10 20) Oken MM, Creech RH, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5: , Eastern Cooperative Oncology Group Robert Comis M.D., Group Chair Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 15

17 Systemic Therapy Summary 16 Appendix III Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Publish Date: 18 May 2009 Grades Grade refers to the severity of the AE. The CTCAE displays grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. A semi colon indicates or within the description of the grade. A single dash ( ) indicates a grade is not available. Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for grade selection. Grade 5: Grade 5 (Death) is not appropriate for some AEs and therefore is not an option Activities of Daily Living (ADL): * Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. ** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. CTCAE document available at: Accessed 10 September 2010 Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 16

18 Systemic Therapy Summary 17 CancerCare Manitoba 675 McDermot Avenue Winnipeg, Manitoba, Canada R3E 0V9 CCMB STS: GENU Temsirolimus January 2009 Effective: January 2009 Approved: February 2013 CancerCare Manitoba, February All rights reserved. This material may be freely reproduced for educational and not for profit purposes. No reproduction by or for commercial organization, or for commercial purposes is allowed without written permission of CancerCare Manitoba. Effective: May 2012 Required Update: February 2014 Annual Review: February 2013 Approved: Ferbuary 2013 p. 17