pan-Canadian Oncology Drug Review Final Clinical Guidance Report Arsenic Trioxide (Trisenox) for Acute Promyelocytic Leukemia February 18, 2014 DISCLAIMER Not a Substitute for Professional Advice This report is primarily intended to help Canadian health systems leaders and policymakers make well-informed decisions and thereby improve the quality of health care services. While patients and others may use this report, they are made available for informational and educational purposes only. This report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision making process, or as a substitute for professional medical advice. Liability pCODR does not assume any legal liability or responsibility for the accuracy, completeness or usefulness of any information, drugs, therapies, treatments, products, processes, or services disclosed. 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FUNDING The pan-Canadian Oncology Drug Review is funded collectively by the provinces and territories, with the exception of Quebec, which does not participate in pCODR at this time. pCODR Final Clinical Guidance Report - Arsenic Trioxide (Trisenox) for Acute Promyelocytic Leukemia pERC Meeting: January 16, 2014; Early Conversion: February 18, 2014 © 2013 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW ii INQUIRIES Inquiries and correspondence about the pan-Canadian Oncology Drug Review (pCODR) should be directed to: pan-Canadian Oncology Drug Review 1 University Avenue, suite 300 Toronto, ON M5J 2P1 Telephone: 416-673-8381 Fax: 416-915-9224 Email: [email protected] Website: www.pcodr.ca pCODR Final Clinical Guidance Report - Arsenic Trioxide (Trisenox) for Acute Promyelocytic Leukemia pERC Meeting: January 16, 2014; Early Conversion: February 18, 2014 © 2013 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW iii TABLE OF CONTENTS DISCLAIMER AND FUNDING .......................................................................................... ii INQUIRIES ............................................................................................................. iii TABLE OF CONTENTS ............................................................................................... iiv 1 GUIDANCE IN BRIEF ............................................................................................. 1 1.1. Background ................................................................................................ 1 1.2. Key Results and Interpretation ........................................................................ 1 1.3. Conclusions ................................................................................................ 4 2 CLINICAL GUIDANCE ............................................................................................ 6 2.1 Context for the Clinical Guidance ................................................................. 6 2.2 Interpretation and Guidance ...................................................................... 13 2.3 Conclusions ........................................................................................... 15 3 BACKGROUND CLINICAL INFORMATION .................................................................... 16 4 SUMMARY OF PATIENT ADVOCACY GROUP INPUT ....................................................... 19 5 SUMMARY OF PROVINCIAL ADVISORY GROUP (PAG) INPUT............................................. 24 6 SYSTEMATIC REVIEW .......................................................................................... 26 6.1 Objectives ............................................................................................. 26 6.2 Methods................................................................................................ 26 6.3 Results ................................................................................................. 29 6.4 Ongoing Trials ........................................................................................ 58 7 SUPPLEMENTAL QUESTIONS ................................................................................. 59 8 ABOUT THIS DOCUMENT ..................................................................................... 60 APPENDIX A: LITERATURE SEARCH STRATEGY ................................................................. 61 REFERENCES ......................................................................................................... 65 pCODR Final Clinical Guidance Report - Arsenic Trioxide (Trisenox) for Acute Promyelocytic Leukemia pERC Meeting: January 16, 2014; Early Conversion: February 18, 2014 © 2013 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW iv 1 GUIDANCE IN BRIEF 1.1 Background The purpose of this review is to evaluate the safety and efficacy of arsenic trioxide (ATO; Trisenox) as monotherapy or in combination with ATRA and/or other chemotherapy agents, on patient outcomes compared with appropriate comparators in treatment of patients with: • Previously untreated (first-line) Acute Promyelocytic Leukemia (APL). • Relapsed/Refractory Acute Promyelocytic Leukemia Currently ATO has a Health Canada approved indication for use in induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy and whose APL is characterized by presence of the t(15;17) translocation of PML/RAR-alpha gene expression 22. As per the Health Canada product monograph, induction treatment with ATO is administered intravenously at 0.15 mg/kg daily until bone marrow remission. Total dose should not exceed 60 doses and should be stopped at any time if substantial toxicity occurs. Consolidation treatment is given 3 to 6 weeks after completion of induction therapy, administered intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks. 1.2 Key Results and Interpretation 1.2.1 Systematic Review Evidence First Line setting Three randomized controlled trials met the eligibility criteria for this review. Lo-Coco 20131 evaluated the non-inferiority of ATO in combination with ATRA (n=77) in comparison to ATRA/chemotherapy (n=79) as an induction and consolidation treatment. Powell 20102 evaluated early stage consolidation with (n=244) or without ATO (n=237) monotherapy. Shen 20043 evaluated ATO (n=20), ATRA (n=20) and ATO/ATRA combination (n=21) as induction therapy. Most patient characteristics were well matched within and between trials in the Lo-Coco and Powell studies with no statistically significant differences in baseline characteristics between the study arms. However, the Powell study included low, intermediate and high risk patients as defined by their white blood cell counts while the Lo-Coco study included only low/intermediate risk patients. There were limitations in the Shen study in terms of the sample size, generalizability of the patient population, lack of information on the randomization and blinding and unclear reporting of results that created significant uncertainty in the comparability of Shen 2004 to the two other included studies. Relapsed/Refractory setting No randomized controlled trials comparing ATO with a relevant comparator were identified that met the eligibility criteria of this review. Eleven prospective studies were however identified and included in the systematic review, each incorporating ATO into the treatment of relapsed/refractory APL in different combinations with other agents and at different stages of treatment (e.g. induction, consolidation or both). One study (Wang 20044) included both a prospective arm (ATO monotherapy) arm and a comparative historical cohort (ATRA). One study (Raffoux 20035) was a randomized controlled trial that had ATO in both arms and thus did not pCODR Final Clinical Guidance Report - Arsenic Trioxide (Trisenox) for Acute Promyelocytic Leukemia pERC Meeting: January 16, 2014; Early Conversion: February 18, 2014 © 2013 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 1 provide an appropriate comparison but was considered as a prospective cohorts for the purpose of this review. The remaining 9 studies were single arm, non-randomized, non-comparative studies. (Alimoghaddam 20116, Lazo 20037, , Niu 19998, Shen 20019, Shen 199710, Shigeno 200511, Soignet 200112, Soignet 199813, Yanada 201314). In the Wang 2004 study some patients in the ATRA/ATO and ATO alone arm had received ATO containing treatment in the first line setting. In all other included relapsed/refractory studies, the previous first line treatment regimen of patients was either not reported or included an ATRA/chemotherapy containing regimen. There was variability among the eleven