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Case CCC Study: CASE 4A13  
  
 Clinical Trial Protocol Number CLBH589DUS92T Title: A Phase I/II Study of MLN9708 (Ixazomib) in Combination with Panobinostat and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma ClinicalTrials.gov NCT \#: 02057640  
| Author(s):                | Frederic J. Reu, M.D.                  |
|---------------------------|----------------------------------------|
| Principal Investigator    | Jason Valent, M.D.                     |
| Co-Principal Investigator | Ehsan Malek, MD (University Hospitals) |
| Data Coordinator          | Sherry Fada                            |
| Release date              | March 6, 2014                          |
| Amendment 1               | April 24, 2014                         |
| Amendment 2               | May 6, 2014                            |
| Amendment 3               | June 18, 2014                          |
| Amendment 4               | December 26, 2014                      |
| Amendment 5               | June 3, 2015                           |
| Amendment 6               | September 23, 2015                     |
| Amendment 7               | July 18, 2016                          |
| Amendment 8               | March 1, 2017                          |
| Amendment 9               | April 3, 2017                          |
| CASE 4A13 A9 04/03/2017   |                                        |
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protocol summary

Title: A Phase I/II Study of MLN9708 (Ixazomib) in Combination with Panobinostat and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma
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objectives

The primary objective of this study is to:  
Define the tolerability and safety of MLN9708 (ixazomib) administered on a day 1,8,15 every 28 day schedule up to 4mg in combination with fixed doses of panobinostat and dexamethasone in patients with relapsed or refractory myeloma
The secondary objectives of this study are to:  
Assess response and clinical benefit response rates according to international uniform response criteria and adapted EBMT criteria, respectively (see under 8.1)
Assess progression-free survival (PFS) and overall survival (OS)
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patient population

Specific inclusion and exclusion criteria are detailed in Section 6.1.2 Number of Patients 31 patients (11 in phase I, 20 in phase II) Study Design and Methodology Phase I: This study will use a modified 3 + 3 design to define the tolerability and safety of MLN9708 (ixazomib) administered to at least 6 patients with relapsed or refractory myeloma on a day 1,8,15 every 28 day schedule at up to 4mg in combination with fixed doses of panobinostat and dexamethasone. Dose limiting toxicities (DLTs, see under 5.4) will be assessed at the end of the first cycle, on day 28. The trial will accrue up to three patients at any given DL who will need to be assessed for DLTs before the next three patients can be enrolled. Determination of the highest tolerated dose of two tested dose levels will require treatment of at least 6 patients at the respective dose level with no more than one patient developing a DLT. The first three patients will be treated at DL1. If no patient develops any DLT, the next three patients will be enrolled at DL2. If 1 patient develops any DLT, three additional patients will be enrolled at DL1. If no more than 1 of 6 patients treated at DL1 develops a DLT, the next three patients will be enrolled at DL2. If 2 or more of 2-6 patients treated at DL1 develop DLTs further enrollment will be stopped and a change in the protocol will be discussed. If DL2 opens to enrollment, and 0-1 of the first three patients develop any DLT, additional three patients will be enrolled at DL2 and if no more than 1 of 6 patients treated at DL2 develop any DLT, DL2 will be considered a tolerated MLN9708 dose and further dose escalation will not be done. If 2 of three or up to 6 patients enrolled at DL2 develop any DLT, further enrollment at that dose level will be stopped and enrollment will continue at DL1 unless 6 patients have already been treated at that dose level. If no more than 1 patient treated at DL1 develops any DLT that dose level will be considered tolerated and an intermediate dose level may be discussed. If 2 or more of up to 6 patients treated at DL1 develop a DLT, further enrollment will be stopped and a change in the protocol will be discussed. Phase II: Twenty additional patients will be treated at target doses of DL2 which has been found to be well tolerated without any DLT in phase I.
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treatments administered

| Dose levels  Dose  PO Panobinostat   | PO                           | MLN9708            | PO Dexamethasone   |                 |
|--------------------------------------|------------------------------|--------------------|--------------------|-----------------|
| level                                | (Ixazomib)                   |                    |                    |                 |
| 1                                    | 20mg d 1,3,5,15,17,19 q 28 d | 3mg d1,8,15 q 28 d | 20mg d             | 1,2,8,9,15,16 q |
| 28 d                                 |                              |                    |                    |                 |
| 2                                    | 20mg d 1,3,5,15,17,19 q 28 d | 4mg d1,8,15 q 28 d | 20mg d             | 1,2,8,9,15,16 q |
| 28 d                                 |                              |                    |                    |                 |  
Phase I: Patients will remain on study for six 28-day cycles or until criteria for discontinuation (7.6.1) are met, whichever comes earlier. Decisions on subsequent maintenance therapy will at the discretion of the treating physician but if the patient's myeloma is controlled (at least in stable disease) panobinostat, dexamethasone, and ixazomib may be continued and will be provided free of charge to the patient. This protocol may be amended to include a formal maintenance phase and/or a phase II portion after review of safety and preliminary efficacy data and approval by Novartis, Millennium, and the sponsor institution (Cleveland Clinic). Phase II: Patients will receive therapy according to DL2 and will remain on study until criteria for discontinuation (7.6.1) are met.
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efficacy data collected

The following evaluations will be conducted to assess the efficacy of this regimen: Response will be assessed according to international uniform response criteria and clinical benefit response according to modified EBMT response criteria (8.1), using myeloma panels obtained at the beginning of each cycle that include SPEP, 24 h UPEP, serum and urine IFEs, and serum free light chains. In addition, a baseline bone marrow exam and skeletal survey will be obtained and repeated as clinically indicated, including repeat bone marrow exam for confirmation of complete remission (see also Section 8 schedule of assessments).
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pharmacokinetic/pharmacodynamic/pharmacogenomic/correlative studies collected none.

Safety Data Collected The following evaluations will be conducted to assess the safety of this regimen:
Dose limiting toxicity will be evaluated after the first cycle for patients in phase I Toxicity will be evaluated according to CTCAE version 4.0, weekly during the first cycle and whenever the dose of a drug is increased, then at the start of each subsequent CASE 4A13 A9 04/03/2017 4
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cycle statistical procedures

Due to low patient numbers and short study duration results will only be described. Appropriate statistical analysis will be added if the study is extended into a phase II evaluation. Phase II: Kaplan-Meier survival and progression-free survival estimates will be calculated.
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table of contents

| PROTOCOL SUMMARY 3 Table of contents 5 List of abbreviations 8 1 Introduction 11 1.1 Overview of targeted Multiple Myeloma 11 1.2 Overview of Panobinostat 12 1.2.1 Anticancer activity of DAC inhibitors 12 1.2.2 Panobinostat (LBH589) 13 1.2.3 Overview of clinical experience 14 1.2.4 Human pharmacokinetics 18 1.2.5 Cardiac Safety 20 1.3 Overview of MLN9708 (Ixazomib) 22 1.3.1 Scientific Background 22 1.3.2 Nonclinical Pharmacology 22 1.3.3 Nonclinical Pharmacokinetics 23 1.3.4 Safety Pharmacology 24 1.3.5 In Vivo Toxicology 24 1.3.6 Clinical Experience 25 1.3.7 Pharmacokinetics and Drug Metabolism 26 1.3.8 Clinical Trial Experience Using the Oral Formulation of MLN9708 ... 26 1.3.9 Relapsed and/or Refractory Multiple Myeloma 31 1.3.10 Newly Diagnosed Multiple Myeloma (NDMM) 34 1.3.11 Clinical Trial Experience Using the Intravenous Formulation of  MLN9708 36 1.3.12 Potential Risks of MLN9708 36 2 Study rationale/purpose 38 3 Study objectives 39 3.1 Primary Objective 39 3.2 Secondary Objective 39 4 Study endpoints: 39CASE 4A13 A9 04/03/2017 5   |
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| 4.1                                                                                                                                 | Primary endpoints:                                                                                                                                     |
| 4.2                                                                                                                                 | Secondary endpoints: .....................................................................................................................39           |
| S                                                                                                                                   | Overall study design, treatment cycles, and study duration ...................................................40                                       |
| Study design and treatment cycles                                                                                                   |                                                                                                                                                        |
| 5.1                                                                                                                                 |                                                                                                                                                        |
| 5.2                                                                                                                                 | Study duration                                                                                                                                         |
| 5.3                                                                                                                                 | Dose levels                                                                                                                                            |
| Dose limiting toxicity ..........................................................................................................41 |                                                                                                                                                        |
| 5.4                                                                                                                                 |                                                                                                                                                        |
| 6                                                                                                                                   | Study population                                                                                                                                       |
| 6.1.1                                                                                                                               | Patient population                                                                                                                                     |
| 6.1.2                                                                                                                               | Inclusion and exclusion criteria .................................................................42                                                   |
| 6.2                                                                                                                                 | Definition Relapsed Myeloma and Refractory Myeloma                                                                                                     |
| 6.2.1                                                                                                                               | Refractory Myeloma .......................................................................................46                                           |
| 6.2.2                                                                                                                               | Relapsed Myeloma............................................................................................46                                         |
| 7                                                                                                                                   | T Treatments .......................................................................................................................................47 |
| 7.1                                                                                                                                 | Investigational therapy                                                                                                                                |
| 7.1.1                                                                                                                               | Panobinostat ........................................................................................................47                                |
| 7.1.2                                                                                                                               | MMLN9708 (Ixazomib) .......................................................................................48                                          |
| Cardiac precautions                                                                                                                 |                                                                                                                                                        |
| 7.1.3                                                                                                                               |                                                                                                                                                        |
| 7.2                                                                                                                                 | DEXAMETHASONE                                                                                                                                          |
| 7.3                                                                                                                                 | Mandatory concomitant therapy                                                                                                                          |
| Instructions for Initiation of a New Cycle ...............................................................................51        |                                                                                                                                                        |
| 7.4                                                                                                                                 |                                                                                                                                                        |
| 7.5                                                                                                                                 | Dose modifications for adverse events ............................................................................................51                   |
| Dose reduction guidelines                                                                                                           |                                                                                                                                                        |
| 7.5.1                                                                                                                               |                                                                                                                                                        |
| 7.5.2                                                                                                                               | Dose Re-Escalation Guidelines                                                                                                                          |
| 7.5.3                                                                                                                               | Dose modifications for study drug-related toxicity (see section                                                                                        |
| 7.5.4 for dose modifications for prolonged QTc): ...................................53                                              |                                                                                                                                                        |
| 7.5.4                                                                                                                               | Dose modifications for prolonged QTcF ........................................................58                                                       |
| 7.6                                                                                                                                 | Management of Clinical Events                                                                                                                          |
| 7.6.1                                                                                                                               | Study drug discontinuation ...............................................................................63                                           |
| 7.6.2                                                                                                                               | Follow-up for toxicities                                                                                                                               |
| 7.7                                                                                                                                 | O O THE CONCOMITANT MEDICATIONS                                                                                                                        |
| Summary of commonly used allowed supportive concomitant                                                                             |                                                                                                                                                        |
| 7.7.1                                                                                                                               | medications                                                                                                                                            |
| 7.7.2                                                                                                                               | Summary of prohibited concomitant medications and supplements.....65                                                                                   |
| 7.7.3                                                                                                                               | Anti-coagulant therapy                                                                                                                                 |
| 7.8                                                                                                                                 | Precautions and Restrictions ...................................................................................................67                     |
| 7.9                                                                                                                                 | Contraception Requirements ......................................................................................................67                    |
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| 7.9.1                   | CYP2D6 Substrates 69                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| 7.9.2                   | Drugs that can inhibit/induce CYP3A4/5 69                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| 7.10                    | Treatment compliance 70                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| 8                       | Visit schedule and assessments 70 8.1 Efficacy / response assessments and criteria 71 8.1.1 Progressive Disease 73                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| 9                       | Safety assessments 73 9.1.1 Adverse events 74 9.1.2 Vital signs 74 9.1.3 Physical examination 74 9.1.4 Laboratory evaluations 75 9.1.5 Serum pregnancy test 75 9.1.6 ECG 75 9.2 Drug levels and pharmacokinetic assessments 77                                                                                                                                                                                                                                                                                                                                         |
| 10                      | Safety monitoring 77 10.1 Novartis Instructions for rapid notification of serious adverse events 77 10.2 Millennium Instructions for rapid notification of serious adverse events 78 10.3 Any other form deemed appropriate by the sponsor-investigatorAdverse  Event of Special Interest Definition 80 10.4 Millennium Rules for Monitoring of Adverse Events and Period of  Observation 80 10.5 Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 81 10.6 Millennium Product Complaints 81 10.7 Serious Adverse Events 82 10.8 Pregnancies 82 |
| 11                      | Protocol amendments, or changes in study conduct 83                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| 12                      | Data review and management 83 12.1 Data Management 83 12.2 Analyses and Reporting 83 Data Safety Monitoring Plan 84 12.3 Study Monitoring 84 12.3.1 Investigator Responsibilities 84                                                                                                                                                                                                                                                                                                                                                                                   |
| 13                      | Statistical methods 84 13.1 Datasets to be Analyzed 84 13.1.1 Primary objectives and endpoints 84 13.1.2 Secondary objectives and endpoints 85                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 14                      | Procedures and instructions 85                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
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| 14.1           | Publication of results 85                                                                                                                                                                                                   |
| 14.2           | Disclosure and confidentiality 86                                                                                                                                                                                           |
| 14.3           | Discontinuation of study 86                                                                                                                                                                                                 |
| 15             | Ethics and Good Clinical Practice 86 15.1 Institutional Review Board/Independent Ethics Committee 86 15.2 Informed consent 87 15.3 Investigator and Site Responsibility for Drug Accountability 87 15.4 Record Retention 87 |
| 16             | USE OF INFORMATION 87                                                                                                                                                                                                       |
| 17             | References 88                                                                                                                                                                                                               |
| 18             | Appendices 93                                                                                                                                                                                                               |
| 19             | Medications which have a risk of causing Torsades de pointes ventricular arrhythmia  should be avoided 93                                                                                                                   |
| 20             | Medications which are known strong CYP3A4/5 inhibitors to be used with caution 95                                                                                                                                           |
| 21             | Medications which are known CYP2D6 substrates to be used with caution 96                                                                                                                                                    |
| 22             | Cockroft-Gault estimation of CrCl 97 22.1.1 Millennium Pregnancy Reporting Form 98                                                                                                                                          |
| 23             | Summary of Changes 102                                                                                                                                                                                                      |  
| List of abbreviations AE adverse event ALT alanine aminotransferase/glutamic pyruvic transaminase/GPT ANC absolute neutrophil count APL acute promyelocytic leukemia ASCO American Society of Clinical Oncologists AST aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT ATRA all trans-retinoic acid AUC area under the curve BCR-ABL a fusion gene of the BCR and ABL genes BUN blood urea nitrogen CIS carcinoma in-situ Cmax maximum concentration of drug CML chronic myelogenous leukemia CNS central nervous system CR complete response/remission CS&E clinical safety and epidemiology CTCAE NCI common terminology criteria for adverse events (version 3.0) CTCL cutaneous T-cell lymphomaCASE 4A13 A9 04/03/2017   | 8   |
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| CV                      | coefficient of variation                                             |
| DLT                     | dose-limiting toxicity                                               |
| DNA                     | deoxyribose nucleic acid                                             |
| ECG                     | 12 lead electrocardiogram                                            |
| ECOG                    | Eastern Cooperative Oncology Group                                   |
| eRT                     | eResearchTechnology                                                  |
| FACT                    | functional assessment of cancer therapy                              |
| FDA                     | food and drug administration                                         |
| G-CSF                   | granulocyte colony-stimulating factor (e.g. filgrastim)              |
| GM-CSF                  | granulocyte-macrophage colony-stimulating factor (e.g. sargramostim) |
| H3, H4                  | histones H3, H4                                                      |
| HAT                     | histone acetyltransferase                                            |
| HDAC                    | histone deacetylase                                                  |
| HDACi                   | histone deacetylase inhibitor                                        |
| hERG                    | human ether-a-go-go related gene                                     |
| HIV                     | human immunodeficiency virus                                         |
| i.v.                    | intravenous(ly)                                                      |
| ICH                     | international conference on harmonization                            |
| IEC                     | independent ethics committee                                         |
| IRB                     | institutional review board                                           |
| LLN                     | lower limit of normal                                                |
| LVEF                    | left ventricular ejection fraction                                   |
| mg/m2                   | milligrams per square meter                                          |
| MM                      | Multiple myeloma                                                     |
| RRMM                    | Relapsed or refractory multiple myeloma                              |
| MTD                     | maximum tolerated dose                                               |
| MUGA                    | multiple uptake gated acquisition scan                               |
| MWF                     | monday, wednesday, friday                                            |
| NCI                     | national cancer institute                                            |
| NDMM                    | Newly diagnosed multiple myeloma                                     |
| NHL                     | non-hodgkin's lymphoma                                               |
| NIH                     | national institutes of health                                        |
| PD                      | pharmacodynamic                                                      |
| P-gp                    | p-glycoprotein                                                       |
| PK                      | pharmacokinetic                                                      |
| PLT                     | platelet                                                             |
| PR                      | partial response                                                     |
| REB                     | research ethics board                                                |
| CASE 4A13 A9 04/03/2017 | 9                                                                    |  
| SAE   | serious adverse event           |
|-------|---------------------------------|
| SAHA  | suberoylanilide hydroxamic acid |
| SD    | stable disease                  |
| SOP   | standard operating procedure    |
| T4    | thyroxine                       |
| TSH   | thyroid stimulating hormone     |
| ULN   | upper limit of normal           |
| WBC   | white blood cell                |
| WNL   | within normal limits            |
| WOCBP | women of childbearing potential |
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1 introduction

1.1 Overview of targeted Multiple Myeloma Multiple myeloma, a cancer of antibody producing plasma cells, is the second most common hematologic malignancy in the United States. Based on SEER data (http://seer.cancer.gov/statfacts/html/mulmy.html, accessed 1/31/2013) it is estimated that 21,700 individuals were diagnosed with multiple myeloma in 2012 and that 10,710 died of the disease. Treatment has improved life expectancy with major milestones marked by the introduction of oral melphalan therapy in the late 1950s, corticosteroids prednisone or dexamethasone shortly thereafter, high dose melphalan with autologous stem cell transplant in the 1990s, and discovery of profound antimyeloma effects with the use of "new drugs" thalidomide, bortezomib, and lenalidomide around the turn of the century 1. With improved life expectancy myeloma prevalence increases and was 71,213 in 2009 (http://seer.cancer.gov/statfacts/html/mulmy.html, accessed 1/31/2013). Almost all patients still experience disease progression and ultimately their disease becomes refractory to available standard therapy which includes various combinations of "new drugs" corticosteroids, and conventional chemotherapeutic agents. More recent progress includes development of carfilzomib, a second generation proteasome inhibitor which in contrast to bortezomib does not cause significant neurotoxicity and produces at least minor responses as single agent in more than one third of patients with refractory myeloma 2 leading to FDA approval in 2012.  
Pomalidomide, an analogue of lenalidomide, in combination with dexamethasone yielded about similarly promising results in refractory myeloma 3-5 and obtained FDA approval in 2013.  
Despite these developments, the majority of patients with relapsed and refractory multiple myeloma do not respond to available therapy creating an unmet need for further drug development. One of the mechanisms of increasingly uncontrollable growth of cancer cells during clonal evolution as it occurs in most cancers including myeloma is epigenetic silencing of genes required for senescence, differentiation, cell death, and immune attack 6. The panhistone deactelyase inhibitor panobinostat may restore intrinsic and extrinsic growth control by reactivation of respective genes and pathways through its chromatin opening effects and enhance cell death induction through inhibition of deacetylation of non-histone proteins. In a clinical study that enrolled patients who were refractory to their last bortezomib containing regimen, panobinostat added to bortezomib and dexamethasone yielded a remarkable clinical benefit response (at least minor response) of about 50% 7. The need for parenteral administration and neurotoxic adverse events with the use of bortezomib has led to the development of the oral proteasome inhibitor MLN9708 which has shown single agent activity in relapsed and refractory myeloma without clinically significant neuropathy 8-10. The maximal tolerated dose for MLN9708 when given as a single agent in either a twice-a-week (2mg/m2) 10 or weekly (2.97mg/m2) 9 administration schedule has been determined. Dosing of MLN9708 became more straightforward after analysis of pharmacokinetic data of patients on IV and PO clinical trials revealed that body size only affects distribution but not AUC of MLN9708, allowing formulation of fixed tablet strengths 11. In combination with lenalidomide and dexamethasone, MLN9708 can safely be given at 4mg weekly for 3 out of 4 weeks 8 and a phase 3 study for upfront therapy in transplant-ineligible patients has already opened (NCT01564537). Panobinostat may synergize with MLN9708 and dexamethasone in relapsed and refractory myeloma in a similar way as with bortezomib. In this study we will investigate whether MLN9708 at up to 4mg day 1,8,15 every 28 days can be given safely in combination with a fixed dose schedule of panobinostat and dexamethasone, selected based on the experience with twice a week bortezomib combination at effective doses but adjusted to the 4 week MLN9708 schedule. The most refractory myeloma patient population often requires combination of more than three agents for disease control. MLN9708, panobinostat, and dexamethasone may serve as a platform for addition of agents. Lenalidomide has been shown to synergize with proteasome inhibitors and corticosteroids12,13 and to be well tolerated in combination with MLN9708 and dexamethasone8. It appears to synergize with histone deacetylase inhibitors as well14 and patients with relapsed and refractory Hodgkin's lymphoma appear to tolerate twice the amount of panobinostat proposed here in combination with standard lenalidomide 25mg day 1-21 every 28 days15. The three-drug oral regimen we propose to develop here may therefore lend itself for further intensification by addition of another active compound to treat the most refractory myelomas.without need for parenteral administration.
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1.2 overview of panobinostat 1.2.1

Alterations in chromosome structure play critical roles in the control of gene transcription. These epigenetic alterations include modification of histones and others proteins by acetylation and/or phosphorylation. Normally, these modifications are balanced finely and are highly reversible in normal tissues, but they may be imbalanced and heritable in tumor cells. DAC inhibitors increase histone acetylation, thereby modulating the expression of a subset of genes in a coordinated fashion. Several tumors suppressor genes associated with the malignant phenotype are repressed by epigenetic mechanisms in sporadic cancers. Thus therapy with DAC inhibitors may alter tumor phenotype and inhibit growth in such tumors. Multiple hallmarks of cancer are regulated by acetylation/deacetylation:  
DAC inhibition targets both histone and nonhistone proteins. Targeting the acetylation status of nonhistone, tumor-associated proteins that mediate proliferation may be the underlying antitumor mechanism of DAC inhibitors 16.  
Nonhistone proteins regulated by acetylation include α-tubulin, p53, HIF-1, and HSP90.  
These proteins are substrates of DACs 17.
CASE 4A13 A9 04/03/2017 12 The ability of a single agent to target multiple molecular features of tumor cells may result in good efficacy against a range of different tumor types.  
HSP90 is involved in protein stability and degradation; the inhibition of HSP90 affects protein turnover in diseases such as multiple myeloma and B-cell malignancies 18 Acetylated HIF-1 is degraded and can no longer act as a tumor growth factor. Class II
DAC inhibitors target histone deacetylase (HDAC or DAC) 6, resulting in increased acetylation of HIF-1 and decreased vascular endothelial growth factor (VEGF), thereby inhibiting angiogenesis 19.  
Both acetylation and ubiquitylation often occur on the same lysine residue, but these processes cannot occur simultaneously. Acetylation allows for increased stability, and ubiquitylation leads to protein degradation. Therefore, DACs decrease the half-life of a protein by exposing the lysine residue for ubiquitylation 20.
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1.2.2 panobinostat (lbh589)

Panobinostat (LBH589) is a deacetylase inhibitor (DACi) belonging to a structurally novel cinnamic hydroxamic acid class of compounds. It is a potent class I/II pan-DAC inhibitor (panDACi) that has shown anti-tumor activity in pre-clinical models and cancer patients.  
Deacetylases (DAC) target lysine groups on chromatin and transcription factors and various non-histone proteins such as p53, tubulin, HSP90 and Rb. Panobinostat is formulated as an oral capsule and a solution for intravenous (i.v.) injection. Both the oral and i.v. formulations are currently being investigated in ongoing Phase I and Phase II studies in advanced solid tumors and hematological malignancies. Inhibition of DAC provides a novel approach for cancer treatment. Histones are part of the core proteins of nucleosomes, and acetylation and deacetylation of these proteins play a role in the regulation of gene expression. Highly charged deacetylated histones bind tightly to the phosphate backbone of DNA, inhibiting transcription, presumably, by limiting access of transcription factors and RNA polymerases to DNA. Acetylation neutralizes the charge of histones and generates a more open DNA conformation. This conformation allows transcription factors and associated transcription apparatus access to the DNA, promoting expression of the corresponding genes. The opposing activities of two groups of enzymes, histone acetyltransferase (HAT) and DAC control the amount of acetylation. In normal cells a balance exists between HAT and DAC activity that leads to cell specific patterns of gene expression. Perturbation of the balance produces changes in gene expression. Several lines of evidence suggest that aberrant recruitment of DAC and the resulting modification of chromatin structure may play a role in changing the gene expression seen in transformed cells. For example, silencing of tumor suppressor genes at the level of chromatin is common in human tumors 21-28 and DAC complexes have been shown to be crucial to the activity of the AML-specific fusion proteins PLZF-RAR-α, PML-RAR-α, and AML1/ETO 2932. DAC inhibitors (DACi) have been shown to induce differentiation, cell cycle arrest or apoptosis in cultured tumor cells, and to inhibit the growth of tumors in animal models 33-39. In addition, DACi have been shown to induce expression of p21, a key mediator of cell cycle arrest in G1 phase and cellular differentiation 40-43.  
Tumor growth inhibition and apoptosis in response to DACi treatment may also be mediated through changes in acetylation of non-histone proteins (e.g., HSP90, p53, HIF-1α, α-tubulin). For example, the chaperone protein HSP90 has been shown to be acetylated in cells treated with DACi 44-46. Acetylation of HSP90 inhibits its ability to bind newly synthesized client proteins, thus preventing proper client protein folding and function. In the absence of HSP90 function, misfolded proteins are targeted for degradation in the proteasome. Many proteins that require HSP90 association are critical to cancer cell growth, including ErbB1, ErbB2, AKT, Raf, KDR, and BCR-ABL. Acetylation of HSP90 in cells treated with DACi inhibits the chaperone function of HSP90, leading to degradation of the client proteins and eventual cell death. The potential clinical utility of the use of DACi in cancer therapy was first suggested by the activity of the DACi, sodium phenylbutyrate, against acute promyelocytic leukemia (APL). An adolescent female patient with relapsed APL, who no longer responded to all trans-retinoic acid (ATRA) alone, achieved a complete clinical remission after treatment with a combination of ATRA and the DACi sodium phenylbutyrate 47.
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1.2.3 overview of clinical experience

In clinical studies, both oral and i.v. formulations of panobinostat are being explored for further development. As of 31st December 2009, twenty-six clinical studies, including clinical pharmacology (CP), phase I and phase II trials, as well as one recently started randomized phase III study, have either been completed or are ongoing. In Table 5-1, "completed" studies are studies that have achieved final data base lock; all other studies are identified as "ongoing". A total of 1116 patients were enrolled (248 for i.v. and 868 for oral), received at least one dose of panobinostat, and for whom safety data are available. These patients constitute the safety population. The most common AEs, regardless of their study drug relationship, concern the gastrointestinal tract (nausea, diarrhea and vomiting mostly of grade 1/2). For the hematopoietic system, the most frequent findings continue to be thrombocytopenia, anemia and neutropenia, mostly of grade 3/4, while febrile neutropenia, as expected, has been noted much more frequently in patients being treated for hematologic malignancies involving the bone marrow. Additional common toxicities include fatigue Grade 3/4 reported with a frequency of 9.2% in an every week (QW) dosing schedule vs 15.7% in an every other week (QOW) dosing schedule. The most common ECG findings adjudicated by central review included post-baseline increase in frequency of sinus tachycardia, T-waves changes (flat, biphasic, inverted), as well as depressed ST segment findings. The most frequently encountered laboratory abnormalities in both QW and QOW schedules and regardless of disease, refer to hematological parameters, including decreased WBC, platelet and neutrophil count and hemoglobin. Worsening of these hematologic parameters was more evident for the QW schedule and appears to be dose-dependent. Liver function tests alterations were mostly of grade 1/2 with either schedule, with grade 3 reported at the highest dose of 60 mg TIW QW. Decreasing electrolytes and elevated glucose was mostly grade 1/2 worsening from baseline, but again increased severity (up to grade 3) was seen at the highest dose of 60 mg with the QW schedule. Thyroid function, as monitored by the measurement of TSH and free T4, did not reveal overt hyper- or hypo- thyroidism, with fluctuations in TSH values being within normal limits.  
CASE 4A13 A9 04/03/2017 14 As the number of patients is quite different across doses, the following rules have been applied to report these events in the tables below: in doses where the number (n) of patients is ≥25 patients, AEs reported in ≥10% of patients are listed; in doses where n is <25 patients, AEs reported in ≥50% of patients are listed. If an AE frequency matches the criteria in one dose category, the frequency of that event is shown for all doses. Since the dosing in this study will follow the three-times-per-week schedule, Table 1-1 below, provides a summary of adverse events that occurred in >15% of the patients at any dose.  
| 60                                                                             | mga                             |           |                      |           |
|--------------------------------------------------------------------------------|---------------------------------|-----------|----------------------|-----------|
| N                                                                              | =                               | 54        |                      |           |
| n                                                                              | (%)                             |           |                      |           |
| Any primary system organ class                                                 | 291( 100.0) 22(100.0) 152(93.3) | 54(100.0) |                      |           |
| 20                                                                             | mga                             |           |                      |           |
| N                                                                              | =                               | 293       |                      |           |
| n                                                                              | (%)                             | 30        | mga                  |           |
| N                                                                              | =                               | 22        |                      |           |
| n                                                                              | (%)                             | 40        | mga                  |           |
| N                                                                              | =                               | 163       |                      |           |
| n                                                                              | (%)                             |           |                      |           |
| Primary System Organ Class Preferred term Blood and lymphatic system disorders | 181(61.8)                       | 17( 77.3) | 131( 80.4) 49(90.7)  |           |
| Anemia                                                                         | 60( 20.5)                       | 9( 40.9)  | 51( 31.3)            | 24(44.4)  |
| Neutropenia                                                                    | 52( 17.7)                       | 4( 18.2)  | 38( 23.3)            | 21( 38.9) |
| Thrombocytopenia                                                               | 122( 42.1)                      | 13( 59.1) | 123( 75.5) 31(57.4)  |           |
| Gastrointestinal Disorders                                                     | 232( 79.2)                      | 21( 95.5) | 137( 84.0) 53( 98.1) |           |
| Abdominal pain                                                                 | 29( 9.9)                        | 2( 9.1)   | 23( 14.1)            | 17( 31.5) |
| Constipation                                                                   | 42( 14.3)                       | 2( 9.1)   | 27( 16.6)            | 13( 24.1) |
| Diarrhea                                                                       | 150( 51.2)                      | 15( 68.2) | 94( 57.7)            | 42( 77.8) |
| Nausea                                                                         | 132( 45.1)                      | 11( 50.0) | 90( 55.2)            | 34( 63.0) |
| Vomiting                                                                       | 64( 21.8)                       | 6( 27.3)  | 62( 38.0)            | 24( 44.4) |
| General Disorders and Site Conditions                                          | 219( 74.7)                      | 17( 77.3) | 112( 68.7) 49( 90.7) |           |
| Asthenia                                                                       | 50( 17.1)                       | 2( 9.1)   | 26( 16.0)            | 11( 20.4) |
| Fatigue                                                                        | 118( 40.3)                      | 12( 54.5) | 66( 40.5)            | 37( 68.5) |
| Edema peripheral                                                               | 57( 19.5)                       | 6( 27.3)  | 24( 14.7)            | 17( 31.5) |
| Pyrexia                                                                        | 59( 20.1)                       | 8( 36.4)  | 4( 25.2)             | 20( 37.0) |
| Investigations                                                                 | 133( 45.4)                      | 10( 45.5) | 52( 31.9)            | 36( 66.7) |
| Blood creatinine increased                                                     | 35( 11.9)                       | 1( 4.5)   | 9( 5.5)              | 11( 20.4) |
| Weight decreased                                                               | 42( 14.3)                       | 6( 27.3)  | 20( 12.3)            | 17( 31.5) |
| Metabolism and nutrition disorders                                             | 167( 57.0)                      | 13( 59.1) | 74( 45.4)            | 48( 88.9) |
| Anorexia                                                                       | 45( 15.4)                       | 10( 45.5) | 16( 9.8)             | 24( 44.4) |
| Decreased appetite                                                             | 43( 14.7)                       | 1( 4.5)   | 35( 21.5)            | 12( 22.2) |
| CASE 4A13 A9 04/03/2017                                                        | 15                              |           |                      |           |  
Table 1-1All grade adverse events regardless of causality in patients receiving oral panobinostat three-times-a-week every-week (TIW QW)  
| 60                                                                                                    | mga                                                                                                                                                                                                                                                          |           |           |           |
|-------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|-----------|-----------|
| N                                                                                                     | =                                                                                                                                                                                                                                                            | 54        |           |           |
| n                                                                                                     | (%)                                                                                                                                                                                                                                                          |           |           |           |
| Hypokalaemia                                                                                          | 31( 10.6)                                                                                                                                                                                                                                                    | 6( 27.3)  | 22( 13.5) | 24( 44.4) |
| 20                                                                                                    | mga                                                                                                                                                                                                                                                          |           |           |           |
| N                                                                                                     | =                                                                                                                                                                                                                                                            | 293       |           |           |
| n                                                                                                     | (%)                                                                                                                                                                                                                                                          | 30        | mga       |           |
| N                                                                                                     | =                                                                                                                                                                                                                                                            | 22        |           |           |
| n                                                                                                     | (%)                                                                                                                                                                                                                                                          | 40        | mga       |           |
| N                                                                                                     | =                                                                                                                                                                                                                                                            | 163       |           |           |
| n                                                                                                     | (%)                                                                                                                                                                                                                                                          |           |           |           |
| Primary System Organ Class Preferred term Musculoskeletal and connective tissue  disorders 107( 36.5) | 10( 45.5)                                                                                                                                                                                                                                                    | 59( 36.2) | 23( 42.6) |           |
| Back Pain                                                                                             | 33( 11.3)                                                                                                                                                                                                                                                    | 3( 13.6)  | 14( 8.6)  | 9( 16.7)  |
| Nervous system disorders                                                                              | 142( 48.5)                                                                                                                                                                                                                                                   | 13( 59.1) | 70( 42.9) | 36( 66.7) |
| Dizziness                                                                                             | 39( 13.3)                                                                                                                                                                                                                                                    | 3( 13.6)  | 11( 6.7)  | 8( 14.8)  |
| Dysgeusia                                                                                             | 42( 14.3)                                                                                                                                                                                                                                                    | 6( 27.3)  | 21( 12.9) | 18( 33.3) |
| Headache                                                                                              | 46( 15.7)                                                                                                                                                                                                                                                    | 5( 22.7)  | 27( 16.6) | 12( 22.2) |
| Respiratory, thoracic and mediastinal  disorders 111( 37.9)                                           | 10( 45.5)                                                                                                                                                                                                                                                    | 72( 44.2) | 32( 59.3) |           |
| Cough                                                                                                 | 30( 10.2)                                                                                                                                                                                                                                                    | 5( 22.7)  | 29( 17.8) | 14( 25.9) |
| Dyspnea                                                                                               | 43( 14.7)                                                                                                                                                                                                                                                    | 5( 22.7)  | 23( 14.1) | 13( 24.1) |
| Skin and subcutaneous tissue disorders                                                                | 142( 48.5)                                                                                                                                                                                                                                                   | 8( 36.4)  | 54( 33.1) | 26( 48.1) |
| Pruritus                                                                                              | 54( 18.4)                                                                                                                                                                                                                                                    | 0( 0.0)   | 13( 8.0)  | 3( 5.6)   |
| a.                                                                                                    | Includes patients from [B1101], [B2101], [B2102] Group X and Y, [B2201], [B2202],  [B2203], [B2211], [B2212], [E2214]; events occurring in ≥10% of patients A patient with multiple occurrences of an AE in one SOC is counted only once in the  AE category |           |           |           |  
As shown on the above table 1-1, AEs have been reported for 519 patients (97.6% of the safety population) for the QW schedule. The most commonly reported AEs across doses were diarrhea in 301 patients (56.6%), thrombocytopenia in 289 patients (54.3%), nausea in 267 patients (50.2%) and fatigue in 233 patients (43.8%). Table 1-2All grade adverse events regardless of causality in patients receiving oral panobinostat three-times-a-week every-other-week (TIW QOW)  
| 60                                                  | mga       |           |           |
|-----------------------------------------------------|-----------|-----------|-----------|
| N                                                   | =         | 24        |           |
| n                                                   | (%)       |           |           |
| Any primary system organ class                      | 28(100.0) | 18(100.0) | 24(100.0) |
| 30                                                  | mga       |           |           |
| N                                                   | =         | 28        |           |
| n                                                   | (%)       | 45        | mga       |
| N                                                   | =         | 18        |           |
| n                                                   | (%)       |           |           |
| Primary                                             | System    | Organ     | Class     |
| Preferred term Blood and lymphatic system disorders | 16( 57.1) | 14( 77.8) | 21( 87.5) |
| Anemia                                              | 5( 17.9)  | 6( 33.3)  | 11( 45.8) |
| CASE 4A13 A9 04/03/2017                             | 16        |           |           |  
| Confidential                              | 60        | mga        |                        |          |           |
|-------------------------------------------|-----------|------------|------------------------|----------|-----------|
| N                                         | =         | 24         |                        |          |           |
| n                                         | (%)       |            |                        |          |           |
| Neutropenia                               | 3( 10.7)  | 5( 27.8)   | 10( 41.7)              |          |           |
| Thrombocytopenia                          | 10( 35.7) | 10( 55.6)  | 14( 58.3)              |          |           |
| 30                                        | mga       |            |                        |          |           |
| N                                         | =         | 28         |                        |          |           |
| n                                         | (%)       | 45         | mga                    |          |           |
| N                                         | =         | 18         |                        |          |           |
| n                                         | (%)       |            |                        |          |           |
| Primary                                   | System    | Organ      | Class                  |          |           |
| Preferred term Gastrointestinal Disorders | 25( 89.3) | 17( 94.4)  | 24(100.0)              |          |           |
| Constipation                              | 6( 21.4)  | 3( 16.7)   | 10( 41.7)              |          |           |
| Diarrhea                                  | 15( 53.6) | 11( 61.1)  | 16( 66.7)              |          |           |
| Nausea                                    | 17( 60.7) | 9( 50.0)   | 19( 79.2)              |          |           |
| Vomiting                                  | 12( 42.9) | 6( 33.3)   | 12( 50.0)              |          |           |
| General Disorders and Site Conditions     | 27( 96.4) | 17( 94.4)  | 23( 95.8)              |          |           |
| Asthenia                                  | 5( 17.9)  | 5( 27.8)   | 4( 16.7)               |          |           |
| Fatigue                                   | 18( 64.3) | 12( 66.7)  | 15( 62.5)              |          |           |
| Edema peripheral                          | 6( 21.4)  | 5( 27.8)   | 4( 16.7)               |          |           |
| Pyrexia                                   | 11( 39.3) | 9( 50.0)   | 10( 41.7)              |          |           |
| Investigations                            | 14( 50.0) | 8( 44.4)   | 11( 45.8)              |          |           |
| Weight decreased                          | 10( 35.7) | 5( 27.8)   | 3( 12.5)               |          |           |
| Metabolism and nutrition disorders        | 22( 78.6) | 9( 50.0)   | 18( 75.0)              |          |           |
| Anorexia                                  | 17( 60.7) | 6( 33.3)   | 10( 41.7)              |          |           |
| Hypokalaemia                              | 4( 14.3)  | 3( 16.7)   | 6( 25.0)               |          |           |
| Musculoskeletal                           | and       | connective | tissue  16( 57.1)      | 7( 38.9) | 13( 54.2) |
| disorders Arthralgia                      | 3( 10.7)  | 0( 0.0)    | 6( 25.0)               |          |           |
| Back Pain                                 | 3( 10.7)  | 4( 22.2)   | 3( 12.5)               |          |           |
| Pain in extremity                         | 3( 10.7)  | 2( 11.1)   | 3( 12.5)               |          |           |
| Nervous system disorders                  | 17( 60.7) | 6( 33.3)   | 14( 58.3)              |          |           |
| Headache                                  | 7( 25.0)  | 3( 16.7)   | 6( 25.0)               |          |           |
| Respiratory,                              | thoracic  | and        | mediastinal  15( 53.6) | 8( 44.4) | 17( 70.8) |
| disorders Cough                           | 5( 17.9)  | 4( 22.2)   | 7( 29.2)               |          |           |
| Dyspnea                                   | 9( 32.1)  | 6( 33.3)   | 6( 25.0)               |          |           |
| CASE 4A13 A9 04/03/2017                   | 17        |            |                        |          |           |  
| Confidential  30                                      | mga       |          |          |
|-------------------------------------------------------|-----------|----------|----------|
| N                                                     | =         | 28       |          |
| n                                                     | (%)       | 45       | mga      |
| N                                                     | =         | 18       |          |
| n                                                     | (%)       | 60       | mga      |
| N                                                     | =         | 24       |          |
| n                                                     | (%)       |          |          |
| Primary                                               | System    | Organ    | Class    |
| Preferred term Skin and subcutaneous tissue disorders | 12( 42.9) | 5( 27.8) | 9( 37.5) |
| Pruritus                                              | 5( 17.9)  | 1( 5.6)  | 3( 12.5) |
| Rash                                                  | 3( 10.7)  | 1( 5.6)  | 4( 16.7) |  
a. Includes patients from [B1101], [B2101], [B2102] (Group X and Y), [B2201], [B2202],
[B2203], [B2211], [B2212], [E2214]; events occurring in ≥10% of patients A patient with multiple occurrences of an AE in one SOC is counted only once in the AE category
As shown on the above Table 1-2, AEs have been reported for 70 patients (100% of the safety population) for the QOW schedule. The most commonly reported AEs across doses were fatigue and nausea in 45 patients each (64.3% each), diarrhea in 42 patients (60%), thrombocytopenia in 34 patients (48.6%) and anorexia in 33 patients (47.1%). Of note, the safety profile appears to be qualitatively similar between the two schedules. At present, a quantitative comparison is limited by the significantly different number of patients available in both safety populations.
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1.2.4 human pharmacokinetics

After oral administration, panobinostat is rapidly absorbed with no observed lag phase. Maximum plasma concentrations were generally reached within 1 hour after oral dosing. The absolute bioavailability was 30% (data on file) and the mean (SD) half-life of panobinostat was comparable following i.v. and oral dosing ~15.0 (5) hours. Moderate drug accumulation was observed with oral three-times-a-week schedule but not with the weekly i.v. schedule (1.4-fold drug accumulation with oral three-times-a-week dosing), consistent with the terminal half-life of 15 hours and dosing interval.  
Figure 1-1 **Mean panobinostat plasma concentration versus time profiles following**
single oral or intravenous administration  
  
| Route                                                 | of                                         |                                             |          |
|-------------------------------------------------------|--------------------------------------------|---------------------------------------------|----------|
| administration                                        | &                                          |                                             |          |
| Dose (No. of patients  following single  dose)        | Mean (CV%) Single                          | dose                                        |          |
| Cmax(ng/mL)                                           | Mean (CV%) Single dose AUC0-inf (ng*hr/mL) | Mean (CV%) Multiple dose AUC0-48 (ng*hr/mL) |          |
| i.v. 20 mg/m2 (n=31)                                  | 784 (45)                                   | 1041 (38)                                   | n/a      |
| p.o. 20 mg (n=45)                                     | 22.8 (58)                                  | 194 (58)                                    | 258 (65) |
| p.o. 30 mg (n=49)                                     | 36.2 (62)                                  | 267 (54)                                    | 279 (54) |
| p.o. 40 mg (n=24)                                     | 58.0 (59)                                  | 329 (77)                                    | 270 (59) |
| p.o. 60 mg (n=57)                                     | 66.1 (68)                                  | 362 (62)                                    | 306 (50) |
| p.o. 80 mg (n=18)                                     | 63.5 (58)                                  | 397 (49)                                    | 369 (52) |
| n/a: not applicable  with weekly i.v.  administration |                                            |                                             |          |  
In vitro experiments suggested that the hepatic oxidative metabolism of panobinostat is mediated primarily by cytochrome P450 (CYP)3A4, and to a lesser extent by CYP2D6 and CYP2C19. In addition to monooxygenation, hydrolysis of the hydroxamic sid chain (M43.5) were also found to be mediated (at least in-part) by the CYPs. These same metabolic pathways, were also observed in the recent human ADME and mass balance study [CLBH589B218].
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dose proportionality

A positive and linear dose-exposure relationship was found following single i.v. administration
(1.2 to 20 mg/m2, Rs = 0.83; p<0.0001). After oral dosing with 15 mg to 80 mg of panobinostat, dose-proportionality analysis indicated that systemic exposure increased nearly doseproportionally at doses below 60 mg and there is less than proportional increase in AUC after 60 mg and 80 mg doses of panobinostat. It appears that absorption may become limiting at doses ≥ 60 mg of panobinostat.
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food effect

Influence of food on panobinostat PK was evaluated in patients with advanced cancer who received 20 mg panobinostat twice a week and were randomized to receive panobinostat under fasting, high fat, and normal breakfast conditions [CLBH589B2111]. The overall exposure and inter-patient variability (CV 59%) in 34 patients remained unchanged with or without food, whereas Cmax was transiently reduced by <45% and Tmax prolonged by food (i.e., both normal and high fat breakfast). Since food did not alter the overall extent of absorption, food is unlikely to significantly impact panobinostat's systemic exposure in cancer patients. The findings from this formal food effect are consistent with the results from an earlier pilot food effect [CLBH589B2101] arm 1. Therefore, panobinostat can be administered without regard to food in future studies.
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1.2.5 cardiac safety

As of 31 December 2009, cardiac safety data were available for 532 patients in the TIW QW dose schedule and 70 patients in the TIW QOW dose schedule. All of these patients underwent intensive pre- and post-dose ECG recording to monitor the occurrence of QTcF changes as well as to capture other ECG abnormalities. There are mounting evidences that the most common finding is a QTcF increase of ≤60 msec (CTCAE grade 1) from baseline in both schedules. The absolute maximal QTcF values remain limited to ≤480 msec (grade 1/2). Higher absolute values are infrequent. Of note a QTcF increase >480 msec has been mostly observed at the highest oral dose of 60 mg given TIW QW. There were no cases of torsade de pointes with either schedule for oral panobinostat.
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1.2.5.1 relationship between panobinostat plasma

As presented in Figure 1-2 (i.v.) and Figure 1-3 (po) below, the maximum change of QTcF from baseline does not coincide with the peak plasma concentration-time course of panobinostat for either route of administrations suggesting a possible delayed effect. It is noteworthy (as shown in Table 1-3) that the mean maximum concentration (Cmax) and overall exposure (AUC) for the oral formulation is at least 30-fold and 5-fold, respectively lower than that has been seen with intravenous panobinostat. It does not appear that QTcF change is directly related to panobinostat plasma concentrations.  
Figure 1-2 QTcF change from baseline over time vs. panobinostat conc-time course following the first intravenous panobinostat weekly doses  
  
4
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1.3 overview of mln9708 (ixazomib)

MLN9708 is Millennium's next generation small molecule inhibitor of the 20S proteasome that is under development for the treatment of nonhematologic malignancies, lymphoma, multiple myeloma (MM), and plasma cell dyscrasias. Inhibition of the 20S proteasome has been validated as a therapeutic target for the treatment of malignancies using VELCADE (bortezomib) for Injection, Millennium Pharmaceuticals, Inc.'s first-in-class proteasome inhibitor 48. In an effort to broaden activity against a wider range of tumor types and increase activity in tumor types where VELCADE has shown activity, Millennium has developed the proteasome inhibitor, MLN9708, formulated for both intravenous (IV) and oral (PO) administration.
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1.3.2 nonclinical pharmacology

MLN2238 refers to the biologically active, boronic acid form of the drug substance, MLN9708. MLN9708 refers to the citrate ester of MLN2238. In water or aqueous systems, the equilibrium shifts from MLN9708 to the biologically active boronic acid form MLN2238. All doses and concentrations are expressed as the boronic acid, MLN2238.  
1.3.2.1 **In Vitro Pharmacology**
MLN2238 inhibits β5 site 20S proteasome activity in vitro, with a half-maximal inhibitory concentration (IC50) of 3.4 nM. Potency is reduced roughly 10-fold versus β1 (IC50 = 31 nM) and 1,000-fold versus β2 (IC50 = 3500 nM). MLN2238 was also tested for inhibition against a panel of 103 kinases, 18 receptors (neurotransmitter, ion channel, brain and gut receptors), and 9 serine proteases. In all cases, the IC50 values were > 10 μM. Proteasome inhibition results in the accumulation of poly-ubiquitinated substrates within the cell and leads to cell cycle disruption, with concomitant activation of apoptotic pathways and cell death. Consistent with inhibition of β5 20S proteasome activity, MLN2238 demonstrated potent activity against cultured MDA-MB-231 human breast cancer cells in the WST cell viability assay.
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1.3.2.2 in vivo pharmacology

To determine the activity of MLN2238 in vivo, pharmacodynamic studies were performed in immunocompromised mice bearing either CWR22 human prostate or WSU-DLCL2 (human diffuse large B-cell lymphoma [DLBCL]) tumors. Xenograft tumor pharmacodynamic responses were analyzed by assessing 20S proteasome inhibition and by evaluating levels of the protein markers growth arrest and deoxyribonucleic acid (DNA) damage-inducible protein 34 (GADD34) and activating transcription factor-3 (ATF-3). Increased expression of GADD34 and ATF-3 is indicative of a downstream biological response to proteasome inhibition. After a single dose of MLN2238, a clear dose response was observed in CWR22 xenografts as seen in both tumor 20S proteasome inhibition and in changes in GADD34 and ATF-3 expression. In WSU-DLCL2 xenografts, greater tumor proteasome inhibition and greater elevation of CASE 4A13 A9 04/03/2017 22 GADD34 and ATF-3 were observed with MLN2238 compared to bortezomib. Additionally, MLN2238 demonstrated proteasome inhibition in blood, liver, and tumor tissue after a single IV dose of 5, 10, or 14 mg/kg or a single PO dose of 8 or 11 mg/kg to female PHTX-24C
(primary colon cancer) tumorbearing NCR nude mice. MLN2238 demonstrated strong antitumor activity in xenograft models derived from human cancer cell lines or primary human tumors. Antitumor activity was demonstrated with subcutaneous (SC) xenografts of CWR22 prostate, LXFE 409 epidermoid lung carcinoma, and 2 lymphoma models (WSU-DLCL2 and PHTX-22L). MLN2238 also showed antitumor activity in a disseminated model of lymphoma
(OCI-Ly7-7D1-luc cells inoculated intravenously) and in an intraosseous model using MDAMB-231 human breast adenocarcinoma cells. In addition, MLN2238 demonstrated antitumor activity in mouse models of plasma cell malignancy (PCM): the iMycCα/Bcl-XL geneticallyengineered mouse [GEM] model of de novo PCM and disseminated and intraosseous models of PCM generated by IV and intratibial inoculation of the DP54-Luc iMycCα/Bcl-XL mouse cell line. In the CWR22 xenograft model, significant antitumor activity was seen with both PO and IV dosing, demonstrating that this molecule has antitumor activity when administered via different dosing routes. MLN2238 demonstrated stronger antitumor activity than did bortezomib in the 3 lymphoma models, the lung carcinoma model, and the breast cancer model, and similar antitumor activity to bortezomib in the CWR22 model and the PCM models. In summary, MLN2238 is Millennium's next generation dipeptide boronic acid proteasome inhibitor that potently, reversibly, and selectively inhibits the proteasome. There are several features of MLN2238 demonstrated in mouse xenograft models, such as sustained pharmacodynamic effects and activity in xenograft models that do not respond to bortezomib, that suggest that the biodistribution and activity that of MLN2238 may extend beyond that of VELCADE. 1.3.3 Nonclinical Pharmacokinetics The pharmacokinetic (PK) properties of MLN2238 were studied in severe combined immunodeficient (SCID) mice bearing human CWR22 tumor xenografts, Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys. Because of the extensive red blood cell (RBC) partitioning of MLN2238, both blood and plasma PK parameters were determined in these studies. MLN2238 had a very low blood clearance (CL) and a moderate blood volume of distribution at steady-state (Vss) after IV administration. The concentration-versus-time curve of MLN2238 displayed a distinct bi-exponential profile, with a steep initial distribution phase and a long terminal t1/2 (>24 hr) in all species tested. MLN2238 had higher plasma CL and larger plasma Vss than in blood, largely because of the extensive RBC partitioning. The PK properties of MLN2238 after oral administration were studied in rats and dogs. The plasma oral bioavailability (F) was 41% in rats and nearly 100% in dogs. A clinical prototype formulation of the MLN9708 capsule demonstrated that MLN2238 had excellent oral F and an excellent absorption profile in dogs. In addition, interindividual variability, as measured by %CV, in Cmax and AUC0-24hr after oral administration was low to moderate, similar to that after IV administration. The terminal t1/2 after oral administration was also similar to that after IV administration. Metabolism appears to be a major route of elimination for MLN2238, and urinary excretion of the parent drug was negligible (< 5% of dose). In vitro in liver microsomes, the metabolism of MLN2238 was high in mice and low to moderate in all other species studied. MLN2238 is metabolized by multiple cytochrome P450 (CYP) isozymes and non-CYP
CASE 4A13 A9 04/03/2017 23 enzymes and proteins. The rank order of relative biotransformation activity of each of the 5 major human CYP isozymes in the in vivo studies was 3A4/5 (34.2%) >1A2 (30.7%) >2D6 (14.7%) >2C9 (12.1%) >2C19 (negligible). In SD rats, after a single IV dose of [14C]MLN9708, the blood exposure to MLN2238 was the same as that of total radioactivity in the blood, indicating that MLN9708 was completely converted to MLN2238 in vivo and the metabolism of MLN2238 was extremely slow. MLN2238 is neither an inhibitor of CYP isozymes 1A2, 2C9, 2C19, 2D6, and 3A4/5 (IC50 >30 μM, with an estimated inhibition dissociation constant [Ki] >15 μM), nor a time dependent inhibitor of CYP3A4/5 (up to 30 μM). The potential for MLN9708 treatment to produce DDIs via CYP inhibition is inferred to be low. However, there may be a potential for DDIs with a concomitant strong CYP3A4/5 or CYP1A2 inhibitor or a strong CYP3A4/5 inducer because of the possible contribution of CYP3A4/5- and CYP1A2mediated metabolism to the elimination of MLN9708 in humans. Clinical evaluation with CYP3A4/5 as a strong inhibitor or inducer is planned. 1.3.4 **Safety Pharmacology** Evaluation of the effect of MLN9708 on cardiovascular (CV), respiratory, and central nervous system (CNS) function was conducted as part of the Good Laboratory Practice (GLP)-compliant repeat-dose toxicology studies. In exploratory safety pharmacology studies, MLN2238 was a weak inhibitor of the cloned cardiac potassium (K+) human ether à-gochannel in vitro, with an IC50 of 59.6 μM, which exceeds, by approximately 200-fold, the plasma Cmax (111 ng/mL [0.3 μM]) predicted to occur in humans at the optimally efficacious dose after IV administration. In the GLP-compliant, 1-cycle PO toxicology study in beagle dogs, an increase in QTc was seen in male dogs at nontolerated doses, and a potential increase in QTc was seen in male dogs at tolerated doses. However, increased QTc was not seen in female dogs at any dose, despite similar plasma Cmax values. Additionally, in GLP-compliant 2- and 5-cycle IV and 5-cycle PO toxicology studies in beagle dogs, there were no changes in electrocardiograms, heart rate, and waveform intervals (PR, QRS, QT, and QTcV), even though dogs in the IV studies had higher MLN2238 plasma Cmax values than in the 1-cycle PO study. In GLP-compliant PO and IV repeat-dose toxicology studies up to 5 cycles in duration, there were no MLN9708-related effects on clinical signs or physical examination findings indicative of impaired respiratory or CNS function at tolerated doses. These data suggest that MLN2238 has a low potential for cardiovascular, CNS, or respiratory alterations.
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1.3.5 in vivo toxicology 1.4.1.1

After PO administration of MLN2238, the exposures that were tolerated in rats were similar to those tolerated in dogs, indicating similar species sensitivity. Additionally, PO administration for 5 cycles to rats and dogs resulted in higher plasma exposures of MLN2238 on Day 94 than on Day 0, indicating accumulation of MLN2238. Dose-limiting toxicity (DLT) in the GLPcompliant PO toxicology studies up to 5 cycles in duration in rats and dogs was primarily due to effects in the gastrointestinal (GI) and lymphoid systems. Additionally, at doses below those associated with DLT, alterations in leukocyte and coagulation parameters consistent with an CASE 4A13 A9 04/03/2017 24 inflammatory response were seen in both rats and dogs, and neuronal degeneration of the sympathetic, dorsal root, and end organ ganglia was seen mainly in dogs (possibly due to higher exposures). All of the effects seen in the GLP-compliant PO toxicology studies in both rats and dogs at tolerated doses were reversible/reversing and can be monitored in the clinic with routine clinical observations (GI disturbances and opportunistic infections secondary to lymphoid depletion), clinical pathology assessments (inhibition of erythropoiesis, thrombocytopenia, and inflammatory leukogram), and neurologic assessment, as are commonly done for patients treated with bortezomib. MLN9708 did not cause significant toxicities that have not been previously observed after dosing with bortezomib,11 and the neurologic lesions in these studies are similar to what has been described after treatment with bortezomib and are believed to be the cause of the peripheral neuropathy observed in patients treated with bortezomib.
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1.4.1.2 intravenous dosing

After IV administration of MLN2238, the exposures that were tolerated in rats were similar to those tolerated in dogs, indicating similar species sensitivity. In GLP-compliant IV toxicology studies, the target tissues for dogs and rats were similar and consisted of the bone marrow, peripheral ganglia, intestines, and lymphoid tissues. In addition, kidneys, adrenal and lacrimal glands (rats) and perianal glands (dogs) were also identified as target organs in the 5-cycle studies. The effects seen with the IV studies were largely consistent with the toxicologic effects seen with PO dosing; however, the greater severity/frequency or additional target organs seen with IV dosing were likely a result of the higher exposures relative to PO dosing. DLT was primarily due to GI and lymphoid depletion effects in both rats and dogs, although some of the microscopic features in those organs differed between the species. All of the effects seen in the GLP-compliant IV toxicology studies in both rats and dogs at tolerated doses were reversible/reversing and can be monitored in the clinic. Additionally, these effects were consistent with the toxicities associated with and described after treatment with bortezomib 11.
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1.4.2 genotoxicity

MLN2238 was not mutagenic in a GLP-compliant bacterial reverse mutation assay (Ames assay).
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1.3.6 clinical experience

As of 30 April 2012, 382 patients have been treated with MLN9708 across 9 enrolling, sponsor-led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing schedules. MLN9708 is available as an intravenous and oral formulation. Regardless of the route of administration in the twice-weekly dosing schedule, MLN9708 is given on Days 1, 4, 8, and 11 of a 21-day cycle; in the weekly dosing schedule, the drug is given on Days 1, 8, and 15 of a 28-day cycle. To date, the development of oral MLN9708 has focused on multiple myeloma [relapsed and/or refractory and newly diagnosed] and a different yet related plasma CASE 4A13 A9 04/03/2017 25 cell dyscrasia, systemic light chain (AL) amyloidosis. A clinical pharmacology study looking at drug-drug interactions, the effect of food, and bioavailability also uses the oral formulation. Details of these trials can be found in ClinicalTrials.gov and the MLN9708 IB.
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1.3.7 pharmacokinetics and drug metabolism

Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the biologically active boronic acid form of MLN9708 [MLN2238]) has multi-exponential disposition with a rapid initial phase that is largely over by 4 hours. Oral MLN9708 is rapidly absorbed with a median time to first maximum plasma concentration (Tmax) of approximately 0.5 to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 days.[1] Results of a population PK analysis (N = 137) show that there is no relationship between body surface area (BSA) or body weight and clearance (CL). Also, based on stochastic simulations for fixed dose, exposures are independent of the individual patient's BSA.[2] Based on these data, a recommendation was made for fixed dosing in clinical trials. An absolute bioavailability of 67% was determined for MLN9708 using the population PK analysis. See the IB for information on the PK for IV doses of MLN9708. Metabolism appears to be the major route of elimination for MLN9708, with negligible urinary excretion of the parent drug (< 3% of dose). In vitro studies of liver microsomes show that MLN9708 is metabolized by multiple cytochrome P450 enzymes (CYPs) and non-CYP enzymes/proteins. The rank order of relative biotransformation activity of the 5 major human CYP isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%).  
MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4, nor is it a timedependent inhibitor of CYP3A4/5. The potential for MLN9708 treatment to produce DDIs via CYP inhibition is inferred to be low; however, there may be a potential for DDIs with a concomitant strong CYP3A4 or CYP1A2 inhibitor because of the potential for first-pass metabolism when MLN9708 is administered via the PO route and because of the moderate contribution of CYP3A4- and CYP1A2-mediated metabolism of MLN9708 in human liver microsomes. MLN9708 may be a weak substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance associated protein (MRP2) efflux pump transporters. MLN9708 is not an inhibitor of P-gp, BCRP, and MRP2. The potential for DDIs with substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be low.
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1.3.8 clinical trial experience using

In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma), a total of 242 patients have been treated as of 30 April 2012. These patients have been treated with different doses of MLN9708, either as a single agent treatment or in combination with currently clinically available treatments. Information regarding the ongoing studies, patient populations, and doses investigated are included in Table 1-1.  
| Table 1-4                                                                                                                                                                                            | Ongoing Studies of Oral MLN9708                                                                                                              |                                                                                                                       |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|
| Trial/ Population                                                                                                                                                                                    | Description                                                                                                                                  | Doses Investigated                                                                                                    |
| C16003 RRMM N = 58                                                                                                                                                                                   | PO, twice weekly (TW), single agent                                                                                                          | 0.24-2.23 mg/m2 , TW MTD: 2.0 mg/m2 DLT: rash, thrombocytopenia                                                       |
| C16004 RRMM N = 52                                                                                                                                                                                   | PO, weekly (W), single agent                                                                                                                 | 0.24-3.95 mg/m2 , W MTD: 2.97 mg/m2 DLT: rash, nausea, vomiting, diarrhea                                             |
| C16005 NDMM N = 65                                                                                                                                                                                   | PO, W, combination with LenDex                                                                                                               | 1.68-3.95 mg/m2 , W                                                                                                   |
| 28 day cycle                                                                                                                                                                                         | MTD: 2.97 mg/m2 DLT: nausea, vomiting, diarrhea, syncope RP2D*: 4.0 mg fixed (switched to fixed dosing in  phase 2, relevant to 2.23 mg/m2 ) |                                                                                                                       |
| C16006 NDMM N = 28                                                                                                                                                                                   | Arm A*: 3-3.7 mg, fixed dose, TW DLT: rash, thrombocytopenia, subileus Arm B*: 5.5 mg, fixed dose, W DLT: Esophageal ulcer                   |                                                                                                                       |
| C16007 RR-AL N = 6                                                                                                                                                                                   | PO, TW (Arm A- 42 day cycle) and W  (Arm B- 28 day cycle), combination  with melphalan and prednisone PO, W, single agent                    | 4-5.5 mg, fixed dose*, W MTD: 4 mg DLT: thrombocytopenia, dirrhea, dyspnea, acute  rise in creatinine, cardiac arrest |
| C16008 NDMM N=11                                                                                                                                                                                     | PO, TW, combination with LenDex 21                                                                                                           | 3.0-3.7 mg fixed dose* W                                                                                              |
| day cycle                                                                                                                                                                                            | MTD: 4 mg DLT:                                                                                                                               |                                                                                                                       |
| C16009 Solid  tumors,  Lymphomas N = 22                                                                                                                                                              | PO, W, single agent                                                                                                                          | 5.5 mg fixed dose* W                                                                                                  |
| C16010 RRMM N = 1                                                                                                                                                                                    | PO, W, combination with LenDex                                                                                                               | 4.0 mg fixed dose* W                                                                                                  |
| TBMC010034 RRMM N = 5                                                                                                                                                                                                      | PO, W, single agent in 1s part of study  then in combination with LenDex in 2nd part                                                         | 3.0 mg fixed dose* W DLT: thrombocytopenia, nausea, hypertension,  diarrhea                                           |
| Abbreviations: RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = body  surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus |                                                                                                                                              |                                                                                                                       |  
Abbreviations: RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = body surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO =
orally; RRMM = relapsed and/or refractory multiple myeloma; RPh2D = recommended phase 2 dose
* Approximate body surface area (BSA) and fixed dosing equivalence: 3 mg ~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg ~ equivalent to 2.97 mg/m2 BSA
dosing.
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overview of the oral formulation

The emerging safety profile indicates that oral MLN9708 is generally well tolerated with predominant toxicities largely reversible, able to be monitored by routine clinical examinations and manageable by dose reductions, discontinuation, or standard supportive care. From experience from phase 1 through 2 studies the major toxicities can be managed to allow repeat treatment cycles over periods extending beyond 24 months. In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral MLN9708 in patients with differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma), a total of 146 patients have been treated as of 30 April 2012. These patients have been treated with different doses of MLN9708 as they are all phase 1 trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled safety population from single-agent oral MLN9708 Studies (C16003, C16004, C16007, and C16009) is shown in Table 1-2.
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table 1-5 summary of most

| Preferred Term and Incidence                                                                                                                                                                                                                                                    |                                                                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|
| Primary System Organ Class                                                                                                                                                                                                                                                      | N=146 n (%)                                                                                        |
| Subjects with at Least One Adverse Event 135 (92) Gastrointestinal disorders 102 (70)                                                                                                                                                                                           | Nausea 68 (47); Diarrhoea 55 (38); Vomiting 51 (35);  Abdominal pain 21 (14); Constipation 21 (14) |
| General disorders and administration site conditions                                                                                                                                                                                                                            | Fatigue 71 (49); Pyrexia 31 (21); Oedema peripheral                                                |
| 98 (67)                                                                                                                                                                                                                                                                         | 15 (10)                                                                                            |
| Blood and lymphatic system disorders 77 (53)                                                                                                                                                                                                                                    | Thrombocytopenia 60 (41); Anaemia 30 (21);  Neutropenia 23 (16); Leukopenia 15 (10)                |
| Nervous system disorders 63 (43)                                                                                                                                                                                                                                                | Headache 20 (14); Dizziness 18 (12)                                                                |
| Metabolism and nutrition disorders 60 (41)                                                                                                                                                                                                                                      | Decreased appetite 39 (27) Dehydration 21 (14)                                                     |
| Respiratory, thoracic and mediastinal disorders 60  (41)                                                                                                                                                                                                                        | Cough 22 (15); Dyspnoea 21 (14)                                                                    |
| Skin and subcutaneous tissue disorders 60 (41)                                                                                                                                                                                                                                  | Rash macular 17 (12)                                                                               |
| Musculoskeletal and connective tissue disorders 56  (38)                                                                                                                                                                                                                        | Arthralgia 20 (14); Back pain 17 (12)                                                              |
| Infections and infestations 54 (37)                                                                                                                                                                                                                                             | Upper respiratory tract infection 21 (14)                                                          |
| Source: MLN9708 Investigator's Brochure Edition 6  Treatment emergent is defined as any AE that occurs after administration of the first dose of any study drug  through 30 days after the last dose of any study drug, any event that is considered drug-related regardless of |                                                                                                    |  
the start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently considered by the investigator to be drug-related.  
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as the denominator In the 3 studies actively enrolling patients to investigate oral MLN9708 in combination with standard combination regimens in patients with newly diagnosed multiple myeloma, a total of 96 patients have been treated as of 30 April 2012. These patients have been treated with different doses of MLN9708 in combination with lenalidomide and dexamethasone in 2 trials (C16005 and C16008) and with melphalan and prednisone in 1 trial (C16006). The most frequent (at least 10%) adverse events occurring in the pooled safety population from Studies C16005, C16006, and C16008 is shown in Table 1-3. In combinations trials, related is defined as possibly related to any drug in the combination regimen, not just specifically related to MLN9708.
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table 1-6 summary of most

| Preferred Term and Incidence                                                                                                                                     |                                                                    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| Primary System Organ Class                                                                                                                                       | N= 96 n (%)                                                        |
| Subjects with at Least One Adverse Event 135 (92)                                                                                                                | Nausea 32 (33); Constipation 29 (30); Vomiting 25                  |
| Gastrointestinal disorders 70 (73)                                                                                                                               | (26) Diarrhoea 22 (23)                                             |
| General disorders and administration site conditions                                                                                                             | Fatigue 37 (39); Oedema peripheral 20 (21); Pyrexia                |
| 64 (67)                                                                                                                                                          | 19 (20)                                                            |
| Skin and subcutaneous tissue disorders 57 (59)                                                                                                                   | Rash 13 (14)                                                       |
| Nervous system disorders 46 (48)                                                                                                                                 | Neuropathy peripheral 13 (14); Dysgeusia 12 (13) Dizziness 11 (11) |
| Musculoskeletal and connective tissue disorders 45  (47)                                                                                                         | Back pain 18 (19); Muscle spasms 10 (10)                           |
| Blood and lymphatic system disorders 42 (44)                                                                                                                     | Thrombocytopenia 28 (29); Anaemia 22 (23);  Neutropenia 19 (20)    |
| Infections and infestations 40 (42)                                                                                                                              | Upper respiratory tract infection 17 (18);                         |
| Metabolism and nutrition disorders 38 (40)                                                                                                                       | Decreased appetite 11 (11)                                         |
| Respiratory, thoracic and mediastinal disorders 34  (35)                                                                                                         | Dyspnoea 13 (14); Cough 11 (11)                                    |
| Psychiatric disorders 23 (24)                                                                                                                                    | Insomnia 15 (16)                                                   |
| Source: MLN9708 Investigator's Brochure Edition 6.  Treatment emergent is defined as any AE that occurs after administration of the first dose of any study drug |                                                                    |  
Source: MLN9708 Investigator's Brochure Edition 6. Treatment emergent is defined as any AE that occurs after administration of the first dose of any study drug  
through 30 days after the last dose of any study drug, any event that is considered drug-related regardless of  
the start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently considered by the investigator to be drug-related.  
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as the denominator.  
The clinical experience with MLN9708 also shows early signs of antitumor activity as evidenced by at least a 50% reduction in disease burden in some patients and prolonged disease stabilization in others across all ongoing trials. The antitumor activity has been seen with single-agent MLN9708, when combined with established therapies, and across the malignancies studied (advanced solid tumors [3], non-Hodgkin's disease, Hodgkin's disease
[4], relapsed and/or refractory multiple myeloma [RRMM; 5; 6], relapsed or refractory systemic light chain amyloidosis [RRAL; 7], and newly diagnosed multiple myeloma [NDMM; 8; 9; 10]) to date. Though additional data are needed to characterize the clinical benefit of this drug, the emerging data supports the ongoing development of MLN9708. Of particular relevance to this study (C16011) is the clinical experience from Studies C16004 and C16007 in which single-agent MLN9708 is administered weekly in patients with RRMM or RRAL, respectively. 1.3.9 Relapsed and/or Refractory Multiple Myeloma Study C16004 is an open-label, dose-escalation, phase 1 study of MLN9708 administered weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients with MM enrolled in the dose-escalation component of the study have relapsed following at least 2 lines of therapy, which must have included bortezomib, thalidomide (or lenalidomide), and corticosteroids. The dose-escalation phase of the trial has completed. In this study, 2 of 3 patients experienced protocol-defined DLTs (Grade 3 rash and Grade 3 nausea, vomiting, and diarrhea) at a dose of 3.95 mg/m2. As per protocol, subsequent patients were treated at 1 dose level below (2.97mg/m2) where 1 of 6 patients experienced a DLT (Grade 3 nausea, vomiting, and diarrhea). The MTD of weekly oral MLN9708 was determined to be 2.97 mg/m2. Once the MTD was established, cohorts of patients representing the heterogeneous patient population currently seen in clinical practice were enrolled in order to further evaluate the safety, tolerability, efficacy, PK, and pharmacodynamics of oral MLN9708. The MTD expansion cohorts enrolling are: 1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression while on therapy or within 60 days after the last dose of therapy]; 2. Carfilzomib expansion cohort  
3. Proteasome Inhibitor-Naïve expansion cohort
4. VELCADE-Relapsed expansion cohort Final study results are not available for this ongoing trial, but preliminary data suggest MLN9708 has antitumor activity in heavily pretreated MM patients, with durable responses/disease control, and is generally well tolerated.[11,12] As of the 30 April 2012 data cut, these patients are considered heavily pretreated as evidenced by a median number of 4 (range 1–13) prior lines of therapy, with 66% refractory to the last line of therapy. Patients have received a median of 2 cycles of therapy (range, 1- 11). Five patients have achieved objective response: 1 patient achieved a VGPR and 4 patients achieved a PR. Additionally, 15 patients achieved durable disease stabilization for up to 9.5 months. At data cut-off, 15 patients remain on treatment; discontinuation of treatment was primarily due to progressive disease (69%). A summary of the safety profile of patients treated in Study C16004 is outlined in Table 1-4. Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline Grade 1 PN at study entry.
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table 1-7 study c16004 oral

| Common TEAEs as of 30 April 12 (N= 52)                                                                                                                                                                                      |                                                                                                                                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| Most Common (> 20%) Any Grade and Irrespective                                                                                                                                                                              | Thrombocytopenia (54%)                                                                                                                                    |
| of Cause                                                                                                                                                                                                                    | Fatigue (48%) Nausea (44%), diarrhea (44%) Vomiting (37%) Decreased appetite (33%) Rash* (31%) Anemia (25%) Neutropenia (23%)                             |
| Drug-Related Grade  3 in > 5% of patients                                                                                                                                                                                  | Thrombocytopenia (38%) Diarrhea and neutropenia 17% (each), fatigue and  lymphopenia 10% (each), nausea and decreased  appetite 8% (each) and vomiting 6% |
| Source: MLN9708 Investigator's Brochure Edition 6 * Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash pruritic, pruritus,, rash erythematous, exfoliative rash, and rash popular |                                                                                                                                                           |  
Dose reductions required were due to AEs that included rash, neutropenia, thrombocytopenia, diarrhea, nausea, vomiting, dehydration, hypotension, increase in serum creatinine, abdominal CASE 4A13 A9 04/03/2017 32 pain, ileus, fatigue, and pneumonia. The AEs reported for the 5 patients who were required to discontinue treatment included Grade 2 MLN9708-related nausea/vomiting in 1 patient treated above the MTD, Grade 3 MLN9708-related diarrhea in a second patient, related Grade 3 thrombocytopenia, related Grade 2 dyspnea, and notrelated Grade 4 elevation in creatinine(1 patient each). There were no on-study deaths. Study C16007 is evaluating single agent weekly , Day 1, 8, and 15 of a 28-day cycle, oral dosing in patients with RRAL after at least 1 prior therapy. The objectives of this study are to determine the safety, tolerability, and MTD, as well as to determine hematologic and organ response rates in this patient population. The starting dose level was selected from Study C16004 as previously described. In Study C16007 the dose was switched from the BSA-based dosing to the fixed dose, thereby the 4.0 mg fixed starting dose in Study C16007 corresponds to the 2.23 mg/m2 dose (one dose level below MTD) from Study C16004. This study is currently enrolling patients in the dose-expansion portion of the trial. As of 30 April 2012, 14 patients have been treated in this study. At the first dose level of 4.0 mg, 1 of 6 patients experienced a protocol-defined DLT (that is, thrombocytopenia that lasted more than 2 weeks, which met the definition of a DLT due to the delay in starting Cycle 2). As per protocol, the dose was escalated to 5.5 mg for the next cohort of patients where 2 of 5 patients experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, Grade 2 acute rise in serum creatinine, and Grade 4 cardiac arrest, n=1). The latter patient did not appear to have cardiac AL amyloidosis by echocardiogram on study entry, but did have substantial renal involvement. After the occurrence of this DLT, diagnoses included cardiac involvement and CHF. The MTD of weekly oral MLN9708 was determined to be 4.0 mg. Following the establishment of the MTD, patients are currently being enrolled in to 1 of 2 cohorts:
proteasome inhibitor naïve or proteasome inhibitor exposed.[13] As of the 30 April 2012 data cut, the patients enrolled in the study are considered heavily pretreated, as evidenced by a median number of 3 prior lines of therapy (range 1–7), with 38% and 46% of patients having been previously treated with bortezomib and lenalidomide, respectively. To be eligible for the study, patients must have amyloid involvement of the heart, kidney, or both; at the data cut the organ involvement distribution was 6, 4, and 4 patients, respectively. Patients have received a median of 2.5 cycles of therapy (range, 1-12). Eight patients remain on treatment. Early signs of activity have been reported. There were 11 patients who have received at least 1 cycle of therapy with completed response assessments (9 in the 4.0 mg [MTD] cohort and 2 in the 5.5 mg cohort). The overall hematologic response rate at MTD is 56% (5 patients achieved a hematologic response [4 VGPR and 1 PR]; 3 patients showed no change, and 1 patient had an early progression. A summary of the safety profile of patients treated in Study C16007 is outlined in Table 1-5. Overall, 86% of patients experienced a TEAE of any grade and of any cause.
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table 1-8 study c16007 oral

| Most Common (> 20%)                               | Nausea (50%)                                                                                                                           |
|---------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|
| Any Grade and Irrespective of Cause               | Fatigue (36%) Thrombocytopenia (29%) Diarrhea (29%) Decreased Appetite (21%) Peripheral Edema (21%) Dyspnea (21%) Abdominal pain (21%) |
| Drug-Related Grade  3 in more than 3 Patients    | Thrombocytopenia 5 patients, rash 3 patients,  dehydration 2 patients, fatigue 2 patients                                              |
| Source: MLN9708 Investigator's Brochure Edition 6 |                                                                                                                                        |  
One patient discontinued study drug administration due to a TEAE (patient with DLT of acute rise in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted above). No death has been reported. The potential risks reported with MLN9708 use, pooled from all studies using the oral formulations, were anticipated based on preclinical data and previous experience with VELCADE and are noted in the MLN9708 IB, SMA, and ICF documents. Regardless of whether MLN9708 is administered on the once weekly or twice weekly dosing schedule, there is consistency among the type of TEAEs reported, despite some differences in the frequency and severity of the reported events. While the predominant potential toxicities may be severe in some cases, they are largely reversible, and can be managed by routine clinical monitoring and standard medical interventions, which may include dose reductions and supportive care. Please refer to the MLN9708 IB and SMA for further information. 1.3.10 Newly Diagnosed Multiple Myeloma (NDMM) In Study C16005, MLN9708 is given weekly (Days 1, 8, and 15), in combination with lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle. Enrollment to this study is closed.  
CASE 4A13 A9 04/03/2017 34 Clinical data as of 30 April 2012 is available. The MTD in Study C16005 was determined to be 2.97 mg/m2 given weekly in a 28-day cycle with LenDex. The DLTs were urticarial rash, dizziness, nausea, orthostatic hypotension, vomiting, diarrhoea, and syncope. The recommended phase 2 dose (RP2D) estimation was established following evaluation of the available data from the phase 1 portion of the trial which included, but was not limited to, analyses of efficacy results and adverse events (Grade 3/4 AEs, SAEs, all grades peripheral neuropathy, and treatment discontinuation). Given that the dose of MLN9708 at 2.97 mg/m2 compromised the maximal dosing of lenalidomide and that the dose of 2.23 mg/m2is very tolerable and clinically active, Millennium designated 2.23 mg/m2as the RP2D after evaluation of the data and discussion with investigators. The RP2D of 2.23 mg/m2has been translated into a fixed dose of 4.0 mg based on the results from the population PK analysis. Enrollment in this study has been completed; final study results are not available, but preliminary data suggests oral MLN9708 given weekly plus lenalidomide and dexamethasone in a 28-day cycle appears well tolerated with manageable toxicity and encouraging antitumor activity. In Study C16005, 15 of 15 (100%) patients in the dose escalation portion of the study experienced at least 1 TEAE irrespective of grade or causality. At the MTD across all dose expansion cohorts 49 of 53 patients (including 3 patients from the dose escalation cohort [92%]) reported at least 1 TEAE irrespective of grade or causality. In the MTD cohorts, fatigue was the most common AE reported (38%). Other common AEs reported include nausea (32%), constipation (30%), upper respiratory infection (23%), and peripheral oedema (21%). Skin toxicity, primarily erythematous rash, occurred in 62% of patients (of note, rash is an overlapping toxicity with MLN9708 and lenalidomide). Peripheral neuropathy was reported in 13% of patients; Grade 3 in 1 patient. A summary of the overall safety profile of patients treated in Study C16005 is outlined in Table 1-6. Overall, 100% of 65 patients experienced at least one TEAE of any grade and of any cause.  
| Most Common (> 20%) Any Grade and Irrespective of   | Fatigue (37%)                                                                                                                                                           |
|-----------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Cause                                               | Nausea (34%) Constipation (31%) Vomiting (28%) Diarrhoea (26%) Thrombocytopenia (23%) Upper respiratory tract infection (22%) Anaemia and oedema peripheral ( 20% each) |
| Drug-Relateda Grade  3 in  2 Patients             | Nausea, vomiting (n=3 each)                                                                                                                                             |
| CASE 4A13 A9 04/03/2017                             | 35                                                                                                                                                                      |
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table 1-9 study c16005 oral

Source: MLN9708 Investigator's Brochure Edition 6.  
a Related means to ANY drug in the study drug combination.  
The most common drug-related SAEs reported in Study C16005 as of 30 April 2012 include pneumonia, infection, diverticulitis, localised infection, gastrointestinal haemorrhage, respiratory syncytial virus (RSV) pneumonia faecaloma, pyrexia, pneumonia respiratory syncytial viral, non-cardiac chest pain, peripheral oedma, asthenia, hyponatraemia vomiting, diarrhoea, nausea, chest pain, dehydration, anemia, dizziness, peripheral sensory neuropathy, orthostatic hypotension, embolism, muscular weakness, acute renal failure, blood creatinine increased, maculopapular rash, atrial fibrillation, syncope, hypotension, and deep vein thrombosis, and back pain. As of the clinical data cutoff, 4 patients have discontinued treatment due to TEAEs including gastrointestinal haemorrhage, angioedema, syncope, and RSV pneumonia. One death was reported for a patient with RSV pneumonia; the event was deemed by the investigator to be related to treatment with MLN9708.
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1.3.11 clinical trial experience using

See the IB for descriptions of the 2 ongoing studies investigating IV MLN9708 in advanced solid tumors and advanced lymphoma (Studies C16001 and C16002, respectively). Please refer to the current MLN9708 Investigator's Brochure (IB) and Safety Management Attachment (SMA) for more information.
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1.3.12 potential risks of mln9708

Safety information from toxicology studies as well as the preliminary safety information gained from clinical Studies C16001, C16002, C16003, C16004, C16005, C16006, C16007, C16008, and C16009 has been used to guide the safety evaluation of MLN9708. As of 30 April 2012, safety data is available for 382 patients who have received multiple cycles of therapy (between 1 and 28 cycles of MLN9708 therapy). Adverse events reported in MLN9708 clinical trials are generally consistent with the class-based effects of proteasome inhibition and are generally similar to what has been previously reported with VELCADE, though the severity of some, for example peripheral neuropathy, is less. While some of the potential toxicities may be severe, they can be managed by clinical monitoring and standard medical intervention, or, as needed, CASE 4A13 A9 04/03/2017 36 dose modification or discontinuation. Each protocol recommends that patients are monitored closely for the anticipated potential toxicities, as well as for any unanticipated toxicities when they receive MLN9708, and for at least 30 days after their last dose.
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1.3.12.1 potential risks by system

Blood and lymphatic system disorders: Neutropenia, anemia, lymphopenia. Reductions in blood counts may predispose patients to an increased susceptibility to infection (see Infections and infestations below) and anemia. Reticulocytopenia was described in animals and may be associated with anemia.  
Gastrointestinal disorders: Constipation, intestinal obstruction including ileus and intussusception (described in animal studies), abdominal pain.  
General disorders and administration site conditions: Pyrexia, chills, influenza like illness, edema peripheral.  
Infections and infestations: Pneumonia. Lymphopenia may be associated with increased risk of infection, including re-activation of herpes zoster.  
Investigations: Blood creatinine increased (see Renal and urinary disorders below).  
Metabolism and nutrition disorders: Decreased appetite, dehydration, electrolyte imbalance.  
Musculoskeletal and connective tissue disorders: Back pain, myalgia, arthralgia, bone pain, pain in extremity.  
Nervous system disorders: Headache, dizziness, neuropathy peripheral (includes pain, burning sensation, and numbness), and syncope. In addition, autonomic and motor neuropathy may be observed, as both have been reported for VELCADE, another proteasome inhibitor. Posterior reversible encephalopathy syndrome (PRES) has been reported with MLN9708 (this event was reported after the data cut-off date, 30 April 2012). PRES has also been reported for VELCADE (refer to VELCADE for Injection Package Insert).  
Renal and urinary disorders: Renal impairment, renal failures, and renal failure acute have been reported in association with dehydration due to nausea, vomiting, anorexia, and/or diarrhea, the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and/or disease progression. In some situations, this has been severe, requiring temporary dialysis.  
Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, upper respiratory tract infection, pneumonitis.  
Skin and subcutaneous tissue disorders: A rare risk is Stevens-Johnson Syndrome, a severe, life-threatening or deadly rash with skin peeling and mouth sores, which should be managed symptomatically according to standard medical practice. Stevens-Johnson syndrome has also been reported for VELCADE (refer to VELCADE for Injection Package Insert). It is also reported as risk with lenalidomide, an agent used in the treatment of hematologic malignancies including in combination with proteasome CASE 4A13 A9 04/03/2017 37
inhibitors. For more information about this risk with lenalidomide refer to the Revlimid (lenalidomide) Package Insert.  
Vascular disorders: Hypotension, orthostatic hypotension.  
Other: Acute phase response that may result in fever and metabolic changes (observed only in nonclinical studies). Infrequent incidences of tumor lysis syndrome have also been reported. Supplemental information is provided in the current edition of the IB. 2 **Study rationale/purpose** Multiple myeloma refractory to bortezomib and refractory to, relapsed after, or ineligible for IMiDs constitutes an unmet medical need with EFS and OS of 5 and 9 months, respectively, and response and clinical benefit response rates of 24 and 34%, respectively 49. A recently presented study suggests bortezomib refractoriness of multiple myeloma may be overcome by combination with panobinostat and dexamethasone. Enrolled patients were refractory to their last bortezomib containing regimen and achieved a remarkable response rate of 35% and clinical benefit response rate of 53% 7. The oral proteasome inhibitor MLN9708 (ixazomib)
appears to not only be more convenient than bortezomib but also safer; with an otherwise comparable safety profile it has not caused any severe neuropathy at doses that had single agent activity in relapsed and refractory multiple myeloma when used in a twice a week dosing schedule 10 or administered weekly 9. The MTD for MLN9708 (ixazomib), when given twice a week (day 1,4,8,11 every 21 days) to patients with relapsed or refractory multiple myeloma was established at 2mg/m2, whereas weekly administration (day 1,8,15 every 28 days) was tolerated at higher doses (MTD 2.97mg/m2) in a comparable patient population 9,10. Another study used MLN9708 (ixazomib) in a weekly administration schedule (day 1,8,15 every 28 days) in combination with lenalidomide (25mg day 1-21 every 28 days) and dexamethasone (40mg once a week) in newly diagnosed multiple myeloma 8. This study also found the MTD of MLN9708
(ixazomib) to be at 2.97mg/m2 but recommended 2.23mg/m2 for phase 2 evaluation because of improved tolerance. The most common possibly MLN9708 (ixazomib) related adverse events in these studies were thrombocytopenia, neutropenia, fatigue, and gastrointestinal adverse events including nausea and diarrhea. Gupta et al. analyzed pharmacokinetic data of the active metabolite of MLN9708 (ixazomib) from 4 trials that used either IV or PO dosing.  
Using a non-linear mixed effects modeling approach he found that body size affected only volume of distribution but not maximal or AUC concentrations 11. A decision was therefore made by the manufacturer Millennium to use flat dosing in future trials, using 2.3mg, 3mg, and 4mg tablets. Here we aim to develop an "all oral" regimen of proteasome and histone deacetylase inhibition in combination with dexamethasone for future phase 2 study and as a platform for addition of further drugs. Phase II extension: Patients in phase I (median age 65, range 50-73, median previous regimens 5, range 2-10) tolerated treatment without DLT and without non-hematologic severe (grade 3 or higher) adverse event according to CTCAE vs.4.03. Three patients developed grade 3 hematologic toxicities (2 neutropenia, 1 thrombocytopenia). Worst diarrhea was grade 1 (n=6), worst nausea grade 2 (n=1) and 4 additional patients developed transient grade 1 nausea. Other possibly panobinostat or ixazomib related grade 1/2 adverse events included thrombocytopenia (n=5), neutropenia (n=3), fatigue (n=2), anemia (n=2), anorexia (n=1) and arthralgia (n=1).  
CASE 4A13 A9 04/03/2017 38 Median QTcF before treatment start was 405 msec (range 378-430) and increased on average by 4.3% (maximally by 13%). One patient developed transient grade 1 QTcF prolongation to 552 msec. No other cardiac adverse events were observed. Of the 11 patients in phase I, one reached PR, two reached MR, and one had stable disease for 6 months. All patients entered the study with disease refractory to their last regimen, and in two of the responding patients (1PR, 1MR) this included a proteasome inhibitor an IMiD, and a glucocorticosteroid (carfilzomib, pomalidomide, dexamethasone in the MR patient, bortezomib, dexamethasone, lenalidomide in the MR patient). Overall, we are encouraged by activity in extensively pretreated patients and by excellent tolerance of this regimen so far. In phase II we aim to extend the study cohort by an additional 20 patients who will be treated until progression or other reasons for discontinuation arise (7.6.1) to strengthen the safety analysis and obtain a more reliable estimate of activity.
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3 study objectives

3.1 Primary Objective Define the tolerability and safety of MLN9708 (ixazomib) administered on a day 1,8,15 every 28 day schedule up to 4mg in combination with fixed doses of panobinostat and dexamethasone in patients with relapsed or refractory myeloma.  
3.2 **Secondary Objective**
Assess response and clinical benefit response rates according to international uniform response criteria and adapted EBMT criteria, respectively (see under 8.1)
Assess progression-free survival (PFS) and overall survival (OS)
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4 study endpoints 4.1 primary

Dose limiting toxicity (phase I) and tolerance according to CTCAE vs. 4.03 (phase I
and II)
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4.2 secondary endpoints

Response to panobinostat, dexamethasone, ixazomib (MLN9708) will be assessed according to international uniform response criteria and clinical benefit response according to modified EBMT response criteria, comparing myeloma panels obtained at the beginning of each cycle that include SPEP, 24 h UPEP, serum and urine IFEs, and serum free light chains to results at screening. In addition a baseline bone marrow exam and skeletal survey will be obtained and repeated as clinically indicated and for assessment of complete remission (bone marrow).  
Progression-free survival will be measured from study entry to progression or death of any cause, whichever comes first.  
CASE 4A13 A9 04/03/2017 39 Overall survival for all will be measured from study entry to death from any cause.
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5 overall study design treatment

Phase I: This study will use a modified 3 + 3 design to define the tolerability and safety of MLN9708 (ixazomib) administered to at least 6 patients with relapsed or refractory myeloma on a day 1,8,15 every 28 day schedule at up to 4mg in combination with fixed doses of panobinostat and dexamethasone. Dose limiting toxicities (DLTs, see under 5.4) will be assessed at the end of the first cycle, on day 28. The trial will accrue up to three patients at any given DL who will need to be assessed for DLTs before the next three patients can be enrolled. Determination of the highest tolerated dose of two tested dose levels will require treatment of at least 6 patients at the respective dose level with no more than one patient developing a DLT. The first three patients will be treated at DL1. If no patient develops any DLT, the next three patients will be enrolled at DL2. If 1 patient develops any DLT, three additional patients will be enrolled at DL1. If no more than 1 of 6 patients treated at DL1 develops a DLT, the next three patients will be enrolled at DL2. If 2 or more of 2-6 patients treated at DL1 develop DLTs further enrollment will be stopped and a change in the protocol will be discussed. If DL2 opens to enrollment, and 0-1 of the first three patients develop any DLT, additional three patients will be enrolled at DL2 and if no more than 1 of 6 patients treated at DL2 develop any DLT, DL2 will be considered a tolerated MLN9708 dose and further dose escalation will not be done. If 2 of three or up to 6 patients enrolled at DL2 develop any DLT, further enrollment at that dose level will be stopped and enrollment will continue at DL1 unless 6 patients have already been treated at that dose level. If no more than 1 patient treated at DL1 develops any DLT that dose level will be considered tolerated and an intermediate dose level may be discussed. If 2 or more of up to 6 patients treated at DL1 develop a DLT, further enrollment will be stopped and a change in the protocol will be discussed. Phase II: Twenty additional patients will be treated at target doses of DL2 which has been found to be well tolerated without any DLT in phase I.  
5.2 Study duration Phase I: Patients will remain on study for six 28-day cycles or until criteria for discontinuation (7.6.1) are met, whichever comes earlier. Decisions on subsequent maintenance therapy will at the discretion of the treating physician. If the patient's myeloma is controlled in at least stable disease panobinostat may be continued free of charge to the patient. Follow up after completion of cycle 6 is at the discretion of the treating physician but if panobinostat is continued, monitoring for electrolyte abnormalities, especially potassium and magnesium, at a frequency appropriate for the respective patient, is recommended. This protocol may be amended to include a formal maintenance phase and/or a phase II portion after review of safety and preliminary efficacy data. Phase II: Patients will receive therapy according to DL2 and will remain on study until criteria for discontinuation (7.6.1) are met.
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5.3 dose levels dose levels

| PO Panobinostat   | PO                           | MLN9708            | PO Dexamethasone             |
|-------------------|------------------------------|--------------------|------------------------------|
| (Ixazomib)        |                              |                    |                              |
| 1                 | 20mg d 1,3,5,15,17,19 q 28 d | 3mg d1,8,15 q 28 d | 20mg d 1,2,8,9,15,16 q  28 d |
| 2                 | 20mg d 1,3,5,15,17,19 q 28 d | 4mg d1,8,15 q 28 d | 20mg d 1,2,8,9,15,16 q  28 d |  
Dose limiting toxicity (DLT) will be assessed during the first cycle and be defined as the following drug-related adverse events according to CTCAE version 4.03 (if an adverse event is attributed to progressive disease, it will not be counted as DLT):
Grade 4 or higher neutropenia or thrombocytopenia that does not resolve to grade 3 or lower within 7 days after detection while MLN9708 (ixazomib) and panobinostat are held.  
Use of G-CSF or platelet transfusions in cycle one Neutropenic fever (with grade 3 or grade 4 neutropenia) QTcF increase to > 480 msec that persists > 7 days after withholding panobinostat and MLN9708 Any grade 3 or higher non-hematologic adverse events except:
o Nausea, vomiting, diarrhea, or electrolyte abnormalities that can be reduced to grade 2 with supportive measures within 7 days
Patients who cannot be assessed for DLT due to progressive disease or other reasons will be replaced. Patients who develop a DLT may remain on study.
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6 study population

Patients with relapsed or refractory myeloma after at least two previous regimens including a proteasome inhibitor and an IMiDTM seen at the Cleveland Clinic Taussig Cancer Center will be screened for enrollment. Approximately 700 patients with multiple myeloma are seen each year at this site and approximately 600 have relapsed or refractory myeloma. The study will be offered to our partner institution within the Case Comprehensive Cancer Center, the Seidman Cancer Center of University Hospitals and Case Western University, where approximately 100 patients with relapsed or refractory multiple myeloma are seen each year. Participation is expected and would not alter per patient costs. We have accrued 11 patients to phase I in about 12 months and expect to enroll to phase II at a faster pace since no interruptions for DLT assessments will be required. We anticipate it will take about 18 months to accrue additional 20 patients to phase II. .
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6.1.1 patient population

Eleven patients have been enrolled to phase I and an additional 20 patients are planned for phase two totaling 31 patients for the entire study.
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6.1.2 inclusion and exclusion criteria

Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and exclusion criteria. Results of all baseline evaluations, which assure that all inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal Investigator prior to enrollment of that patient. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule and required evaluations and all regulatory requirements for informed consent. The written informed consent must be obtained from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the study unless otherwise specified.
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inclusion criteria

1. Male or female patients aged ≥ 18 years old  
2. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed 3. Patients must carry a diagnosis of symptomatic multiple myeloma according to international myeloma working group criteria 50 and have relapsed or refractory disease according to international uniform response criteria and must have previously received therapy with a proteasome inhibitor and an IMiDTM 51,52(see also 6.2).  
4. Must have measurable disease defined as any of the following: Serum m-spike > 1g/dL, 24 h urine m-spike of at least 200mg/d, involved serum free light chains > 100mg/L with abnormal serum free light chain ratio, bone marrow plasma cells of at least 30%
5. ECOG PS < 2 6. No gastro-intestinal condition, that in the opinion of the treating physician or the principal investigator significantly limits oral absorption 7. No serious uncontrolled coexisting medical condition 8. Patients must meet the following laboratory criteria:
ANC ≥ 1.0 x 109/L without use of pegfilgrastim in the preceding 21 days and without non-pegylated G-CSF or GM-CSF within 7 days prior to study entry Hemoglobin ≥ 8 g/dl (may be after transfusion of packed red blood cells or use of erythropoiesis stimulating agents)
Platelets ≥ 70x 109/L without platelet transfusion 7 days prior to study entry  
AST and ALT ≤ 2.5 x ULN
Serum bilirubin  1.5 x ULN
Serum potassium ≥ LLN and serum magnesium ≥ LLN (electrolyte levels may be achieved with repletion or other supportive medications like potassium sparing diuretics) Creatinine clearance  30 mL/min according to Cockroft-Gault formula (see Section 22)
Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.  
9. Baseline MUGA or ECHO must demonstrate LVEF ≥ 45%
10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to start of study treatment 11. Male patients, even if surgically sterilized (i.e., status post vasectomy), have to either:
Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study treatment, OR
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.  
12. Female patients have to fulfill one of the following:
Be postmenopausal for at least 1 year before the Screening visit, OR
Be surgically sterile, OR If of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study treatment Oral contraceptives are generally metabolized by CYP3A4. Since the induction potential of panobinostat to induce CYP3A4 is unknown, patients who are using oral contraceptives as a method of contraception, and are sexually active, should use another effective contraceptive method, AND Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
13. At least 7 days must have passed since the last treatment with lenalidomide, pomalidomide, thalidomide, proteasome inhibitors, or low dose cyclophosphamide (up to 50mg daily), at least 21 days must have passed since the last treatment with daratumumab, elotuzumab, investigational therapy and most conventional chemotherapy including cyclophosphamide above 50mg per dose, bendamustine, doxorubicin, cisplatin, and etoposide; and at least 35 days since the last treatment with melphalan.
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exclusion criteria

1. Prior anti-cancer treatment with MLN9708 (ixazomib), HDAC, DAC, HSP90 inhibitors or valproic acid 2. Prior participation in a randomized controlled study that included MLN9708 (ixazomib) in one of the treatment arms independent of whether assigned to MLN9708 (ixazomib) or not 3. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment 4. Female patients who are lactating or have a positive serum pregnancy test during the screening period.  
5. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible)
Any history of ventricular fibrillation or torsade de pointes Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm.  
Screening ECG with a QTcF > 470 msec (QTcF=QT/3√RR). If potassium or magnesium blood levels are below normal limits, consider repeating ECG after correction of these electrolytes.  
Right bundle branch block + left anterior hemiblock (bifascicular block) Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
6. Impairment of GI function or GI disease that may significantly alter the swallowing absorption of panobinostat and MLN9708
CASE 4A13 A9 04/03/2017 44  
7. Patients with diarrhea > CTCAE (version 4.03) grade 2 8. Patient has  Grade 3 peripheral neuropathy, or > Grade 2 with pain on clinical examination during the screening period.  
9. Patients with known metastasis of malignant plasma cells to the central nervous system (if not suspected no specific testing is required)
10. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol 11. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug. If an alternative medication that does not risk QT prolongation can safely be used in the opinion of the treating physician and the treatment is changed to that medication, the patient may be enrolled.  
12. Patients who have not passed the nadir of bone marrow suppression from previous antimyeloma therapy yet. If in doubt, serial CBCs with differential should be obtained.  
13. The corticosteroids prednisone and dexamethasone may be continued until the day before treatment start if all related adverse events are controlled at CTCAE version.4.03 grade < 1.
14. Patients who have received radiation therapy to more than half of the pelvis or more than half of the spine within < 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.  
15. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
16. Systemic treatment, within 14 days before study enrollment, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.  
17. Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis.  
18. Concurrent diagnosis of another malignancy if either systemic treatment or surgery is expected to be required within 2 years from study entry.
19. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.  
20. Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.  
21. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment unless the patient is felt to have fully recovered and any antibiotics that are continued are either beta lactam antibiotics or are specifically allowed on study according to 7.7.1 22. Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial.
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6.2 definition relapsed myeloma and

An ASH/FDA panel has recommended to include clinical criteria to define relapsed myeloma and to separately analyze data for the relapsed as opposed to the refractory group of patients 52.  
In accordance with this consensus statement, International Myeloma Working Group diagnostic criteria 50, and the international uniform response criteria 51 the following definitions will be used:
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6.2.1 refractory myeloma

Biochemical or clinical evidence of loss of disease control within 60 days after the last therapy. Any of the following defines refractory myeloma:
1. Progressive disease (see 8.1.1) on prior therapy  
2. Best response to prior therapy was stable disease (see 8.1) 3. Progressive disease (see 8.1.1) within 60 days of the last therapy
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6.2.2 relapsed myeloma

Not fulfilling criteria for refractory disease and at least one biochemical and at least one clinical criterion fulfilled indicating recurrence of disease more than 60 days after the last therapy:
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one or more biochemical criteria

An increase of 25% from lowest response value in **any one or more** of the following, verified on two consecutive measurements:
1. Serum M-component (absolute increase must be >0.5 g/100 ml) * 2. Urine M-component (absolute increase must be >200mg per 24 h) 3. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >100 mg/l)
4. Bone marrow plasma cell percentage (absolute % must be >10%)
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and one or more clinical

1. Definite development of new bone lesions or soft tissue plasmacytomas  
2. Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. A
definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of each measurable lesion 3. Development of hypercalcemia (corrected serum calcium >11.5mg / 100ml) that can be attributed solely to the plasma cell proliferative disorder 4. Decrease of hemoglobin by at least 2g/dL below the best independent value (without ESA or blood transfusion for at least 28 days) since the end of previous therapy or new decrease in HgB below 10g/dL or to 2g/dL below the lower limit of normal 5. New increase in serum creatinine to > 2mg/dL, or increase by 2mg/dL attributed to myeloma progression
*: If the starting serum m-protein level is >5g/dL an absolute increase of >1g/dL, verified on two consecutive measurements, is sufficient as a biochemical criterion for recurrent disease.
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7 treatments 7.1 investigational therapy

Panobinostat (also known as LBH589) will be provided by Novartis. Oral panobinostat will be supplied as 5-mg, 15-mg, or 20-mg pink/opaque-colored, hard gelatin capsules. Medication labels will comply with US legal requirements and be printed in English. They will supply no information about the patient. The storage conditions for study drug will be described on the medication label. During the study, panobinostat will be administered orally as once daily dose of 20 mg.  
according to the schedule in 5.3.  
Patients should be instructed to take their once-a-day oral dose of panobinostat at the same time each morning. Each dose of panobinostat should be taken with an 8 oz / 240 ml glass of water after a meal. Patients should be instructed to swallow the capsules whole and not chew them. Patients must avoid grapefruit or grapefruit juice and seville (sour) oranges during the entire study. On the days of ECG monitoring, drug administration should be supervised by study center personnel and administration time should be recorded. Subsequently, ECGs should be performed at the predefined time points.) If the patient forgets to take his/her dose during the morning on scheduled treatment day, then he/she should take panobinostat (LBH589) on that same day within 12 hours after the missed dose if possible. After more than 12 hours, that day's dose should be withheld, and the patient should wait to take LBH589 until the next scheduled treatment day (i.e., patients should be instructed not to try to make-up the missed dose after 12 hours). The patient should then continue treatment with the original dosing schedule CASE 4A13 A9 04/03/2017 47 The investigator should instruct the patient to take the study drug exactly as prescribed (promote compliance). All dosages prescribed and dispensed to the patient and all dose changes during the study should be recorded.
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7.1.2 mln9708 (ixazomib)

All protocol-specific criteria for administration of study drug must be met and documented before drug administration. Study drug will be administered only to eligible patients under the supervision of the investigator or identified sub investigator(s). Patients should be monitored for toxicity, as necessary, and doses of MLN9708 should be modified as needed to accommodate patient tolerance to treatment; this may include symptomatic treatment, dose interruptions, and adjustments of MLN9708 dose (see under 7.5).
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7.1.2.1 mln9708 (ixazomib) administration

Capsules of MLN9708 will be supplied by Millennium as capsules of 2.3 mg, 3.0 mg, and 4.0 mg MLN9708. The prescribed administration of MLN9708 doses and schedules in this study are outlined in 5.3 Patients should be instructed to swallow MLN9708 capsules whole, with water, and not to break, chew, or open the capsules. Study drug should be taken on an empty stomach (no food or drink) at least 1 hour before or 2 hours after a meal. A total of approximately 8 ounces (240 mL) of water should be taken with each capsule. Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 72 hours or more away. A double dose should not be taken to make up for a missed dose. If the patient vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the time of the next scheduled dose.
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7.1.2.2 mln9708 destruction

Investigational MLN9708 (expired or end of study) should be destroyed on site according to the institution's standard operating procedure. Be sure to document removal and destruction on drug accountability logs.
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7.1.2.3 packaging and labeling of

For blistered material, the capsules are packaged in cold form foil-foil blisters with a paper backing for child-resistance. MLN9708 is an anticancer drug and as with other potentially toxic compounds caution should be exercised when handling MLN9708 capsules. The study drug MLN9708 capsules will be provided by Millennium. The study drug will be labeled and handled as open-label material, and packaging labels will fulfill all requirements CASE 4A13 A9 04/03/2017 48 specified by governing regulations. The formulation consists of 0.5-, and 2.0-mg capsules for oral administration. MLN9708 capsules should be stored unopened at 2°C to 8°C (36°F-46°F). The capsules are individually packaged in cold form foil-foil blisters in a child-resistant package. The 0.2-, 0.5-
, and 2.0 mg capsules are in 1  4 blister strips that are individually perforated. The strips (1 4) are placed in cartons containing 6 strips (24 total capsules) of the same strength. The 2.3-, 3.0-, and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-resistant cardboard wallet.
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storage handling and accountability

Upon receipt at the investigative site, MLN9708 should remain in the blister and carton provided until use or until drug is dispensed. The container should be stored at the investigative site refrigerated (36°F to 46°F, 2°C to 8°C). All excursions should be brought to Millennium's attention for assessment and authorization for continued use. Ensure that the drug is used before the retest expiry date provided by Millennium. Expiry extensions will be communicated accordingly with updated documentation to support the extended shelf life. In countries where local regulations permit, MLN9708 capsules dispensed to the patient for take-home dosing should remain in the blister packaging and refrigerated as noted above until the point of use. The investigative site is responsible for providing the medication to the patient in the correct daily dose configurations. Approval for any patient for take-home medication must be discussed with Millennium in order to ensure the greatest conformity with repackaging, labeling, and patient compliance. Comprehensive instructions should be provided to the patient in order to ensure compliance with dosing procedures. Patients who are receiving take-home medication should be given only 1 cycle of medication at a time. Patients should be instructed to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) for the duration of each cycle. Patients should be instructed to return their empty blister packs to the investigative site, rather than discarding them. Reconciliation will occur accordingly when the patient returns for their next cycle of take-home medication. Any extreme in temperature should be reported as an excursion and should be dealt with on a case-by-case basis. Because MLN9708 is an investigational agent, it should be handled with due care. Patients should be instructed not to chew, break, or open capsules. In case of contact with broken capsules, raising dust should be avoided during the clean-up operation. The product may be harmful by inhalation, ingestion, or skin absorption. Gloves and protective clothing should be worn during cleanup and return of broken capsules and powder to minimize skin contact. The area should be ventilated and the site washed with soap and water after material pick-up is complete. The material should be disposed of as hazardous medical waste in compliance with federal, state, and local regulations. In case of contact with the powder (e.g., from a broken capsule), skin should be washed immediately with soap and copious amounts of water for at least 15 minutes. In case of contact with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. Medical personnel should be notified. Patients are to be instructed on proper storage, accountability, and administration of MLN9708, including that MLN9708 is to be taken as intact capsules.
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7.1.3 cardiac precautions

All patients must have an assessment of serum potassium, magnesium, and calcium (total corrected for albumin, or ionized calcium) ≤ 72 hours prior to the administration of oral panobinostat on day 1 of cycle 1 and the results must all be ≥ LLN before the first dose of panobinostat is administered. Throughout the study serum biochemistry values including serum potassium, calcium, and magnesium will be monitored closely. On any day and time in which serum potassium, calcium, and magnesium are assessed, if the value is < LLN, then the patient's potassium, calcium, or magnesium should be immediately supplemented following the availability of that laboratory result, in order to minimize the time patients have low values. Patients must then undergo a repeat biochemistry test to demonstrate values ≥ LLN. These values must be ≥ LLN before the patient is re-dosed with oral panobinostat. Patients must be instructed to not take panobinostat if their most recent biochemistry values demonstrates potassium, calcium, or magnesium < LLN. At a minimum, potassium, magnesium, and calcium will be checked according to the protocol. More frequent testing should be done if clinically indicated, e.g. patient has had prior low values, patient is taking medications (e.g., diuretics) that can result in lowering of their potassium, magnesium, or calcium levels.  
7.2 Dexamethasone Dexamethasone will be prescribed as 4mg tablets and charged to the patient's insurance. Dexamethasone tablets should be taken after breakfast with approximately 8 ounces (240 mL) of water. Missed doses can be made up until 72h from the next planned dose. Adherence will be evaluated together with adherence to investigational therapy.
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7.3 mandatory concomitant therapy 7.3.1.1

The risk for shingles is increased with proteasome inhibition and can be decreased with prophylactic acyclovir 53. All patients will receive prophylaxis with acyclovir 400mg orally twice a day or valacyclovir 1000mg orally once a day. If the creatinine clearance of a patient drops below 30ml/min while a patient is on study, acyclovir should be reduced to 200mg twice a day and valacyclovir to 500mg orally once a day.
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7.4 instructions for initiation of

A new course of treatment may begin on the scheduled Day 1 of a new cycle (cycle 2 and beyond) if:
ANC ≥ 1.0 x 109/L (G-CSF and GM-CSF are allowed to achieve this threshold) Platelets ≥ 50x 109/L, without platelet transfusion for > 72h AST and ALT ≤ 3 x ULN
Serum bilirubin  3 x ULN
Serum potassium ≥ LLN and serum magnesium ≥ LLN (electrolyte levels may be achieved with repletion or other supportive medications like potassium sparing diuretics)
QTcF < 480 msec if ECG obtained (mandatory before cycle 2)
Any non-hematologic drug-related adverse events that may have occurred have resolved to ≤ grade 1 or baseline severity. Physician discretion may be used in initiating the next cycle of treatment if the only toxicities that have not resolved to ≤ grade 2 severity are dexamethasone-related toxicities.  
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated at least weekly and a new cycle of treatment will not be initiated until the toxicity has resolved as described above. If a prolonged QTcF prevents re-initiation of therapy for more than 7 days the patient will be taken off study. For phase I patients only: If other criteria to initiate a new cycle are not met by 14 days after the planned start of a new cycle patients also go off study.
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7.5 dose modifications for adverse

For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments are permitted in order to keep the patient on study drugs. If administration of panobinostat, MLN9708 (ixazomib), or dexamethasone must be interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified according to guidelines outlined below. Clinical judgment may be used when deciding which drug to hold or modify in scenarios that are not covered below. Also, if the treating physician feels dose reduction by one level will not suffice to avoid recurrence of an observed profound adverse event, dose reduction by more than one dose level or before the severe adverse event occurs is allowed. If an adverse event is felt not related to study drug but continued use of study drugs may worsen the adverse event, holding the respective study drug until resolution of the adverse event without dose reduction at reinitiation of therapy is allowed. Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 4.03 (CTCAEv4.03, (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf). All interruption or changes to study drug administration must be recoded.
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7.5.2 dose re-escalation guidelines

If an entire cycle was tolerated without need for dose reduction and it is felt that the patient may tolerate a re-escalation of study therapy due to improved disease control or optimized supportive measures, doses may be increased by one level per cycle for either ixazomib (MLN9708) or panobinostat with or without concurrent increase of dexamethasone up to maximally starting dose level.  
Table 7-1 **Dose modification (DM) levels for adverse events attributed to MLN9708**  
| DM Level   | MLN9708 dose modification dependent on starting dose (maintain schedule of  administration on day 1,8,15 every 28 days in all DM levels) Starting dose   |       |
|------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|-------|
| 0          | 3mg                                                                                                                                                      | 4mg   |
| -1         | 2.3mg                                                                                                                                                    | 3mg   |
| - 2        | Discontinue MLN9708                                                                                                                                      | 2.3mg |
| -3         | Discontinue MLN9708                                                                                                                                      |       |  
| DM Level                                | Panobinostat             | dose   | (maintain   | schedule   | of   | administration   | on   | d   |
|-----------------------------------------|--------------------------|--------|-------------|------------|------|------------------|------|-----|
| 1,3,5,15,17,19 q 28 d in all DM levels) |                          |        |             |            |      |                  |      |     |
| 0                                       | 20mg                     |        |             |            |      |                  |      |     |
| -1                                      | 15mg                     |        |             |            |      |                  |      |     |
| -2                                      | 10mg                     |        |             |            |      |                  |      |     |
| -3                                      | 5mg                      |        |             |            |      |                  |      |     |
| -4                                      | Discontinue panobinostat |        |             |            |      |                  |      |     |  
Dose modification (DM) levels for adverse events attributed to panobinostat and MLN9708 Modify dosing schedules as outlined in table 7-1 and 7-2 alternating between panobinostat and MLN9708, starting with panobinostat
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table 7-3 dose modification (dm)

| DM Level                | Dexamethasone               |
|-------------------------|-----------------------------|
| 0                       | 20mg d 1,2,8,9,15,16 q 28 d |
| CASE 4A13 A9 04/03/2017 | 52                          |  
| -1   | 20mg d 1,8,15,22 q 28 d   |
|------|---------------------------|
| -2   | 16mg d 1,8,15.22 q 28 d   |
| -3   | 12mg d 1,8,15,22 q 28 d   |
| -4   | Discontinue dexamethasone |  
7.5.3 Dose modifications for study drug-related toxicity (see section 7.5.4 for dose