Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med 2016;374: DOI: /NEJMoa

2 Supplement to: Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes

3 Clinical Development PKC412, Midostaurin Clinical Trial Protocol CPKC412D2201 A single arm, phase II, open-label study to determine the efficacy of 100mg twice daily oral dosing of Midostaurin administered to patients with Aggressive Systemic Mastocytosis or Mast Cell Leukemia +/- an Associated Hematological Clonal Non-Mast Cell Lineage Disease Authors: Heinemann H, Huntsman A, Yin O, Schimansky T, Lanza C Document type: Clinical Trial Protocol for Oncology EUDRACT number: Version number: 00 Development phase: II Document status: Final Release date: 17-Apr-2008 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

4 Novartis Confidential Page 2 Oncology Clinical Trial Protocol (Version No. 00) Table of contents Table of contents...2 List of Post-text supplements (PTS)...4 List of figures...4 List of tables...4 List of abbreviations...6 Oncology clinical study protocol summary Background Overview of Aggressive Systemic Mastocytosis and Mast Cell Leukemia Overview of midostaurin Study rationale/purpose Objectives Primary objectives Secondary objectives Exploratory objectives Study design Population Inclusion criteria Exclusion criteria Treatment Investigational drug Known undesirable effects of study drug/treatment How supplied Preparation and storage Treatment arms Patient numbering Treating the patient Study drug/study treatment Permitted study drug adjustments Other concomitant medications Study drug discontinuation Premature patient withdrawal Visit schedule and assessments Information to be collected on screening failures Patient demographics/other baseline characteristics Treatments...35 This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

5 Novartis Confidential Page 3 Oncology Clinical Trial Protocol (Version No. 00) 7.4 Efficacy Major Response Partial Response No Response Safety Adverse events Physical examination, height, weight, vital signs Performance status Laboratory evaluations Radiological examinations Patient-reported outcomes Pharmacokinetics Pharmacokinetic blood sample collection Pharmacokinetic urine sampling Analytical method Sample handling and shipment Biomarkers Special analyses Histopathology KIT mutational analysis Safety monitoring Serious adverse event reporting Pregnancies Data Monitoring Committee Data review and data management Site monitoring Data collection Database management and quality control Statistical methods and data analysis Populations for analysis Patient demographics/other baseline characteristics Treatments (study drug, concomitant therapies, compliance) Primary objective Primary endpoint Analysis of primary endpoint Statistical hypothesis, model, and method of analysis Handling of missing values/censoring/discontinuations...56 This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

6 Novartis Confidential Page 4 Oncology Clinical Trial Protocol (Version No. 00) 10.5 Secondary objectives Efficacy Duration of response Time to response Overall survival rate KIT mutational status Safety Exploratory/Supportive analyses Pharmacokinetics Patient-reported outcomes/ Quality of Life Clinical benefit All C-Findings combined Subgroup analyses Other analyses Interim analysis Sample size calculation Power for analysis of critical secondary variables Administrative procedures Protocol Adherence References (available upon request)...62 List of Post-text supplements (PTS) N/A List of figures Figure 5-1 Proposed Algorithm using WHO criteria...22 List of tables Table 5-1 ECOG Performance Status*...21 Table 6-1 CYP3A4/5 Inhibitors...29 Table 6-2 CYP3A4/5 Inducers...29 Table 7-1 Visit evaluation schedule...32 Table 7-2 Overview of Response Criteria*...37 Table 7-3 Definition of Responses in measurable C-Findings*...38 Table 7-4 Pharmacokinetic blood sampling schedule...44 This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

7 Novartis Confidential Page 5 Oncology Clinical Trial Protocol (Version No. 00) Table 7-5 Pharmacokinetic urine sampling schedule...45 Table 10-1 Acceptable combinations for initial and confirmed response...53 Table 10-2 PK parameters...58 This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

8 Novartis Confidential Page 6 Oncology Clinical Trial Protocol (Version No. 00) List of abbreviations AE AHNMD ALT AML ASM AST b.i.d. CF CEL CML CMML CRF CS&E CRD CRO CT ECG EOS HES ICH IEC i.v. IRB ISM MCL MRI o.d. p.o. REB SAE SOP SM SSM US adverse event associated hematological clonal non-mast cell lineage disease alanine aminotransferase/ glutamic pyruvic transaminase/gpt Acute Myeloid Leukemia Aggressive Systemic Mastocytosis aspartate aminotransferase/ glutamic oxaloacetic transaminase/got bis in diem/ twice a day C-Finding Chronic Eosinophilic Leukemia Chronic Myeloid/ Myelogenous Leukemia Chronic Myelomonocytic Leukemia Case Report/Record Form Clinical Safety and Epidemiology Clinical Research and Development Contract Research Organization Computed Tomography Electrocardiogram End of study Hypereosinophilic Syndrome International Conference on Harmonization Independent Ethics Committee intravenous(ly) Institutional Review Board Indolent Systemic Mastocytosis Mast Cell Leukemia Magnet Resonance Imaging omnia die/ once a day per os/ by mouth/ orally Research Ethics Board Serious Adverse Event Standard Operating Procedure Systemic Mastocytosis Smouldering Systemic Mastocytosis Ultrasound This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

9 Novartis Confidential Page 7 Oncology Clinical Trial Protocol (Version No. 00) Oncology clinical study protocol summary Investigational drug Protocol no. Study phase Study title Background Purpose/rationale Objectives PKC412, Midostaurin CPKC412D2201 Phase II A Single Arm, Phase II, Open-Label Study to Determine the Efficacy of 100mg Twice Daily Oral Dosing of Midostaurin Administered to Patients with Aggressive Systemic Mastocytosis or Mast Cell Leukemia +/- an Associated Hematological Clonal Non-Mast Cell Lineage Disease. Aggressive Systemic Mastocytosis (ASM) and Mast Cell Leukemia (MCL) are myeloproliferative neoplasms with limited treatment options and generally poor prognosis. At present, there is no approved standard treatment available to treat ASM or MCL beyond therapies limiting mediator related symptoms. Several cases have been described in the literature about treatment of advanced stages of SM with cytoreductive drugs such as Interferon- combined with or without prednisolone or with cladribine with variable response rates and accompanied with compliance limiting side effects (Hauswirth et al. 2004, Patnaik et al. 2007). There is no treatment available to reliably reduce the mast cell burden of ASM and MCL patients which is resulting in organ dysfunction, reduced quality of life and poor prognosis. In order to address this unmet medical need the purpose of this prospective multinational phase II study is to determine the efficacy and safety of midostaurin in patients with ASM or MCL with or without an Associated Hematological Clonal Non-Mast Cell Lineage Disease (AHNMD). Preclinical data have shown that midostaurin can block the growth of Ba/F3 cells transformed by the D816V KIT gene at a IC 50 of approximately 30 nm to 40 nm. A case of a patient with advanced mast cell leukemia treated with 100 mg b.i.d. midostaurin has been reported in which a partial response was observed within 3 months accompanied by a significant resolution of liver function abnormalities and a significant decline in the percentage of peripheral blood mast cells and serum histamine level (Gotlib et al. 2005). Preliminary results of an ongoing phase II trial in advanced systemic mastocytosis revealed high overall response rates of approximately 73 % (Gotlib et al. 2007) in 15 patients. Primary To determine the efficacy of midostaurin in patients with ASM or MCL with or without an AHNMD when administered orally at a dose of 100 mg b.i.d. continuously for 6 cycles (of 4 weeks each) as measured by overall response rate Secondary To evaluate the duration of response To evaluate the time to response To evaluate overall survival To evaluate the safety and tolerability of midostaurin in patients with aggressive systemic mastocytosis or mast cell leukemia (+/- an AHNMD) To characterize the KIT mutational status at baseline and after 6 cycles of therapy and evaluate potential associations with efficacy outcomes Exploratory This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

10 Novartis Confidential Page 8 Oncology Clinical Trial Protocol (Version No. 00) Endpoints (efficacy, safety) Study design Population Inclusion/ Exclusion criteria To explore the pharmacokinetic (PK) profile of midostaurin in patients with ASM or MCL (+/- an AHNMD) To explore potential correlations between improvements in quality of life and observed response rates To explore the clinical benefit as defined as the sum of all responses (MR and PR) plus stable disease (SD) To explore changes in all C-Findings combined, including non-measurable ones Primary Overall response rate (ORR) Secondary Duration of response Time to response Adverse event rate Overall survival (OS) KIT mutational status at diagnosis and after 6 cycles of therapy Exploratory PK QOL Clinical benefit Changes in all C-Findings combined This is a single arm, phase II study to determine the efficacy and safety of twice daily oral midostaurin in patients with aggressive systemic mastocytosis or mast cell leukemia (+/- an AHNMD). Patients will receive 100 mg b.i.d. midostaurin continuously. Patients will be allowed to receive midostaurin until progression of their disease, intolerable toxicity or withdrawal due to any cause whichever is earlier. This study is designed using an adapted Fleming two stage design. Forty patients will be enrolled in the first stage, and an additional 20 in the second stage. The analysis of the primary endpoint occurs after all patients still in the study have received 6 cycles of treatment or at an earlier time point if there is sufficient information to establish the response criteria for all patients. If a supportive analysis is performed on the stage 1 and stage 2 patients then this takes place when all stage 2 patients have had 12 cycles of treatment or else have shown progression, intolerable toxicity or withdrew due to any cause. When there is sufficient information available on the first stage data to determine the outcome using the Fleming decision rule criteria, the second stage enrollment can be triggered. Patients with aggressive systemic mastocytosis or mast cell leukemia, with or without an AHNMD (associated hematological clonal non-mast cell lineage disease) are eligible for this study. Patients must also fulfill all inclusion and exclusion criteria. Inclusion Aged >18 and 70 years of age Patient must give written informed consent ECOG performance status of 0-3 This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

11 Novartis Confidential Page 9 Oncology Clinical Trial Protocol (Version No. 00) Life expectancy > 12 weeks ECG QTc interval 450 ms Meeting the following laboratory values: AST and ALT 2.5 x Upper Limit of Normal (ULN), if caused by ASM/MCL 5 x ULN Serum Bilirubin 1.5 x ULN, if related to ASM/MCL 3 x ULN Serum Creatinine 2.0 mg/dl Diagnosed with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) according to the WHO criteria for SM plus the established criteria for ASM or MCL documented by: Diagnosis of SM will be based: either on the presence of one major plus at least one minor criterion, or of at least 3 minor criteria: Major criterion: Multifocal dense infiltrates of mast cells (>15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s). Minor criteria: >25% of all mast cells are atypical cells (type I or type II) on bone marrow smears or are spindle-shaped in mast cell infiltrates detected on sections of visceral organs c-kit point mutation at codon 816 in the bone marrow or another extracutaneous organ Mast cells in bone marrow or blood or another extracutaneous organ express CD2 or/and CD25 Baseline serum tryptase concentration > 20 ng/ml (in the case of an associated myeloid neoplasm, is not valid as an SM criterion) Additionally, patients with ASM and MCL also have to present with one or more of the following measurable C-Findings*: ANC<1.0 x 10 9 /L or Hgb < 10g/L or platelets <100 x10 9 /L Hepatomegaly with impaired liver function - i.e. elevated transaminases and/or bilirubin levels and/or hypoalbuminemia (with or without ascites or portal hypertension) Palpable splenomegaly with hypersplenism (e.g. as documented by thrombocytopenia i.e. platelets < 100,000/ µl) Malabsorption with hypoalbuminemia and/or significant weight loss defined as >10% weight loss over the last 6 months *Note: Patients presenting with only non-evaluable C-Findings such as skeletal lesions or hepatomegaly only with ascites or portal hypertension, are not permitted to be included into the study. C- Findings need to be documented to result from local aggressive mast cell infiltrates i.e., any other cause/disease must be ruled out For patients with MCL the following criterion has to be met (in addition to the SM and ASM criteria as mentioned above): Bone marrow aspirate smears show 20% or more immature mast cells Typically, there is also an elevated percentage of mast cells in the blood. This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

12 Novartis Confidential Page 10 Oncology Clinical Trial Protocol (Version No. 00) Patient numbering Exclusion Patients unwilling or unable to comply with the protocol. Any other concurrent severe known disease (except carcinoma in-situ) concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within previous 6 months and poorly controlled hypertension, chronic renal disease, or active uncontrolled infection) which could compromise participation in the study. Confirmed diagnosis of HIV infection or active viral hepatitis. Female patients who are pregnant or breast-feeding or adults of reproductive potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the study in both sexes for fertile patients. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of midostaurin. Women considered not of childbearing potential include any of the following: no menses for at least 2 years or menses within 2 years but amenorrheic for at least 6 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal postmenopausal range (according to definition of postmenopausal for laboratory used) or bilateral oophorectomy or radiation castration and amenorrheic for at least 6 months. Patients who have demonstrated relapse to more than two prior regimen of SM treatment - regardless of treatment regimen for supportive care (e.g. symptom limiting therapies). Patients who have received any investigational agent, chemotherapy, interferon-, or 2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to Day 1. Patients who have aggressive systemic mastocytosis with eosinophilia and known positivity for the FIP1L1-PDGFR fusion unless they have demonstrated relapse or disease progression on prior imatinib therapy. Patients on imatinib and known to be KIT D816V negative unless they have demonstrated relapse, resistance or intolerance to imatinib. Patients who have received any treatment of midostaurin prior to study entry. Patients who have received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment. Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1. Patients with any pulmonary infiltrate including those suspected to be of infectious origin. In particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray are not eligible until pulmonary infiltrates have completely resolved. Exception: Patients with ASM/MCL +/- AHNMD related pleural effusion as confirmed by the investigator are permitted to enter the study. There will be no IVRS. The patient number will be comprised of the 4-digit center number plus 5-digit individual patient number. This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

13 Novartis Confidential Page 11 Oncology Clinical Trial Protocol (Version No. 00) Investigational and control drugs Dose, regimen, treatment cycle Supply, preparation, and administration Visit schedule and assessments Efficacy assessment(s), Response criteria Phase II, single arm midostaurin in 25 mg capsules = study drug Midostaurin will be administered at a dose of 100 mg b.i.d. continuously in cycles of 4 weeks each, until disease progression, intolerable toxicity, or withdrawal due to any cause whichever is earlier. Study drug midostaurin will be provided as soft gelatin capsules in child resistant blisters and supplied as open-labeled bulk supply in packages with 8 blisters, each blister with eight capsules. Each capsule contains 25 mg midostaurin. Patient supplies will be dispensed accordingly at each visit. Midostaurin should be administered with water following breakfast and dinner. Prophylactic use of anti-emetic therapy is highly recommended. Study medication dispensing and returning to and from the patients must be recorded for each patient. Each patient will receive a Drug Compliance Log to ensure compliance and tracking of midostaurin doses. Please refer to visit schedule/ Table 7-1 Please refer to section 7.4. Overall response rate will consist of confirmed Major or Partial responses. Responses to be confirmed at least 4 weeks apart. Major Response Complete resolution of at least one C-Finding and no progression in other C- Findings with the following sub-classifications: Complete remission - disappearance of all mast cell infiltrates in affected organs, decrease of serum tryptase levels to < 20 ng/ml, and disappearance of SM-associated organomegaly. Incomplete remission - decrease in mast cell infiltrates in affected organs and/or substantial decrease (> 50%) of serum tryptase level from baseline and/or visible regression of organomegaly. Pure clinical response - no response in mast cell infiltrates, tryptase levels, organomegaly that would reach the score of a complete or incomplete remission (see above). Partial Response Incomplete regression of one or more C-Finding(s) without complete regression and without progress in other C-Findings. Good partial response - > 50% regression of one or more C-Findings and no progression in other C-Findings Minor response - 50% regression of one or more C-findings and no progression in other C-Findings No Response Stable disease - C-Finding parameters show constant range Progressive disease - one or more C-Findings show progression Special safety assessment(s) Patient reported outcomes An ECG must be performed within 14 days prior to day 1, on day 3, at the end of each cycle and at the time of study completion/ discontinuation. QOL will be assessed using the SF-12 in combination with the MSAS (Memorial Symptom Assessment Scale) to be completed once every cycle. This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

14 Novartis Confidential Page 12 Oncology Clinical Trial Protocol (Version No. 00) Pharmacokinetics Biomarker assessments Statistical methods and data analysis Blood samples for midostaurin pharmacokinetics will be collected at predose (0 hour), 1, 2, 3, 6, 9 and 12 hours post-dose on day 1, and then at pre-dose on day 3, 8, 15, 22 and 28 of cycle 1, day 15 and 28 of cycle 2, and then on day 28 of subsequent cycles. To explore the potential CYP3A4 induction by midostaurin, urinary ratio of 6ß-hydroxycortisol to cortisol will be measured and used as an in vivo marker for assessment of CYP3A4 activity. Morning spot urine samples will be collected prior to dosing on day 1, 3, 8, 15, 22 and 28 of cycle 1, day 15 and 28 of cycle 2, and then on day 28 of subsequent cycles. Histopathological features and KIT mutation (e.g. D816V) status will be determined and centrally reviewed on patient bone marrow and peripheral blood samples obtained at trial entry, and as specified in the visit schedule. Tryptase levels are being assessed at regular intervals during the study as defined by the assessment schedule. Please refer to visit schedule Table 7-1 and section 7.9. Following the intention-to-treat principle, all patients enrolled in the first stage who are not screen-failures will be included in the full analysis set. This is the primary efficacy analysis population for the first stage analysis. Demographic and baseline characteristics and all efficacy analyses will be based on the full analysis set. For analyses of safety measures, the safety analysis set is defined as patients who took at least one dose of midostaurin and with a valid post baseline safety assessment. The patient analysis set will be described regarding demographic characteristics and baseline disease characteristics, including summary of C-Findings. The stage one analysis occurs when all patients still in the study have received 6 cycles (of 4 weeks each) of treatment or at an earlier time point if there is sufficient information to establish the response assessment for all patients. If a confirmatory analysis is performed on the stage one and stage two patients it will occur when all stage two patients have received 6 cycles of treatment or at an earlier time point if there is sufficient information to establish the response assessment for all patients. If stage two patients are enrolled to support the positive results on the stage one patients the analysis will occur when all stage two patients have received 12 cycles of treatment or at an earlier time point if there is sufficient information to establish the response assessment for all patients. The primary analysis of the primary efficacy endpoint is overall response rate (ORR), based on confirmed responses, using established criteria (Valent et al 2003a) evaluated at the end of each of 6 consecutive cycles of 4 weeks each. All secondary efficacy endpoints will be evaluated on the complete set of data available at this time point. These include duration and time to response, overall survival, and KIT mutational status. Exploratory endpoints will include PK, quality of life, clinical benefit and change in all C-Findings combined. Safety findings will be summarized for the safety analysis set - AEs will be tabulated according to MedDRA primary SOC and within each SOC, by MedDRA preferred term. Specific AEs of interest will be defined and tabulated. Laboratory data will be summarized by shift tables of baseline This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

15 Novartis Confidential Page 13 Oncology Clinical Trial Protocol (Version No. 00) CTC grade by worst on-study CTC grade. Based on cases in the literature and on the preliminary results from an ongoing investigator-initiated study (2213), in which 11 of 15 patients with ASM achieved a major or good partial response we consider the proportion of responders under the null hypothesis is 0.30, and under the alternative, The trial has an adapted Fleming two stage design which allows rejection of the null hypothesis or alternative hypothesis on the stage one data. The first stage will enroll 40 patients and the second stage will enroll an additional 20 patients. If at the time of the analysis of the stage one patients at least 19 of the 40 patients enrolled are responders the null hypothesis H 0 : p 0.30 will be rejected. The analysis conducted at this stage will then be considered as the primary analysis for the primary efficacy end point. The study would still include a second stage but the analysis on the patients from both stages would then be a supportive analysis with the purpose to provide more information on safety and a more precise response estimate (point estimate + 95% CI). If at the time of analysis of stage one patients 14 or fewer of the 40 patients enrolled are responders the alternative hypothesis Ha: 0.50 will be rejected. The study would then terminate for futility. If at the time of the analysis of the 40 stage one patients the number of responders is between 15 and 18 inclusive the study would continue to enroll the stage two patients. If for the analysis of the primary endpoint on the 60 patients the number of responses is 27 or more, then the null hypothesis would be rejected. A nominal alpha-level of will be associated to this design using a one sided binomial exact test. The overall power for the design (probability of rejecting the null hypothesis at the end of stage one or stage two) is 84% with 68% power for rejecting the null hypothesis at the end of stage one. This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

16 Novartis Confidential Page 14 Oncology Clinical Trial Protocol (Version No. 00) 1 Background 1.1 Overview of Aggressive Systemic Mastocytosis and Mast Cell Leukemia Mastocytosis is a very heterogeneous disease of bone marrow origin and is characterized by abnormal growth and accumulation of mast cells in one or more organ systems. The current World Health Organization classification system for mast cell disease defines two major subgroups - cutaneous mastocytosis (CM) and systemic mastocytosis (SM) which are further divided into different disease variants (Vardiman et al. 2002, Valent et al. 2005, Valent et al. 2007). SM is a condition, defined by multifocal histological lesions in the bone marrow and other extracutaneous organs, together with cytological and biochemical signs of systemic disease (Valent et al 2005). SM can show either an indolent or an aggressive clinical course. Depending on the stage of the disease, infiltration of organs may occur with or without impairment of organ function and patients can shift from one category of mast cell disease into another. In all categories, mediator-related symptoms may occur and may represent a serious clinical problem. Infiltration of organs by mast cells may cause cytopenias, osteolysis, pathologic fractures, hepatosplenomegaly, lymphadenopathy, and malabsorption (Vardiman et al. 2002, Valent et al. 2005, Valent et al. 2007). The WHO classification divides SM into the following subvariants: (1) indolent systemic mastocytosis (ISM) including smouldering systemic mastocytosis (SSM), (2) SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD), (3) aggressive systemic mastocytosis (ASM), (4) mast cell leukemia (MCL) and (5) extracutaneous mastocytoma (MCS) (Valent 2001, Vardiman et al. 2002). Aggressive Systemic Mastocytosis (ASM) and Mast Cell Leukemia (MCL) are very rare, comprising only a small proportion of all SM cases. ASM is characterized by a pathologic infiltration of diverse organs by neoplastic mast cells, with resulting impairment of organfunction (bone marrow, liver, spleen, gastrointestinal tract, skeletal system). Respective clinical/laboratory findings are called C-Findings. In this context, mast cell infiltration with associated organomegaly only (B-Finding, as seen in SSM) but no sign of impaired organ function (organopathy) should not be regarded as C-Finding. However, when organopathy is accompanied by significantly impaired organ function the clinical finding is called C-Finding, provided that the organopathy can clearly be attributed to a local aggressive mast cell infiltrate i.e. other potential pathological causes can be excluded. In contrast to the indolent forms of SM in which the patients can stay for many years or even decades with good prognosis, patients with the aggressive form of SM or MCL have a poor prognosis and are candidates for cytoreductive or targeted therapy to limit organ infiltration and further organ damage (Valent et al. 2005, Valent et al. 2007, Horny et al. 2007). Some of the C-Findings are not readily accessible for measurement in order to evaluate a potential response to treatment in a more reproducible, unbiased manner. Therefore, patients to be included in this trial have to present with at least one measurable C-Finding at baseline which can quantitatively be evaluated for response in an unbiased way and only those This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

17 Novartis Confidential Page 15 Oncology Clinical Trial Protocol (Version No. 00) responses based on the specified C-Findings will be included in the overall response rate. As a consequence, the current trial will exclude patients who present with only those C-Findings which are not measurable in an unbiased way, such as hepatomegaly with only ascites and/or only portal hypertension and/or with only skeletal lesions such as osteolyses and/or severe osteoporosis with pathologic fractures. However, these C-Findings are generally listed in the literature as also being characteristic for ASM and MCL but they will not be included in the study efficacy evaluation. Never-the-less, these may still contribute to the mast cell disease symptoms of eligible patients and hence will also be assessed at baseline and during the study as applicable. In about 25-30% of SM patients, an associated hematological clonal non-mast cell lineage disease (AHNMD) is diagnosed. The subvariant categories of AHNMD include SM-AML (acute myeloid leukemia), SM-CMML (chronic myelomonocytic leukemia), and SM-CEL (chronic eosinophilic leukemia). Generally, separate treatment plans for the SM and the AHNMD should be established for these patients. Patients with CEL-associated SM carrying the FIPL1-PDGFR fusion gene are recommended to be treated with imatinib (Valent et al. 2007) and can be included into this study only if they have shown relapse or intolerable toxicity to imatinib-therapy. The most important growth factor seems to be stem cell factor (SCF) also termed mast cell growth factor or KIT ligand. SCF induces the development of mast cells from their uncommitted CD34+ progenitors. The effects of SCF on mast cells and mast cell progenitors are mediated through KIT, a tyrosine kinase receptor (for SCF) encoded by the KIT protooncogene. SCF and SCF-dependent activation of KIT are essential to the development and differentiation of mast cells. Gain-of-function mutations in the kinase domain of KIT are associated with enhanced growth of mast cells and their progenitors. Such mutations (particularly mutation Asp-816-Val or D816V) are frequently detected in patients with SM (Valent et al. 2005). Thus the D816V-mutated variant of KIT seems to be an attractive target of therapy. Specific gene defects are well recognized as the oncogenic factors in SM. The KIT D816V mutation expressed in neoplastic mast cells is by far the most common and is found in all variants of SM. Highly sensitive methods have detected that up to 93 % of patients with SM carry the D816V KIT mutation. Several other KIT gene defects have been identified in patients with mast cell disease, but likely represent each less than 5% of diagnosed patients (Sotlar et al. 2003, Garcia-Montero et al. 2006, Valent et al. 2005). Treatments for SM can be divided into two broad categories (1) those intended to control mast cell mediator-related symptoms (e.g. antihistamines, epinephrine, or corticosteroids) and (2) those intended to limit the MC burden (e.g. cytoreductive or targeted therapies). Due to the heterogeneous nature of the disease an individualized approach to the treatment strategy is indicated. To date, there is no approved standard therapy to treat SM available and there are only limited options for the treatment of ASM and MCL with the exception of imatinib being approved in the US in KIT D816V negative patients. Therefore, these patients are recommended to be treated with imatinib and should be refractory or develop progression or intolerable toxicity prior to enrolment into this trial. There have been several case reports of treatment with Interferon- (INF-) combined with or without prednisolone in patients with ASM. However, response rates were variable and usually short-lived and limited tolerability This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

18 Novartis Confidential Page 16 Oncology Clinical Trial Protocol (Version No. 00) led to early discontinuation of treatment in some cases (Hauswirth et al. 2004, Akin and Metcalfe 2004, Valent et al. 2007). Preclinical data revealed that midostaurin shows activity against neoplastic human mast cells carrying the D816V mutation (Growney et al. 2005, Gleixner et al. 2006). Additionally, treatment with oral midostaurin 100 mg b.i.d. has resulted in responses in a patient with mast cell leukemia who was D816V positive (Gotlib et al. 2005). Moreover, a high overall response rate of 73% was observed in an ongoing trial in patients with ASM (Gotlib et al. 2007) in which not all responding patients carried the D816V mutation. The aim of this study is to determine the efficacy and safety of midostaurin in patients with ASM or MCL with or without an associated hematological clonal non-mast cell lineage disease (AHNMD) independent of the mutational status of these patients, in order to target a group of patients reflecting a relatively wide spectrum of neoplastic mast cell proliferation. 1.2 Overview of midostaurin Midostaurin (PKC412) is an inhibitor of all major isoforms of protein kinase C (the major transducer of lipid second messengers and phorbol esters), the tyrosine kinase associated with the vascular endothelial growth factor (VEGF) receptor and most importantly of class III tyrosine protein kinases involved in hematopoiesis and leukemia such as FLT3. Midostaurin can also exert inhibitory activity on other mutated tyrosine kinases implicated in a variety of diseases, like KIT (systemic mast cell disease, gastrointestinal stromal tumors [GIST]), PDGFR (GIST) or FGFR1 (myeloproliferative disorder [MPD]). Midostaurin has shown strong inhibitory activity on neoplastic human mast cells carrying the KIT D816V mutation. Preclinical data has shown that midostaurin can block the growth of Ba/F3 cells transformed by the D816V c-kit gene at a 50% inhibitory concentration (IC 50 ) of approximately nm (Growney et al. 2005, Gleixner et al. 2006). Additionally, a case of a patient with advanced mast cell leukemia treated with 100 mg bid midostaurin has been reported in which a partial response was observed within 3 months accompanied by a significant resolution of liver function abnormalities and a significant decline in the percentage of peripheral blood mast cells and serum histamine levels (Gotlib et al. 2005). Preliminary data of an ongoing phase II trial in patients with advanced systemic mastocytosis treated with 100 mg b.i.d. midostaurin revealed high overall response rates of 73 % (Gotlib et al. 2007). However, the detected mutation rate of 60% for KIT D816V mutation-bearing patients was lower than the observed overall response rate and certain responding patients were confirmed not to carry the D816V mutation (Gotlib et al. 2007). Therefore, regardless of the relatively small sample size in that study, this appears suggestive of midostaurin efficacy also in patients not harboring the KIT D816V mutation. However, in line with the molecular basis for the majority of responses observed, independent of number of previous therapies, the current trial will allow patients who have shown relapses of up to two prior treatment regimen in order to limit the heterogeneity of the patient population while permitting the majority of patients with mast cell disease to enter the trial. In conclusion, midostaurin appears to be active in the treatment of patients with ASM and MCL, including patients who have the D816V mutation of KIT. However, it appears This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

19 Novartis Confidential Page 17 Oncology Clinical Trial Protocol (Version No. 00) justifiable to allow study participation for patients with ASM/MCL regardless of their KIT mutation status. The pharmacokinetics (PK) of midostaurin has been extensively studied, including the single dose PK and ADME studies in healthy subjects, and multiple doses PK studies in subjects with diabetes mellitus, solid tumors, progressive CLL or NHL, metastatic melanoma, Stage IIIb and IV non-small cell lung cancer, and AML. Following single oral administration, midostaurin is well absorbed with an estimated absorption of >90% in human subjects. The onset of absorption is rapid, with peak plasma concentrations occuring at 1-3 hours post-dose. Following multiple oral doses, concentrations of midostaurin accumulated significantly in the first 3-5 days, then declined with time until a steady state is reached. Such a time-dependent PK profile of midostaurin has been observed consistently in various studies. The exact mechanism for the declining concentration of midostaurin is unclear at present, but it is most likely due to auto-enzyme induction. Because midostaurin and its major metabolites are all highly bound to plasma proteins (including albumin and alpha-acid glycoprotein), a protein binding interaction between midostaurin and its metabolites could be an alternative mechanism for the observed time-dependent kinetics. Midostaurin is predominantly metabolized in the liver via cytochrome P4503A (CYP3A) isoenzymes to form two major active metabolites, CGP62221 (via O-demethylation) and CGP52421 (via hydroxylation) in human. The terminal elimination half-life was estimated to be 25 hours, 39 hours, and 16 to 31 days for midostaurin, CGP62221 and CGP52421, respectively, following a single oral dose of 50 mg [ 14 C] midostaurin in healthy subjects. Since midostaurin is potentially associated with auto-enzyme induction resulting in timedependent pharmacokinetics, the elimination half-life of midostaurin and its metabolites (CGP62221 and CGP52421) would be expected to be shorter at steady-state upon repeated dosing than those from a single dose. Midostaurin strongly binds to the plasma proteins (~95%). Fecal excretion is the major pathway for elimination of midostaurin and its metabolites, while urinary excretion is a very minor pathway (about 4% of the dose). Midostaurin exhibited moderate variability in its pharmacokinetics, with inter-subject variability (CV%) averaged 36.3% and 36.7% for the peak plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) respectively [Study C99-PKC- 001] [Study PKC412A2107]. As Midostaurin is primarily metabolized by the liver, patients with AST/ALT levels increased above 2.5 times the upper limit of normal (ULN) and patients with bilirubin levels increased above 1.5 times the ULN will be excluded from the study. However, patients with ASM/MCL frequently present with liver-impairment and two ASM/MCL patients with liver dysfunction have already been treated with midostaurin which led to a significant improvement of their hepatic symptoms. Therefore, the trial will include patients who present with AST/ALT up to 5 times the ULN or with bilirubin up to 3 times the ULN if these are documented to be caused by their ASM/MCL disease. Please also refer to the Investigator Brochure and to section for additional information and for undesirable effects. This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST

20 Novartis Confidential Page 18 Oncology Clinical Trial Protocol (Version No. 00) 2 Study rationale/purpose Currently, in all forms of systemic mastocytosis treatment is primarily focusing on limiting mediator related symptoms caused by the increased amount of mast-cells. Limited treatment options have lead to varying and inconsistent approaches in order to target the actual cause of the disease. However, the advanced stage and poor prognosis of aggressive systemic mastocytosis and mast cell leukemia requires a therapy to reliably reduce the mast cell burden in this disease which is resulting in organ dysfunction, reduced quality of life and poor prognosis. Beyond treatment of mediator related symptoms there is no approved therapy available for ASM nor an actual standard treatment that is generally established and widely accepted. Recently, interferon- has increasingly been used as first line treatment combined with or without prednisolone, with variable response rates and accompanied by considerable toxicity. 2-chlorodeoxyadenosine (2-CdA, cladribine) has been recommended as second line treatment of ASM in patients who are refractory or intolerant to interferon-. Only individual case reports of responses to treatment with 2-CdA in patients with ASM have been described in the literature accompanied by side effects which were mostly related to bone marrow suppression. To date, most of the case reports in the literature were often based on small series and have been exploratory in nature or retrospectively assessed; consequently a large variability for the overall response rate was observed. Taking this into account, it is considered clinically relevant to set the null hypothesis for overall response rate for this trial to 30%. On the other hand, our clinical experience with midostaurin in a prospective IIT supported setting the alternative hypothesis to 50%. (Gotlib et al. 2006, Gotlib et al. 2007, Hauswirth et al. 2004, Wilson et al. 2006, Patnaik et al. 2007). This trial is the largest prospectively planned study in ASM/MCL using highly stringent and reproducible eligibility and response criteria. In order to address the aforementioned unmet medical need the purpose of this prospective multinational phase II study is to determine the efficacy and safety of midostaurin in patients with ASM or MCL with or without an associated hematological clonal non-mast cell lineage disease (AHNMD). 3 Objectives 3.1 Primary objectives To determine the efficacy of midostaurin in patients with aggressive systemic mastocytosis or mast cell leukemia with or without an associated hematological clonal non-mast cell lineage disease (AHNMD) when administered orally at a dose of 100 mg b.i.d. continuously for 6 cycles (of 4 weeks each) as measured by overall response rate (ORR). 3.2 Secondary objectives To evaluate the duration of response To evaluate the time to response To evaluate the safety and tolerability of midostaurin in patients with aggressive systemic mastocytosis and mast cell leukemia (+/- an AHNMD) To evaluate the overall survival rate (OS) This document (090095a88132b387 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 4/23/2008 5:00:21 PM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Schimansky Thorsten in Basel at Wed, Apr 23, :40:28 CEST Approved for report publication by Labed Alice in Basel at Wed, Apr 23, :29:52 CEST Approved for report publication by Heinemann Heidrun in Basel at Wed, Apr 23, :13:53 CEST