clinical study protocol
protocol information

Protocol Number: MMRC-043, University of Chicago IRB \#12-1725 Study Title: Open-label, Single-arm, Phase 2 Study of the Initial and Post-Transplant Treatment with Carfilzomib, Lenalidomide and Low dose Dexamethasone (CRd) in Transplant Candidates with Newly Diagnosed, Multiple Myeloma Requiring Systemic Chemotherapy Lead Institution Name: University of Chicago Medical Center Lead Principal Investigator **Information:** Andrzej Jakubowiak, MD, PhD Professor of Medicine Director, Myeloma Program Section of Hematology/Oncology The University of Chicago Medical Center 5841 S. Maryland Ave, MC 2115 Chicago, IL 60637-6613 Phone: 773-702-4005 Fax: 773-702-0963 ajakubowiak@medicine.bsd.uchicago.edu A Multi-institutional Study Done In Collaboration with The Multiple Myeloma Research Consortium. Participating sites include institutional members of the University of Chicago Personalized Cancer Care Consortium.  
Statistician: Kent Griffith, MPH, MS
Investigational Products: Drug Company Supplied: Carfilzomib (Onyx) IND\# 105821 Commercial Agents: Dexamethasone, Revlimid  
| Original Version Version 1.0 Version 2.0 Version 3.0 Version 4.0 Version 5.0 Version 5.1 Version 5.2 Version 6 Version 6.1 Version 6.2 Version 7   | August 31, 2012 September 26, 2012 November 19, 2012 March 19, 2013 January 31, 2014 July 15, 2014 October 15, 2014 May 20, 2015 July 28, 2015 October 21, 2015 July 6, 2016 October 5, 2016                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PROTOCOL SYNOPSIS                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Title:                                                                                                                                             | Open-Label, Single-arm, Phase 2 Study of the Initial and  Post-Transplant Treatment with Carfilzomib, Lenalidomide  and Low dose Dexamethasone (CRd) in Transplant  Candidates with Newly Diagnosed Multiple Myeloma (MM)  Requiring Systemic Chemotherapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Objectives:                                                                                                                                        | Primary Objectives: To determine the rate of stringent CR (sCR) after 8 cycles of CRd  (4 cycles of induction + ASCT + 4 cycles of CRd consolidation). Secondary Objectives:  Overall response rate defined as partial response or better (>PR)  including the rate of VGPR or better (>VGPR) and near  complete response or better (sCR/CR/nCR) across entire  treatment in high risk and low risk patients Duration of response (DOR), Progression free survival (PFS),  Time to progression (TTP), and Overall Survival (OS) Exploratory Objectives: Determination of the rate of minimal residual disease in patients  who achieved CR Prospective evaluation of candidate markers of response to CRd  established in the completed CRd trial Evaluation of markers of response and duration of response to  treatment strategy using CRd with or without transplant |  
Study Design: This is a multi-center, open-label, Phase 2 study in which transplant candidates with newly diagnosed MM requiring systemic chemotherapy will receive initial induction with CRd followed by autologous stem cell transplant (ASCT) followed by CRd consolidation followed by CRd maintenance. The study will determine the efficacy of the treatment strategy by determining the rate of sCR after completion of a total 8 cycles of CRd (4 cycles of induction, followed by ASCT followed by 4 cycles of CRd consolidation). Carfilzomib will be administered at 20 mg/m2 as an IV infusion on Days 1, 2 and then at 36 mg/m2 on Days 8, 9, 15, and 16 in cycle 1 of a 28day cycle and at 36 mg/m2 for the remaining cycles. Cycles 1 -
4 represent induction. Lenalidomide will be administered PO at 25 mg per dose on Days 1- 21 of the 28-day cycle for preASCT induction Cycles 1 - 4 and Dexamethasone will be administered PO or IV between 30 minutes and 4 hours preceding the carfilzomib dose at 40 mg per dose on Days 1, 8, 15, and 22 in cycle 1-4. After Cycle 4, subjects will proceed into stem cell harvest (SCC) with use of growth factors or as per current standards of care and then to single ASCT. In the CRd consolidation phase, which will be initiated after 3 months post-ASCT evaluation (days 70-90 but not more than day 120), Carfilzomib will be used IV at the last tolerated dose on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for CRd consolidation cycles (overall CRd Cycles 5-8) and in the CRd maintenance phase at last tolerated dose as an IV infusion on Days 1, 2, 15, and 16 of a 28-day cycle for CRd maintenance (overall Cycles 9-18). Lenalidomide will be used at the last tolerated dose but not higher than 15 mg per dose as initial dose in the CRd consolidation phase and at the last tolerated dose in the CRd maintenance phase on days 1-21 in 28 day cycles. In discussion with the Lead Principal Investigator and on a case-by-case basis, provisions may be made to start at a lower than 15 mg dose of lenalidomide for participants with adequate hematologic parameters following ASCT and/or to escalate lenalidomide dose up to 25 mg per dose after completion of 1 cycle of CRd consolidation for participants with adequate hematologic parameters. Dexamethasone will be administered PO or IV between 30 minutes and 4 hours preceding the carfilzomib dose at 20 mg per dose on Days 1, 8, 15, and 22 in the consolidation phase at last tolerated dose in CRd Cycles 58, and at 20 mg (or last tolerated dose) per dose on days 1, 8, 15, and 22 in the CRd maintenance phase (overall CRd cycle 918).  
Study Population: Newly diagnosed multiple myeloma, autologous stem cell  
transplant candidates  
Inclusion Criteria: *Disease-related*:
1. Newly diagnosed, myeloma requiring systemic chemotherapy as per IMWG uniform criteria (see Appendix B)
- Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids or lenalidomide or bortezomib-based regimens does not disqualify the patient (the treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle)
- Bisphosphonates are permitted 2. Suitable and interested to proceed to ASCT. (Refer to 6.4) 3. Measurable disease, prior to initial treatment as indicated by one or more of the following:
- Serum M-protein ≥ 0.5 g/dL
- Urine M-protein ≥ 200 mg/24 hours - If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable Demographic 4. Males and females ≥ 18 years of age 5. Life expectancy of more than 3 months 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (See Appendix C)
Laboratory 7. Adequate hepatic function, with bilirubin < 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times ULN
8. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, hemoglobin
≥ 8 g/dL, platelet count ≥ 75 x 109/L. Subjects may receive RBC transfusions or platelet transfusions, if clinically indicated in accordance with institutional guidelines. However, screening platelet count should be independent of platelet transfusions for at least 2 weeks.  
9. Calculated or measured creatinine clearance of ≥ 50 mL/minute, calculated using the following formula of Cockcroft and Gault:  
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Or creatinine below 2 g/dl Ethical/Other 10. Written informed consent in accordance with federal, local, and institutional guidelines 11. Females of childbearing potential (FCBP) [defined as sexually mature females who: 1) have not undergone a hysterectomy or bilateral oophorectomy; or 2) have not been naturally postmenopausal for at least 24 consecutive months
(ie, has had menses at any time in the preceding 24 consecutive months)] must agree to ongoing pregnancy testing.  
12. FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before Day 1 Cycle 1 and the second pregnancy test must be performed within 24 hours of Day 1 Cycle 1. The subject may not receive lenalidomide until the Treating Investigator has verified that the results of these pregnancy tests are negative, and must agree to ongoing pregnancy tests as outlined in the protocol. For patients already on Revlimid, continuation of current testing schedule is permitted as long as it is not interrupted during the transition to CRd therapy.  
13. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The 2 methods of reliable contraception must include a highly effective method (ie, intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and an additional effective (barrier) method (ie, latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed.  
14. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.  
15. Male subjects must agree to inform his physician if he has had unprotected sexual contact with a female who can become pregnant or if he thinks for any reason that his sexual partner may be pregnant.  
16. Male subjects must agree not to donate semen or sperm while taking lenalidomide and/or carfilzomib and 28 days after the last Lenalidomide/Carfilzomib dose.  
17. All study participants must be registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.  
18. The ability to take aspirin or other appropriate VTE
prophylaxis 19. Subjects must agree to adhere to all study requirements, including birth control measures and pregnancy testing, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring Exclusion **Criteria:** *Disease-related* 1. Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as <0.5 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, or disease only measured by serum free light chain 2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
3. Waldenström's macroglobulinemia or IgM myeloma 4. Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
5. Participation in an investigational therapeutic study for other reasons than symptomatic myeloma within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater 6. Participation in another clinical trial unless approved by the Lead Principal Investigator
clinical study protocol
concurrent conditions

7. Pregnant or lactating females 8. History of allergy to mannitol 9. Major surgery within 3 weeks prior to first dose 10. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities  
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11. Uncontrolled hypertension or diabetes 12. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose 13. Known or suspected HIV infection, known HIV
seropositivity 14. Active hepatitis A, B, or C infection 15. Non-hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone 16. Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent 17. Significant neuropathy (Grades 3-4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment 18. Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (eg, lansoprazole), enteric-coated aspirin, allopurinol or if a history of prior thrombotic disease, warfarin or low molecular weight heparin 19. Subjects in whom the required program of PO and IV
fluid hydration is contraindicated, eg, due to pre-existing pulmonary, cardiac, or renal impairment 20. Subjects with known or suspected amyloidosis of any organ 21. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis.  
22. No coverage or not-acceptable by patient co-pay for Lenalidomide.  
Study Treatment: Subjects will receive carfilzomib, lenalidomide, and dexamethasone. All subjects are planned to receive 4 cycles of CRd induction. After completion of induction, all eligible patients will proceed to stem cells harvest followed by ASCT. Patients who recover from ASCT toxicities will resume protocol treatment starting at 70-90 days post stem cell infusion (not later than 120) in the consolidation and the maintenance portion of the protocol. No toxicities will be recorded from the ASCT period.  
| An individual subject will be considered off-treatment  following a 30-day safety follow-up period after the last cycle  of CRd treatment. Subjects who have not progressed upon  completion or discontinuation of the study will be followed for  up to 5 years from the safety follow-up visit for disease  progression or the start of a new treatment regimen.   |                                                                                                                                                                                                                                                                                                                                                   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Primary Endpoint:                                                                                                                                                                                                                                                                                                                                                    | To determine the rate of stringent CR (sCR) after 8 cycles of CRd  (4 cycles of induction + ASCT + 4 cycles of CRd consolidation).                                                                                                                                                                                                                |
| Secondary Endpoints:                                                                                                                                                                                                                                                                                                                                                 | Overall response rate defined as partial response or better (>PR)  including the rate of VGPR or better (>VGPR) and near  complete response or better (sCR/CR/nCR) across entire  treatment in high risk and low risk patients Duration of response (DOR), Progression free survival (PFS),  Time to progression (TTP), and Overall Survival (OS) |
| Exploratory Endpoints:                                                                                                                                                                                                                                                                                                                                               | Determination of the rate of minimal residual disease in patients  who achieved CR Prospective evaluation of candidate markers of response to CRd  established in the completed CRd trial Evaluation of markers of response and duration of response to  treatment strategy using CRd with or without transplant                                  |
| Statistical Methods:                                                                                                                                                                                                                                                                                                                                                 | A total of 70 patients will be enrolled in a single-stage Phase II  design. Patients who decline transplant for other reasons than  toxicities will be replaced. It is anticipated that most will resume  post-transplant CRd at the consolidation phase but those who do  not, will not be replaced.                                             |  
Newly Diagnosed Symptomatic Myeloma  
\begin{tabular}{l} CRd induction x 4 cycles \\ \end{tabular}  \begin{tabular}{l} \end{tabular}  \begin{tabular}{l} \end{tabular}  \begin{tabular}{l} \end{tabular}  \begin{tabular}{l} CRd consolidation x 4 cycles (CRd Cycles 5-8) \\ \end{tabular}  \begin{tabular}{l} CRd maintenance x 10 cycles (CRd cycles 9-18) \\ \end{tabular}  \begin{tabular}{l} \end{tabular}  \begin{tabular}{l} \end{tabular}  \begin{tabular}{l} \end{tabular}  \begin{tabular}{l} \end{tabular}
CONFIDENTIALITY STATEMENT This document contains confidential information. It is provided for the sole use of the Principal Investigator, Sub-investigators, Staff, Institutional Review Board or Independent Ethics Committee, and Regulatory Authorities. By accepting this document, you agree to maintain the information as confidential and to use it only for the purpose of conducting the study.  
Open-label, Single-arm, Phase 2 Study of the Initial and Post-Transplant Treatment with Carfilzomib, Lenalidomide and Low dose Dexamethasone (CRd) in Transplant Candidates with Newly Diagnosed, Multiple Myeloma Requiring Systemic Chemotherapy Protocol Acceptance Form I have read this protocol and agree to conduct the study as outlined herein, in accordance with Good Clinical Practices (GCPs) and the Declaration of Helsinki, and complying with the obligations and requirements of clinical Investigators and all other requirements listed in 21 CFR part 312.  
Investigator Signature Date Print Investigator Name and Title Date  
| TABLE OF CONTENTS                                                                                                                              |                                                                                                                                                                |
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| CLINICAL STUDY PROTOCOL                                                                                                                        |                                                                                                                                                                |
| Original Version                                                                                                                               |                                                                                                                                                                |
| August 31, 2012                                                                                                                                |                                                                                                                                                                |
| September 26, 2012 .                                                                                                                           |                                                                                                                                                                |
| November 19, 2012                                                                                                                              |                                                                                                                                                                |
| PROTOCOL SYNOPSIS                                                                                                                              |                                                                                                                                                                |
| TABLE OF CONTENTS                                                                                                                              |                                                                                                                                                                |
| INTRODUCTION                                                                                                                                   |                                                                                                                                                                |
| l                                                                                                                                              | Multiple Myeloma ...................................................................................................................18                         |
| 1.1                                                                                                                                            |                                                                                                                                                                |
| 1.2                                                                                                                                            | Combinations of Proteasome Inhibitors and Immunomodulatory Agents .........18                                                                                  |
| 1.3                                                                                                                                            | Carfilzomib Background.................................................................................................20                                      |
| CARFILZOMIB Toxicology STudies ...........................................................20                                                   |                                                                                                                                                                |
| 1.3.1                                                                                                                                          | Carfilzomib Preclinical Antitumor Activity ...............................................21                                                                   |
| 1.3.2                                                                                                                                          |                                                                                                                                                                |
| 1.3.3                                                                                                                                          | Phase 1 Experience with Carfilzomib as a Monotherapy ......................22                                                                                  |
| 1.3.4                                                                                                                                          | Phase 2 Experience with Carfilzomib as a monotherapy.......................23                                                                                  |
| Dose Rationale .............................................................................................................................25 |                                                                                                                                                                |
| 1.4                                                                                                                                            | Lenalidomide Background.................................................................................................27                                     |
| 1.5                                                                                                                                            |                                                                                                                                                                |
| 1.6                                                                                                                                            | Experience with Carfilzomib in Combination with lenalidomide and                                                                                               |
| dexamethasone                                                                                                                                  |                                                                                                                                                                |
| 1.7                                                                                                                                            | Study Rationale                                                                                                                                                |
| 2                                                                                                                                              | OBJECTIVES .................................................................................................................................................34 |
| Primary Objective ...............................................................................................................34            |                                                                                                                                                                |
| 2.1                                                                                                                                            |                                                                                                                                                                |
| 2.2                                                                                                                                            | Secondary Objectives                                                                                                                                           |
| 2.3                                                                                                                                            | Exploratory objectives ................................................................................................34                                      |
| 3                                                                                                                                              | EXPERIMENTAL PLAN ...............................................................................................................34                            |
| 3.1                                                                                                                                            | Study Design                                                                                                                                                   |
| 3.2                                                                                                                                            | Number of Centers                                                                                                                                              |
| 3.3                                                                                                                                            | Number of Subjects                                                                                                                                             |
| Estimated Study Duration ..............................................................................................37                      |                                                                                                                                                                |
| 3.4                                                                                                                                            | T Treatment Schema ..............................................................................................................37                            |
| 3.5                                                                                                                                            |                                                                                                                                                                |
| 3.6                                                                                                                                            | Inclusion Criteria ...........................................................................................................37                               |
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| Confidential                                                                                                                                   | 5 OCT 2016                                                                                                                                                     |
clinical study protocol
table of contents

| 3.7   | Exclusion Criteria 40                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
|-------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 4     | SUBJECT ENROLLMENT 41 4.1 Patient Enrollment and Registration 41                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| 5     | TREATMENT 42 5.1 General Procedures 42 5.2 Drug Administration 43 5.2.1 Pretreatment Preparation 43 5.2.2 Dexamethasone 44 5.2.3 Carfilzomib 45 5.2.4 Lenalidomide 46 5.2.5 Treatment Compliance 47 5.3 Instructions for Initiation of a New Cycle 48 5.4 Dose Modification Guidelines 48 5.4.1 Hematologic Toxicity 50 5.4.2 Non-hematologic Toxicity 50 5.4.3 Conditions Not Requiring Dose Reduction 57 5.4.4 Treatment Discontinuation 58 5.5 Concomitant Medications 58 5.5.1 Required Concomitant Medications 58 5.5.2 Optional and Allowed Concomitant Medications 59 5.5.3 Excluded Concomitant Medications 60 5.6 Safety Guidance for Investigators 60 5.6.1 "First-dose Effect" 60 5.6.2 Tumor Lysis Syndrome 61 5.6.3 Renal Function 61 5.6.4 Hydration 62 |
| 6     | STUDY TESTS AND OBSERVATIONS 62 6.1 Screening (Days -21 to -1) 62 6.2 Treatment Cycles 1 through 4 (Induction), Cycles 5-8 (consolidation), and  Cycles 9-18 (maintenance) 65 6.3 End of Cycle 4 67 6.4 stem cell collection and autologous stem cell transplant 67                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |  
| 6.4.1        | Mobilization and collection of autologous peripheral blood stem cells68                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|--------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.4.2        | autologous stem cell transplant procedure 68                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| 6.5          | 3 MONTHS POST TRANSPLANT 68                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| 6.6          | END OF CYCLE 8 (END of cycle 4 crd consolidation) 69                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| 6.7          | Long-Term follow-up 69                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| 6.8          | Tumor Response Assessment 70                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| 6.9          | Optional Correlative studies 70                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| 7            | STUDY DISCONTINUATION 72                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 8            | ADVERSE EVENTS 73 8.1 Adverse Events Definitions 73 8.2 Causality 74 8.3 Adverse Events Reporting Procedures 75 8.4 Serious Adverse Events 76 8.4.1 SERIOUS ADVERSE EVENT DEFINITION 76 8.4.2 Serious and Unexpected Suspected Adverse Reaction (SUSAR) 77 8.5 Serious Adverse Event Reporting and Documentation Requirements 78 8.5.1 Expedited Reporting by Lead Principal Investigator to Onyx 78 8.5.2 investigator reporting responsibilites 79 8.5.3 FDA Reporting by the lead principal investigator 80 8.5.4 Adverse Event Updates/IND Safety Reports 81 8.6 Pregnancy 81 |
| 9            | STATISTICAL METHODS AND DATA ANALYSIS 83 9.1 Objectives 83 9.1.1 Primary objectives 83 9.1.2 Secondary Objectives 83 9.1.3 Exploratory Objectives 83 9.2 Population for analysis 84 9.3 Study design and sample size 84 9.3.1 Primary objective 85 9.3.2 Secondary objectives 86 9.3.3 Exploratory objectives 86 9.3.4 Safety analysis 86                                                                                                                                                                                                                                         |
| Confidential | 5 OCT 2016                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |  
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| 10                                                                                                                                                 | INVESTIGATIONAL PRODUCT.........................................................................................87                          |                  |
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| Carfilzomib Description                                                                                                                            |                                                                                                                                             |                  |
| 10.1                                                                                                                                               |                                                                                                                                             |                  |
| 10.1.1 Formulation                                                                                                                                 |                                                                                                                                             |                  |
| 10.1.2  Storage ................................................................................................................................88 |                                                                                                                                             |                  |
| 10.1.3 Accountability                                                                                                                              |                                                                                                                                             |                  |
| 10.1.4  Carfilzomib ordering                                                                                                                       |                                                                                                                                             |                  |
| 10.2                                                                                                                                               | Lenalidomide .......................................................................................................................89      |                  |
| 10.2.1                                                                                                                                             | Description                                                                                                                                 |                  |
| 10.2.2                                                                                                                                             | SUPPLY ..................................................................................................................................89 |                  |
| 10.2.3                                                                                                                                             | Storage conditions                                                                                                                          |                  |
| 10.2.4                                                                                                                                             | AccountAbility                                                                                                                              |                  |
| 10.2.5                                                                                                                                             | Prescribing information ............................................................................90                                      |                  |
| Special handling instructions ...................................................................90                                                |                                                                                                                                             |                  |
| 10.2.6                                                                                                                                             |                                                                                                                                             |                  |
| 10.3                                                                                                                                               | DEXAMETHASONE ........................................................................................................................90    |                  |
| Dexamethasone may be given IV or PO..................................................................90                                            |                                                                                                                                             |                  |
| Description                                                                                                                                        |                                                                                                                                             |                  |
| 10.3.1                                                                                                                                             |                                                                                                                                             |                  |
| 10.3.2                                                                                                                                             | Formulation                                                                                                                                 |                  |
| 10.3.3                                                                                                                                             | Storage conditions                                                                                                                          |                  |
| 10.3.4                                                                                                                                             | Accountibility ....................................................................................................90                       |                  |
| REGULATORY OBLIGATIONS ...............................................................................................91                           |                                                                                                                                             |                  |
| 11                                                                                                                                                 | 11.1                                                                                                                                        | Informed Consent |
| 11.2                                                                                                                                               | Compliance with Laws and Regulations                                                                                                        |                  |
| 1.3                                                                                                                                                | Pre-study Documentation Requirements ...............................................................92                                      |                  |
| 11.4                                                                                                                                               | Subject Confidentiality ..............................................................................................93                    |                  |
| 12                                                                                                                                                 | ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................93                                                     |                  |
| 12.1                                                                                                                                               | Protocol Amendments and Study Termination .........................................................93                                       |                  |
| Study Documentation and Archive                                                                                                                    |                                                                                                                                             |                  |
| 12.2                                                                                                                                               | SOURCE DOCUMENTS ....................................................................................................94                     |                  |
| 12.2.1                                                                                                                                             |                                                                                                                                             |                  |
| 12.2.2                                                                                                                                             | Case rerport form completion .....................................................................94                                        |                  |
| 12.2.3                                                                                                                                             | Archival of records ..........................................................................................95                            |                  |
| 12.2.4                                                                                                                                             | Clinical monitoring procedures                                                                                                              |                  |
| 12.2.5                                                                                                                                             | Data safety and monitoring.........................................................................96                                       |                  |
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| Confidential                                                                                                                                       | 5 OCT 2016                                                                                                                                  |                  |
| Page 14 of 121                                                                                                                                     |                                                                                                                                             |                  |  
| 12.2.6                                                                                                                                                                                                                                                                                                                                       | Protocol deviations 96            |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|
| 12.2.7                                                                                                                                                                                                                                                                                                                                       | Quality assurance and auditing 97 |
| 13                                                                                                                                                                                                                                                                                                                                           | REFERENCES 98                     |
| APPENDIX A. SCHEDULE OF TESTS AND OBSERVATIONS 102 APPENDIX B. MULTIPLE MYELOMA STAGING 108 APPENDIX C. ECOG PERFORMANCE SCALE 110 APPENDIX D. NCI CTCAE VERSION 4.0 111 APPENDIX E. RESPONSE CRITERIA FOR MULTIPLE MYELOMA 112 APPENDIX F. RISKS OF FETAL EXPOSURE, PREGNANCY TESTING 115 APPENDIX G: COCKROFT-GAULT ESTIMATION OF CRCL 117 |                                   |  
APPENDIX H: FACT/GOG-NEUROTOXICITY QUESTIONNAIRE,
VERSION 4.0 118 APPENDIX I: IMWG CRITERIA FOR THE DIAGNOSIS OF MYELOMA119 LIST OF ABBREVIATIONS  
| Abbreviation   | Definition                                       |
|----------------|--------------------------------------------------|
| °C             | degrees Centigrade                               |
| °F             | degrees Fahrenheit                               |
| AE             | adverse event                                    |
| ALT            | alanine aminotransferase                         |
| ANC            | absolute neutrophil count                        |
| aPTT           | activated partial thromboplastin time (also PTT) |
| ASaT           | All Subjects as Treated                          |
| ASCT           | Autologous Stem Cell Transplant                  |
| AST            | aspartate aminotransferase                       |
| bid            | twice daily                                      |
| BSA            | body surface area                                |
| BUN            | blood urea nitrogen                              |
| CBC            | complete blood count                             |
| CFR            | Code of Federal Regulations                      |
| CHF            | congestive heart failure                         |
| CR             | complete response                                |
| CrCl           | Creatinine Clearance                             |
| CRF            | case report form(s)                              |
| CRO            | clinical research organization                   |
| CSR            | Clinical Study Report                            |
| Confidential   | 5 OCT 2016                                       |
| Page 15 of 121 |                                                  |  
| CTCAE          | Common Terminology Criteria for Adverse Events      |
|----------------|-----------------------------------------------------|
| CV             | curriculum vitae                                    |
| dL             | deciliter                                           |
| DLT            | dose-limiting toxicity                              |
| DOR            | duration of response                                |
| DVT            | deep venous thrombosis                              |
| ECG            | electrocardiogram                                   |
| ECOG           | Eastern Cooperative Oncology Group                  |
| FAS            | Full Analysis Set                                   |
| FCBP           | Females of childbearing potential                   |
| FDA            | Food and Drug Administration                        |
| FISH           | fluorescent in situ hybridization                   |
| FLC            | free light chain                                    |
| G-CSF          | granulocyte colony stimulating factor               |
| GCP            | Good Clinical Practice                              |
| GLP            | Good Laboratory Practice                            |
| GM-CSF         | granulocyte macrophage colony stimulating factor    |
| h              | hour(s)                                             |
| HIPAA          | Health Insurance Portability and Accountability Act |
| HIV            | human immunodeficiency virus                        |
| IB             | Investigator Brochure                               |
| ICH            | International Conference on Harmonisation           |
| IEC            | Independent Ethics Committee                        |
| IND            | Investigational New Drug (Application)              |
| INR            | International Normalized Ratio                      |
| IRB            | Institutional Review Board                          |
| IV             | intravenous                                         |
| kg             | kilogram(s)                                         |
| LDH            | lactate dehydrogenase                               |
| mg             | milligram(s)                                        |
| min            | minute(s)                                           |
| mIU            | Milli International Units                           |
| mL             | milliliter(s)                                       |
| MM             | multiple myeloma                                    |
| mm2            | millimeter(s) squared                               |
| mm3            | millimeter cubed                                    |
| MR             | minimal response                                    |
| MRD            | minimum residual disease                            |
| MTD            | maximum tolerated dose                              |
| NCI            | National Cancer Institute                           |
| Confidential   | 5 OCT 2016                                          |
| Page 16 of 121 |                                                     |  
| NHL   | non-Hodgkin's lymphoma                                         |
|-------|----------------------------------------------------------------|
| ORR   | overall response rate                                          |
| PBMC  | peripheral blood mononuclear cells                             |
| PCCC  | Personal Cancer Care Consortium (of the University of Chicago) |
| PD    | progressive disease                                            |
| PFS   | progression-free survival                                      |
| PK    | pharmacokinetics                                               |
| PO    | per os (oral)                                                  |
| PR    | partial response                                               |
| PSA   | prostate-specific antigen                                      |
| PT    | prothrombin time                                               |
| PTT   | partial thromboplastin time                                    |
| QDx5  | daily dosing for five days                                     |
| QIU   | Qualified Investigator Undertaking Form                        |
| RBC   | red blood cell                                                 |
| SAE   | serious adverse event                                          |
| SAP   | Statistical Analysis Plan                                      |
| SCC   | Stem Cell Collection                                           |
| sCR   | stringent complete response                                    |
| SD    | stable disease                                                 |
| SEER  | Surveillance, Epidemiology, and End Results                    |
| SPEP  | serum protein electrophoresis                                  |
| STD10 | severely toxic dose in 10% of animals                          |
| TLS   | Tumor lysis syndrome                                           |
| TTP   | time to tumor progression                                      |
| UCM   | University of Chicago Medicine                                 |
| ULN   | upper limit of the normal range                                |
| UPEP  | urine protein electrophoresis                                  |
| VGPR  | very good partial response                                     |
| WBC   | white blood count                                              |
clinical study protocol
1 introduction 1.1 multiple myeloma

Multiple myeloma is a clonal neoplastic proliferation of plasma cells affecting 19,900 US patients each year.1 Multiple myeloma is characterized by anemia, bone destruction, monoclonal gammopathy, renal failure, hypercalcemia and increased susceptibility to infections. The disease is systemic, and chemotherapy is indicated for management of symptomatic myeloma. Current treatments include combination chemotherapy with regimens using melphalan (Alkeran®), bortezomib (Velcade®), thalidomide (Thalomid®), and lenalidomide (Revlimid®) and their combinations with and without corticosteroids. Younger patients are consolidated with high-dose therapy (ablative chemotherapy or radiation) with autologous stem cell transplantation (ASCT). Although improvements in progression free survival and overall survival have occurred in the past 5 years, even with the best available approved agents, 10-30% of patients fail to respond to the primary therapy, and almost all subjects eventually relapse, with a median overall survival of 44.8 months.2
clinical study protocol
1.2 combinations of proteasome inhibitors

Proteasome inhibitors (bortezomib, carfilzomib) and immunomodulatory agents (thalidomide and lenalidomide) are both highly effective agents in multiple myeloma. Lenalidomide is an immunomodulatory derivative of thalidomide and has both immunomodulatory and antiangiogenic properties which are considered to confer anti-tumor effects. Two pivotal randomized Phase 3 trials established that lenalidomide in combination with high-dose dexamethasone produced a significant improvement in overall response rate and time to tumor progression (TTP) vs. high-dose dexamethasone alone in relapsed multiple myeloma patients with up to 3 prior therapies.3,4 Preclinical studies show that lenalidomide sensitizes multiple myeloma to the proteasome inhibitor bortezomib, suggesting combination therapy may enhance clinical activity. The combination of a proteasome inhibitor and immunomodulatory agent is attractive, as the expected overlapping toxicities would be manageable. A Phase 1 dose-escalation study was conducted to determine the maximum tolerated dose (MTD) and activity of the bortezomib, lenalidomide, and dexamethasone combination in subjects with heavily pre-treated relapsed and/or refractory multiple myeloma.5 The MTD was established as lenalidomide 15 mg and bortezomib 1.0 mg/m2 with 20 to 40 mg dexamethasone. In 36 evaluable subjects, the overall response rate (CR+PR+MR) was 58%, including 6% CR. Although the regimen is active, the requirement for dose reductions of both agents to achieve a tolerable combination may have resulted in suboptimal complete response rates. A phase 2 study followed to evaluate the efficacy and safety of lenalidomide, bortezomib, dexamethasone (RVD) at the phase 1 MTD.  
17 In 63 response-evaluable patients, the overall response rate (CR/nCR+VGPR+ PR+ MR) is currently 86%, including 24% CR/nCR and 67% CR/nCR/VGPR/PR. Response rates according to baseline cytogenetics, disease stage, and prior therapies showed no significant differences according to adverse risk. Toxicities were manageable, consisting primarily of grade (G) 1-2 myelosuppression. Attributable non-hematologic toxicities included deep vein thrombosis (two patients; attributed to lenalidomide), and two episodes of atrial fibrillation (G3) prompting Dex dose reduction. G3 polyneuropathy was reported in one pt attributed to bortezomib and leading to treatment discontinuation despite bortezomib dose reduction. Dose reductions were required for: lenalidomide (13 pts); bortezomib (9 pts) and dexamethasone (26 pts). Lenalidomide and high-dose dexamethasone without a proteasome inhibitor has shown impressive activity in untreated disease. In a Phase 2 study of 34 subjects with newly diagnosed myeloma, subjects received lenalidomide (25 mg Days 1 to 21 of a 28-day cycle) and high-dose dexamethasone (40 mg Days 1 to 4, 9 to 12, and 17-20). The objective response rate was 91%,
with 6% CR, 32% near CR plus VGPR, and 53% PR.12 However, when this regimen was compared with a more conventional delivery of dexamethasone (40 mg Days 1, 8, 15, and 22) in a 445-subject study, the more intensive dexamethasone schedule was associated with significantly shorter overall survival relative to the less intensive regimen (1-year survival rates 86% vs. 96.5%,
respectively).13 The dexamethasone-intensive regimen was associated with higher incidences of thromboembolism, hyperglycemia, and higher incidences of Grades 3 and 4 toxicities overall. Clearly, better and safer combination regimens for newly diagnosed disease are warranted. A recently completed phase 1/2 study of bortezomib in combination with lenalidomide and dexamethasone (RVD) in newly diagnosed subjects with multiple myeloma has yielded promising results.9,10 Patients (N=66) received median 10 cycles of combination treatment and achieved 39%
and 67% across all dose levels had achieved a CR or VGPR, and at MTD 57% and 74%, respectively. The regimen overall was well tolerated; however, dose reductions due to bortezomib were common and 80% of patients developed peripheral neuropathy. In summary, the combination of proteasome inhibitors and immunomodulatory agents seems to be very active and well tolerated in patients with relapsed and/or refractory MM, including patients who have received prior lenalidomide, bortezomib, thalidomide, and SCT. Further investigations with combination therapy with these agents in newly diagnosed disease are warranted.
clinical study protocol
1.3 carfilzomib background

Carfilzomib (PR-171) is a tetrapeptideketoepoxide-based inhibitor specific for the chymotrypsinlike active site of the 20S proteasome. Carfilzomib is structurally and mechanistically distinct from the dipeptide boronic acid proteasome inhibitor bortezomib (Velcade®). In addition, when measured against a broad panel of proteases including metallo, aspartyl, and serine proteases, carfilzomib demonstrated less reactivity against non-proteasomal proteases when compared to bortezomib.  
11,12
clinical study protocol
1.3.1 carfilzomib toxicology studies

In the initial Good Laboratory Practice (GLP)-compliant toxicity studies done by the drug maker, Onyx, carfilzomib was administered to rats and monkeys as two complete two-week cycles of QDx5 for five days with nine days rest13 Administration to rats at 12 mg/m2, the severely toxic dose in 10% of animals (STD10), caused > 90% proteasome inhibition in red blood cells one hour after dosing. Overall, stronger inhibition of the proteasome and longer duration of inhibition was tolerated with carfilzomib compared with bortezomib. Daily administration of bortezomib at antitumor doses is not tolerated in animals, and therefore daily bortezomib has not been given in the clinic. A dose-dependent decrease in proteasome activity was demonstrated in animals, and equivalent levels of proteasome inhibition were achieved with administration of carfilzomib as either an intravenous (IV) push or an IV infusion. The dose-limiting toxicities (DLTs) of carfilzomib in both the rat and monkey 28 day GLP toxicity studies included toxicity to the Page 20 gastrointestinal tract, bone marrow, pulmonary, and cardiovascular systems. No behavioral or histopathological signs of neurotoxicity were observed, and carfilzomib does not cross the bloodbrain barrier. In 6-month rat and 9-month chronic toxicity studies, carfilzomib was administered on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle, mimicking the active anti-tumor regimen being used in ongoing Phase II studies in myeloma and solid tumors.  
13 Tolerability was excellent, with no evidence of peripheral (or central) neurotoxicity, including neuropathology, observed, even at high doses. This is in stark contrast to that observed with bortezomib.  
14,15 DLTs included effects on the gastrointestinal, renal, pulmonary, and cardiovascular systems and appeared to related to Cmax effects. Of note, neutropenia was not observed; rather, transient neutrophilia was seen following acute dosing. Renal, cardiovascular and gastrointestinal toxicities were similar to those observed with bortezomib. Finally, cyclical thrombocytopenia, likely due to inhibition of platelet budding from megakaryocytes, was similar to that seen with bortezomib. Proteasome inhibition in the blood in excess of 90% was achievable at well-tolerated doses, which contrasts with the ~70% proteasome inhibition achieveable with bortezomib at its maximum tolerated dose (MTD). In summary, these animal toxicity studies support the tolerability of carfilzomib in clinical studies, even on intensive dosing schedules and at doses achieving proteasome inhibition in excess of what can be achieve with bortezomib at its MTD on a less intensive schedule.
clinical study protocol
1.3.2 carfilzomib preclinical antitumor activity

Based upon the results of *in vitro* and *in vivo* studies, it is anticipated that the more intense and longer duration of proteasome inhibition that can be achieved with carfilzomib will result in enhanced anti-tumor activity relative to bortezomib. Continuous (72 hr) exposure to carfilzomib is associated with potent cytotoxic and pro-apoptotic activity across a broad panel of tumor-derived cell lines in culture.11, 16 Incubation of hematologic tumor cell lines with carfilzomib for as little as one hour leads to rapid inhibition of proteasome activity followed by accumulation of polyubiquitinated proteins and induction of apoptotic cell death. Carfilzomib has also been demonstrated to be cytotoxic in bortezomib-resistant tumor cell lines.11,16 The anti-tumor efficacy of carfilzomib has been tested in immunocompromised mice implanted with a variety of tumor cell lines. In a human colorectal adenocarcinoma model HT-29, administration of carfilzomib on a twice-weekly Day 1, Day 2 schedule resulted in significant reduction in tumor size and was superior to a twice-weekly Day 1, Day 4 schedule using the same dose of carfilzomib, and a once-weekly dosing schedule using twice the dose level. Bortezomib at its MTD has no activity in this xenograft model using the standard Day 1, Day 4 schedule.11
clinical study protocol
1.3.3 phase 1 experience with

A Phase 1 clinical trial, PX-171-002, testing carfilzomib in subjects with relapsed/refractory hematologic malignancies, is being completed.17 During the dose escalation portion of the trial, 36 subjects received carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Subjects with Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Waldenström's Macroglobulinemia, and Hodgkin's Lymphoma (HL) were enrolled on the study. No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses ranged from 1.2 to 15 mg/m2) of three subjects each. At the 20 mg/m2 dose level, one of eight patients had a Grade 3 renal failure at Cycle 1, Day 2 which was considered possibly related to study drug and lasted for six days. The patient continued on study for the remainder of Cycle 1 before having disease progression. At the 27 mg/m2 dose level, one of six subjects experienced a DLT during Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following Day 2 of dosing. In subjects where the 27 mg/m2 dose was efficacious, a "first dose effect" was seen that included a constellation of findings that appeared to be the clinical sequelae of rapid tumor lysis syndrome (TLS) and/or cytokine release. This effect was notable for fever, chills, and/or rigors occurring during the evening following the first day of infusion. On the second day, three of five subjects with multiple myeloma experienced an increase in creatinine to Grade 2 (including the subject with the DLT). This elevation was rapidly reversible and all three subjects were rechallenged with carfilzomib without recurrence of the events. Interestingly, all three subjects had a rapid decline in serum and/or urine M-protein levels; two subjects achieved a PR and the third subject achieved a minimal response (MR). There were no consistent changes in potassium, calcium, phosphorous, or uric acid levels although some increases in LDH and other markers of tumor lysis were noted. Because of the possible TLS and reversible creatinine elevations, hydration and very-low dose dexamethasone prophylaxis were instituted in subsequent studies and have essentially eliminated clinically significant TLS/creatinine elevations and the other "first-dose" effects. Hematologic toxicities were primarily mild or moderate. The thrombocytopenia reported with carfilzomib is cyclical and similar to that reported with bortezomib. The cause and kinetics of the thrombocytopenia following treatment are different from those of standard cytotoxic agents. To maximize the likely benefit of carfilzomib, subjects with thrombocytopenia should be supported as clinically indicated rather than having treatment reduced due to thrombocytopenia. Of the 36 evaluable patients enrolled in PX-171-002, 20 had MM.  
17 Four MM patients achieved a partial response (PR), one of two at the 15 mg/m2 dose, one of six at the 20 mg/m2 dose, and two of five at the 27 mg/m2 dose. The responses have been rapid in onset, beginning in some subjects after 1-2 doses. The duration of response (DOR) ranged from 134 to 392 days. The minimal effective dose was 15 mg/m2 wherein >80% proteasome inhibition in peripheral blood and mononuclear cells was observed one hour after dosing. The median number of prior therapies for subjects on this trial was five, and responses were seen in subjects who had relapsed from (including some refractory to) bortezomib and/or immunomodulatory agents. Stable disease also occurred in four NHL and five MM subjects, with subjects on therapy for up to 409 days. Such prolonged therapy, at "full" twice-weekly doses, is not possible with bortezomib. These results led to the initiation of two Phase 2 studies.
clinical study protocol
1.3.4 phase 2 experience with

Two Phase 2 clinical studies are ongoing with carfilzomib in MM patients, PX-171-003-A0 (N=46) in relapsed and refractory MM and PX-171-004 (N=39) in relapsed MM. In both studies, patients were dosed with 20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule. In these studies there were four cases of suspected or documented TLS prior to institution of the prophylaxis guidelines. Since these guidelines were implemented, no further cases of TLS have been reported including in >350 additional patients with relapsed or refractory MM treated in ongoing Phase II studies. In both studies, the most common adverse events were fatigue, anemia, thrombocytopenia (primarily cyclical), gastrointestinal, and dyspnea. Almost all were Grades 1 or 2. There were reported cases of increased in serum creatinine that were primarily < Grade 2 and were transient, rapidly reversible, and non-cumulative. A very low rate of treatment-emergent peripheral neuropathy, 2.2% Grade 3/4, was observed in PX-171-003-A0 despite the fact that 78%
of patients had Grade 1/2 neuropathy upon study entry8.  
The response rate in PX-171-003-A0 was 18% PR, 7% MR and 41% SD in these patients that entered the study with progressive disease and were refractory to their most recent therapy, often including bortezomib and/or an immunomodulatory drug (usually lenalidomide). The median time to progression on the PX-171-003-A0 study was 5.1 months with a DOR of 7.4 months (mean follow up of 7.6 months).  
18 A "stepped up" dosing schedule, referred to as 20/27 mg/m2, has subsequently been incorporated into the PX-171-003 study (referred to as PX-171-003-A1) in order to maximize the clinical benefit of carfilzomib. Patients receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter. The study completed enrollment of 266 patients by the end of 2009 and may form the basis for an accelerated approval NDA filing by the end of 2010. To date, this dosing schedule has been well tolerated.  
17 An independent Safety Oversight Group (SOG) evaluated the safety data from the 40 of 250 patients to be enrolled on the 20/27 schedule and agreed that the trial should proceed without modification. No cases of TLS were observed and rates of BUN and creatinine elevation dropped sharply, with Grade 3/4 renal impairment dropping to 2.2% in A1( from 15% in A0), most likely due to hydration and very low dose dexamethasone. The other most common adverse events were similar to the A0 portion of the study. Treatment-emergent peripheral neuropathy remains low on this portion of the study with 15% Grade 1/2 and one (0.7%) Grade 3/4 event reported to date on PX-171-003-A1.  
18 In addition, anemia rates in the PX-171-003-A1 (higher dose) were lower than those reported in the PX-171-003–A0 portion of the study, possibly indicating that the higher dose of carfilzomib is achieving better clearing of neoplastic cells in the bone marrow allowing superior normal marrow reconstitution. Rates of thrombocytopenia and neutropenia were similar in the two cohorts, with Grade 3 neutropenia in ~5% without any Grade 4 neutropenia to date.18 In PX-171-004, a first cohort of patients received 20 mg/m2. The subset of patients (N=54) that had not seen bortezomib had an ORR of 46% (2% CR, 9% VGPR and 35% PR), while the bortezomib treated patients (N=33) had an ORR of 18% (3% CR, 3% VGPR and 12% PR).  
19, 20 The median TTP was 7.6 and 5.3 months in these two groups, respectively. Thus, carfilzomib can induce very high levels of response in patients who have not previously been treated with bortezomib and, even in bortezomib-treated patients, substantial anti-tumor activity is observed. Of note, disease control (PR + MR + SD) was achieved in ~65% of patients with progressive MM entering the study. Patients on these studies have been treated for >12 cycles with good tolerability Page 24 and no cumulative toxicity (e.g., bone marrow, severe fatigue, or neuropathy) have not been observed. The protocol was amended to allow patients to increase to 27 mg/m2 in Cycle 2 or later based on tolerability, similar to that used in PX-171-003 - A1. Further information about the Phase 2 studies is presented in the Investigator's Brochure.
clinical study protocol
1.4 dose rationale

Preliminary data suggest that carfilzomib as a single agent can produce substantial response rates in myeloma subjects across a variety of dosing cohorts. Responses were seen over a wide therapeutic window, from 15 to 27 mg/m2. Maximum proteasome inhibition was seen at doses 11 mg/m2 and higher in whole blood samples taken 1 hour after the first dose. The final analysis of the human pharmacokinetic (PK) data is ongoing but appears to be rapid and similar to the results from the animal studies. Carfilzomib is rapidly cleared from plasma with an elimination half-life of < 60 minutes at the 20 mg/m2 dose. Large, single arm studies of the 27 mg/m2 dose are ongoing and suggest that this dose is very well tolerated with patients being treated for >10 cycles without cumulative toxicities. By the end of 2009, 269 patients with relapsed and refractory multiple myeloma have been enrolled in the PX-171-003-A1 study. The goal of dose escalating to 27 mg/m2 beginning with Cycle 2 is to improve ORR, DOR, and TTP. In multiple preclinical studies, the tolerability of carfilzomib in rats has been shown to be significantly higher when administered as a 30 min infusion as compared to a rapid IV bolus. Toxicities observed with IV bolus injection of carfilzomib above the MTD at a dose of 48 mg/m2 include evidence of prerenal azotemia (transient increases in BUN > creatinine) as well as lethargy, piloerection, dyspnea, and gastrointestinal bleeding. Notably, death occurred in ~50% of animals at 48 mg/m2 when carfilzomib was given as a bolus. Administration of the same dose (48 mg/m2) as a 30 min continuous infusion was well tolerated, with no changes in BUN and creatinine and substantially reduced signs of lethargy, piloerection, or dyspnea. Moreover, all animals in the infusion treatment groups survived. The only toxicity observed following infusion of carfilzomib for 30 min was gastrointestinal bleeding. The reduced toxicity seen with dosing by infusion may reflect the reduced Cmax of carfilzomib vs that with bolus dosing. Inhibition of the pharmacologicaltarget of carfilzomib (the chymotrypsin-like activity of the proteasome) was equivalent in the bolus and infusion treatment groups. In the clinic, the MTD of carfilzomib has not been reached in the multiple myeloma (MM) setting, particularly when administered as a 30' infusion. 27mg/m2 of carfilzomib (bolus administration over 2-10') is well tolerated in MM patients overall and can be tolerated for >12 cycles in late stage MM patients with substantial comorbidities. A phase 1 dose escalation study (PX-171-007) of single agent carfilzomib administered is ongoing and as of 10 July 2009, over 65 patients with solid tumors had started treatment in the initial Phase 2 portion of the study at 36 mg/m2 (bolus administration over 2-10'). A review of the tolerability of 36 mg/m2 carfilzomib in these patients indicates that this regimen was very well tolerated with only one DLT (fatigue) and an overall adverse event profile similar to that seen with the 27mg/m2 carfilzomib experience with bolus dosing (see IB for details). Three patients completed > 12 cycles of therapy at 36 mg/m2 with no evidence of cumulative toxicity. There were no significant DLTs observed; the majority of discontinuations on the study were due to progressive disease. Because of the long-term tolerability carfilzomib, the Phase 1b portion of this study was reopened, and a separate arm for multiple myeloma was added. In the PX-171-007 trial, more recently patients have been treated with carfilzomib given as a 30minute infusion in order to potentially minimize Cmax-related infusion events. The protocol was amended and does of 20/36 (20 mg/m2 given on Days 1 and 2 of cycle 1 only; followed by 36 mg/m2 for all subsequent doses), 20/45, 20/56 mg/m2 and so forth are being investigated. Doses of 20/56 mg/m2 are currently being given in two separate cohorts of patients with advanced MM and advanced solid tumors; the lower doses were well tolerated. Preliminary tolerability information at this dose level (20/56 mg/m2) indicated that it is reasonably well tolerated, with minimal infusion reactions. In some cases at 20/56mg/m2, dexamethasone was increased from 4mg/dose to 8mg with the 56mg/m2 doses in order to reduce fevers and hypotension. As of March 20, 2010, seven patients have received 20/56mg/m2 and are tolerating it. Patients with advanced, refractory MM being treated at 36mg/m2 and 45mg/m2 have shown very good tolerability (>6 months in some cases) with documented minimal and partial responses in these heavily pretreated patients. These data indicate that carfilzomib 30-minute infusion can be given at very high levels, with >95% inhibition of blood proteasome levels achievable and with (at least) acute tolerability. All protocols using ≥36mg/m2 carfilzomib are now administering the drug as a 30-minute infusion. In addition to the above observations, a phase I study of carfilzomib in patients with relapsed and refractory multiple myeloma was reported in abstract form at the 2009 American Society of Hematology meeting which demonstrated that carfilzomib can be safely administered to patients with substantial renal impairment (CrCl< 30, including patients on dialysis) without dose adjustment.21 These data indicate that carfilzomib does not exacerbate underlying renal dysfunction, and confirm the "pre-renal" etiology of the BUN/creatinine elevations observed with IV bolus carfilzomib.
clinical study protocol
1.5 lenalidomide background

Lenalidomide (Revlimid®) is a proprietary IMiD® compound of Celgene Corporation. IMiD® compounds have both immunomodulatory and anti-angiogenic properties which could confer antitumor and antimetastatic effects. Lenalidomide has been demonstrated to possess antiangiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation response to bFGF.  
22 In addition, lenalidomide has a variety of immunomodulatory effects. Lenalidomide stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 production.22 Upregulation of T cell derived IL-2 production is achieved at least in part through increased AP-1 activity.23 Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of mechanisms are postulated to be responsible for lenalidomide's activity against multiple myeloma. Lenalidomide has been shown to increase T cell proliferation, which leads to an increase in IL-2 and IFN-gamma secretion. The increased level of these circulating cytokines augment natural killer cell number and function, and enhance natural killer cell activity to yield an increase in multiple myeloma cell lysis.24 In addition, lenalidomide has direct activity against multiple myeloma and induces apoptosis or G1growth arrest in multiple myeloma cell lines and in multiple myeloma cells of patients resistant to melphalan, doxorubicin and dexamethasone.  
25 Indications and Usage: Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Revlimid® is also approved in combination with dexamethasone for the treatment of patients with multiple myeloma that have received at least one prior therapy.  
Adverse Events: Most frequently reported adverse events reported during clinical studies with lenalidomide in oncologic and non-oncologic indications, regardless of presumed relationship to study medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, disease progression, death not specified and fractures. Complete and updated adverse events are available in the Investigational Drug Brochure and the IND Safety Letters.
clinical study protocol
1.6 experience with carfilzomib in

PX-171-006 is an ongoing Phase 1b study in patients with relapsed multiple myeloma in which carfilzomib is administered in combination with lenalidomide (Revlimid®) and dexamethasone.  
"Low-dose" dexamethasone 40 mg/day is given on Days 1, 8, 15, and 22 in all cases. Carfilzomib is administered IV on Days 1, 2, 7, 8, 15, and 16; lenalidomide is administered PO on Days 1 through 21. Enrollment has closed in this study, and no MTD was reached. The maximum per protocol doses of carfilzomib (27mg/m2) with lenalidomide 25mg and low dose dexamethasone are being used.  
26 After 8 patients tolerated these doses well, an additional 44 patients were enrolled in an "expansion" cohort at this level, and this regimen is being taken into Phase III in study PX-171009. To date, 40 patients were treated in cohorts 1-6 and 44 in the cohort 6 expansion. 27/32 patients in cohorts 1–5 are evaluable for safety and 29/32 for response. Patients were heavily pre-treated; 72% received prior BTZ and 87.5% received prior LEN or thalidomide (Thal). 47% of patients were refractory to their last therapy (typically lenalidomide + high dose dexamethasone; > 84% of patients had a history of neuropathy with 67% BTZ- or Thal-related. No treatment emergent fatigue, neuropathy, or thrombotic events ≥ Grade (G) 3 were observed. Hematological AEs ≥G3 (thrombocytopenia [n=6], anemia [n=4], and neutropenia [n=6]) were reversible. 4 patients had drug-related SAEs as follows: transient G3 sinus bradycardia, G3 upper respiratory tract infection, febrile neutropenia, and G3 diarrhea + G3 urinary infection. ORR and CBR for the 29 evaluable patients are 59% and 72%, respectively. Response data is shown in the table below. Initial responses improved with continued therapy, (up to 18 cycles). Median duration of response has not been reached (median follow-up 5.2 months). No dose-limiting toxicities or deaths attributed to study treatment have been observed. Several patients have completed the study (in the lower dose cohorts) after 18 cycles and are continuing in an extension study. Updated efficacy data are presented in the following table: In the Investigator Initiated CRd study in newly diagnosed MM, the regimen was well tolerated in  
| CRd: Cohorts 1–5 (CFZ: 15 to 20 mg/m2; LEN: 10 to 25 mg)  Overall  (n=13) (n=29)   |         |         |         |
|------------------------------------------------------------------------------------|---------|---------|---------|
| ≥ CR/nCR                                                                           | 5 (31)  | 1 (8)   | 6 (21)  |
| ≥ VGPR                                                                             | 7 (44)  | 4 (31)  | 11 (38) |
| ≥ PR                                                                               | 9 (56)  | 8 (62)  | 17 (59) |
| ≥ MR                                                                               | 11 (67) | 10 (77) | 21 (72) |  
phase I portion of the study up to maximum planned dose (MPD) of carfilzomib 36 mg/m2, lack of overlapping toxicity have allowed for the use of these agents at full doses and for extended periods and the study proceeded to Phase II at MPD and completed enrollment (total 53 patients).  
On both phase I and II, patients receive 8 initial 28-day cycles, with carfilzomib at 20 mg/m2, 27 mg/m2 (Phase I), and 36 mg/m2 (Phase I and II, given IV on days 1, 2, 8, 9, 15, and 16, lenalidomide at 25 mg PO (days 1–21), and dexamethasone at 40/20 mg PO weekly (cycles 1–4/5-8). Patients achieving ≥PR could proceed to stem cell collection (SCC) and autologous stem cell transplant (ASCT) after 4 cycles. Per protocol design, ASCT candidates were offered the option to continue CRd treatment after SCC. After 8 cycles, pts received 28-day maintenance cycles of carfilzomib (days 1, 2 15, 16), lenalidomide days 1–21, and dexamethasone weekly at the doses tolerated at the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. In the phase I, 4 patients were enrolled at carfilzomib 20 mg/m2, 13 at carflizomib 27 mg/m2 and 36 at CFZ 36 mg/m2 (18 in Phase I and 18 in Phase II). Median age was 59 years (range 35-81; including 23 patients 65 or older), 74% were men, 60% ISS stage II/III, 33% of 49 with available data any of del 13 or hypodiploidy by metaphase, or t(4;14), t (14;16), del17 by FISH. As of cut-off date (June 30, 2011), 51 evaluable pts received a median of 8 cycles. Toxicity data (cycles 1-8) were available for 51 pt who have completed at least the first cycle. Hematologic toxicities were reversible and included Grade (G) 3/4 neutropenia in 10%, G3/4 thrombocytopenia in 10%, and G3/4 anemia in 9%. The most common non-hematologic toxicities (all grades) were hyperglycemia (76%), hypophosphatemia (61%), and infection (53 %). G3/4 non-hematologic AEs included DVT/PE while on ASA prophylaxis (10%), mood alteration (2%) and glucose elevations (24%); the last 2 AEs were related to Dexamethasone. Peripheral neuropathy was limited to G1/2 sensory (24%) Forty-five pts continue treatment (2 proceeded to transplant, 1 discontinued for toxicities, 3 for events not related to treatment or per pt wish), and 22 pts continue on treatment in the maintenance phase. The majority of pts did not require any dose modifications, neither in the initial nor in the maintenance phase (31% and 25%, respectively). Responses were rapid with 42 of 49 pts achieving at least PR after 1 cycle. After a median of 8 cycles for all pts (range 1–20), the best response rates per IMWG criteria in 49 evaluable pts who completed at least 1 cycle are shown in Table. Response rates improved with the duration of treatment and reached PR 100%, >VGPR 100%, and CR/nCR 79%. Responses were deep even at lowest dose levels with the majority of pts at level 3 still early in treatment. Responses by ISS stage or cytogenetic status were similar in specific subgroups to overall response results. 24 patients proceeded to stem cell Page 30 collection after a median of 5 cycles of CRd (range 4-9), using growth factors only in 23 patients and cyclophosphamide and growth factors in 1 pt, with a median 6.55 x 106 CD34+ cells/kg collected (range 3.75-9.6); all resumed CRd treatment. After a median of 9.5 months of follow-up, only 1 evaluable patient has progressed, and all are alive. More recent analysis, showed continued improvement of the depth of response with the duration of treatment (median 13 months) and an unprecedented rate of stringent responses (sCR) which at the completion of 8 cycles reached 43%
28  
| ORR (%)                                   | CR/nCR (%)   | VGPR(%)   |     |
|-------------------------------------------|--------------|-----------|-----|
| Tx cycles 1+ (n=49)                       | 94           | 53        | 65  |
| 4+ (n=35)                                 | 100          | 71        | 89  |
| 8+ (n=28)                                 | 100          | 75        | 89  |
| 12+ (n=19)                                | 100          | 79        | 100 |
| CFZ dose, mg/m2 20 (n=4)                  | 100          | 75        | 100 |
| 27 (n=13)                                 | 100          | 85        | 100 |
| 36 (n=32)                                 | 91           | 38        | 47  |
| ISS stage I (n=20)                        | 90           | 50        | 65  |
| II (n=16)                                 | 94           | 44        | 56  |
| III (n=13)                                | 100          | 69        | 77  |
| Cytogenetics n=49 Normal/favorable (n=33) | 91           | 52        | 61  |
| Unfavorable (n=16)                        | 100          | 56        | 75  |  
It was concluded that CRd is highly active and well tolerated allowing the use of full doses for an extended time in patients with newly-diagnosed MM with limited need for dose modification. Responses are rapid and improve over time reaching 100% >VGPR. Efficacy results were comparable across ISS stage and cytogenetic status and early time-to-event data are very encouraging. This study is the first to report the frontline treatment of myeloma with CRd to date, and provides additional support for the ongoing phase 3 ASPIRE trial of CRd vs. Rd in patients with relapsed and/or refractory MM.  
29 Together, these results suggest that carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in combination are active and well tolerated and that there are no significant overlapping toxicities (in the dose ranges tested). Importantly, lenalidomide-associated neutropenia and thrombocytopenia do not appear to be exacerbated by concurrent treatment with carfilzomib, suggesting that carfilzomib will combine well with other anti-cancer agents.
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1.7 study rationale

Considering that autologous stem cell transplant (ASCT) improves the depth of response of even the most active regimens and that post ASCT consolidation further improves this effect,3,4, the current study will investigate whether a combination of initial treatment with 4 cycles of CRd (pre- ASCT induction) followed by ASCT followed by 4 cycles of CRd consolidation improves the rate of sCR compared to the historical rate of sCR determined in the recently completed frontline CRd study with delayed transplant, with comparisons made at the completion of the equivalent duration of treatment without transplant, i.e. after 8 cycles of CRd without transplant.28,30 In addition, the study design will provide an estimate of an impact of ASCT on an overall response, DOR, PFS, and OS in comparison to treatment with CRd induction and CRd maintenance of similar patient population but without transplant. Therefore, this study's results help to answer whether or not we can build upon the already established high activity of the CRd regimen adding of the most active treatment in myeloma, i.e. high dose of melphalan and ASCT to the CRd treatment strategy and further improve sCR rate. The CRd combination shows very high activity without transplant in new myeloma (100% PR
rate, up to 82% VGPR, and 67% CR/nCR rate)1 and is well tolerated in both new myeloma1 as well is in relapsed myeloma.  
2 At the completion of 8 cycles of CRd, 67% of patients achieved nCR/CR and 43% sCR. While the role of autologous stem cell transplant (ASCT) in the era of novel active therapies is currently being evaluated, ASCT remains a standard of care for transplant candidates and still commonly used. Initial therapy with active novel regimens (ie RVD, RVDD, VDT) followed by autotransplant produced excellent post-ASCT response rates with evidence that transplant improves further pre-transplant level of disease cytoerduction.  
3,4 We hypothesized that given the superior activity seen in the CRd combination, this combination will likely improve the depth of response achieved with other regimens prior to transplant, and therefore subsequently at 3 months post-ASCT. Using similar strategy, pre-ASCT and at 3 months post-ASCT patients initially treated with VDT achieved 31% and 52% nCR/CR, respectively (sCR not reported).  
31 Since at least VGPR (including CR/nCR) prior to ASCT and post-ASCT improves progression free survival and overall survival, 5,6 we will use information gained from this study to evaluate if ASCT incorporated into the CRd treatment is a better treatment strategy for initial therapy of patients starting treatment with CRd than an extended treatment with CRd without transplant. Therefore, this study can influence the design of future randomized studies with CRd as initial treatment of newly diagnosed myeloma. The study population for the current protocol, i.e. newly diagnosed multiple myeloma subjects, is expected to have similar characteristics as the study population enrolled in the recently completed CRd study and is expected to tolerate therapy very well, based on our frontline CRd experience, as detailed in Section 1.5 above. Since we established tolerable CRd doses in the recently completed frontline CRd trial, there is no need for Phase 1b study. This study will allow for an assessment of the role of ASCT for patients initially induced with CRd as the results from this study could be compared to the results from the recently completed clinical trial in which all patients, including ASCT candidates continue CRd treatment with a deferred transplant for later. The current standard of care for patients who completed ASCT is lenalidomide maintenance based on the results of 2 randomized studies, which showed superior PFS versus placebo for all patient groups including patient in CR post ASCT (Attal et al ASH 2010, McCarthy et al. ASH 2010), and superior OS (McCarthy et al., IMW 2011). But there is also evidence of benefit of bortezomib-based consolidation (Cavo et al, ASH 2010 and ASH 2011) and maintenance with proteasome inhibitor (bortezomib, the first approved proteasome inhibitor; Sonnefeld et al, ASH 2011) and appearance of superior maintenance when both IMiD and bortezomib are combined (Palumbo et al, ASH 2010, Mateos et al, Lancet Oncology 2011). Based on excellent tolerance of CRd for extended periods of time in the recently completed frontline CRd study (Jakubowiak et al, ASH 2011) we hypothesized that a course of post-ASCT CRd consolidation and CRd maintenance will improve depth of response and progression-free survival in post transplant setting compared to post-ASCT lenalidomide alone. Therefore, PFS from this study—which is one of the study secondary endpoints—will provide an estimate whether this strategy is superior to the initial therapy with any regimen followed by transplant followed by lenalidomide maintenance reported earlier (Attal et al ASH 2010, McCarthy et al. ASH 2010), therefore further enhancing our ability to design future randomized studies with CRd in transplant candidates.
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2 objectives 2.1 primary objective

To determine the rate of stringent CR (sCR) after 8 cycles of CRd (4 cycles of induction
+ ASCT + 4 cycles of CRd consolidation).
clinical study protocol
2.2 secondary objectives

Secondary objectives include characterization of additional efficacy variables:  
- Overall response rate defined as partial response or better (>PR) including the rate of VGPR or better (>VGPR) and near complete response or better (sCR/CR/nCR) across entire treatment in high risk and low risk patients
- Duration of response (DOR), Progression free survival (PFS), Time to progression (TTP), and Overall Survival (OS)
clinical study protocol
2.3 exploratory objectives

Exploratory objective include characterization of following variables:  
- To determine the rate of minimal residual disease by multiparameter-flow cytometry in patients who achieved CR after 4 cycles, transplant, 8 cycles and end of treatment
- Evaluation of MRD by gene sequencing method using the Sequenta platform
(LymphoSIGHT®) in parallel with multi-parameter flow cytometry (MFC)
- Prospective evaluation of candidate markers of response to CRd established in the completed CRd trial
- Evaluation of markers of response and duration of response to treatment strategy using CRd with or without transplant
clinical study protocol
3 experimental plan 3.1 study

This study is a multi-center, open-label, Phase 2 study in which transplant candidates with newly diagnosed MM requiring systemic chemotherapy will receive induction treatment with Page 34 carfilzomib, lenalidomide, and dexamethasone and post autologous stem cell transplant CRd consolidation/maintenance therapy. The study will determine the efficacy of the treatment strategy. The primary endpoint is to determine the response rate (sCR) after completion of a total of 8 cycles of CRd (4 cycles of CRd induction followed by ASCT followed by 4 cycles of CRd consolidation). Definitions of these primary endpoints plus a list of secondary endpoints are given in Section 2.1. Protocol treatment (CRd) will last for a total of 18 cycles (4 cycles prior to ASCT + 4 cycles post ASCT consolidation + 10 cycles of maintenance). This study will enroll 70 patients in the pre-ASCT induction portion of the study and anticipate that most of these will resume protocol treatment at the consolidation/maintenance therapy post ASCT. Patients who complete the CRd induction but who become not eligible for ASCT can be considered to continue protocol treatment after discussion with the Lead Principal Investigator with an additional 4 cycles of CRd as in consolidation regimen followed by 10 cycles of CRd maintenance as in CRd maintenance regimen. Patients who decline transplant for reasons other than toxicities will be replaced. After completion of CRd treatment, it will be recommended that patients continue single-agent lenalidomide maintenance therapy off protocol at the last tolerated dose of lenalidomide, provided the dose is tolerated and there is no evidence of progressive disease.  
Carfilzomib will be administered at 20 mg/m2 as an IV infusion on Days 1 and 2 of Cycle 1 followed by 36 mg/m2 as an IV infusion on Days 8, 9, 15, and 16 for the remainder of Cycle 1 and on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle for the remaining Cycles 2-4 (Cycles 1- 4 represent induction) and at dose last tolerated prior to ASCT on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle for Cycles 5-8 (CRd consolidation). During CRd maintenance (Cycles 9-18), carfilzomib will be administered at the last tolerated dose as an IV infusion on Days 1, 2, 15, and 16 of a 28-day cycle. Lenalidomide will be administered PO daily at 25 mg on Days 1-21 of the 28 day cycle for pre- ASCT induction Cycles 1-4 (induction) and at the last tolerated dose prior to ASCT on Days 1-21 of the 28 day cycle for Cycles 5-8 (CRd consolidation) and Cycles 9-18 (CRd maintenance). The first cycle of consolidation post-transplant must start at a lenalidomide dose no higher than 15 mg. In discussion with the Lead Principal Investigator and on a case-by-case basis, provisions may be made to start CRd consolidation with a lower than 15 mg dose of lenalidomide for participants with inadequate hematologic parameters at 70-90 days following stem cell reinfusion (not later than 120) and/or to escalate lenalidomide dose up to 25 mg per dose after completion of 1 cycle of CRd consolidation for participants with adequate hematologic parameters. Patients that do not complete ASCT but continue on CRd maintenance will follow the same CRd consolidation treatment for 4 cycles followed by 10 cycles of CRd maintenance. Dexamethasone will be administered PO or IV between 30 minutes and 4 hours preceding carfilzomib infusion as follows:
- Cycles 1-4 (induction): 40 mg per dose on Days 1, 8, 15, and 22  
- Cycles 5-8 (CRd consolidation): 20 mg (or last tolerated dose) per dose on days 1, 8, 15, and 22
- Cycles 9-18 (CRd maintenance): 20 mg (or last tolerated dose) on days 1, 8, 15 and 22
Individual subjects should receive 4 cycles of pre-ASCT CRd induction treatment. After cycle 4, subjects will proceed to stem cell harvest with the use of growth factors or as per current standards of care as described in section 6.4. Patients who achieve confirmed CR/nCR prior to completion of 4 cycles of CRd can proceed to stem cell collection (SCC) earlier but then resume treatment for a total of 4 induction CRd cycles. Patients who achieve less than optimal response (≤PR) may be eligible to receive up to two more cycles of induction CRd prior to transplant after approval from the Lead Principle Investigator. The number of post-transplant consolidation cycles will be adjusted accordingly so that the total number of cycles (induction + consolidation) remains at 8.
clinical study protocol
3.2 number of centers

A total of 5 MMRC centers will participate in this study.
clinical study protocol
3.3 number of subjects

This study will enroll 70 patients in the induction portion of the study. Those who do not have ASCT will be replaced.
clinical study protocol
3.4 estimated study duration

The total study enrollment period is expected to be 18-24 months. A subject is considered to have completed the treatment phase of the study 4 weeks (28 days) after the end of the last treatment cycle. Excluding long-term follow-up, the treatment phase of the study will be completed once the last subject completes the 28-day safety follow-up visit (30 days for resolution of toxicity). Subjects who have not progressed will be followed for progression for up to 5 years from the completion of the safety follow-up visit. All subjects will be followed for survival and development of new cancers at least every 3 months for 5 years.
clinical study protocol
3.5 treatment schema

CRd induction X 4 cycles  Stem cell Harvest ASCT CRd consolidation X 4 cycles  CRd maintenance X 10 cycles
$${\mathrm{intessence}}$$
Lenalidomide maintenance
(recommended off protocol maintenance therapy)
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3.6 inclusion criteria

Disease-related:
1. Newly diagnosed, myeloma requiring systemic chemotherapy as per IMWG uniform  
criteria (see Appendix B):
- Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids or lenalidomide or bortezomib-
**5 OCT 2016**
Page 37 of 121 Newly Diagnosed Symptomatic Myeloma based regimens does not disqualify the patient (the treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle)
- Bisphosphonates are permitted 2. Suitable and interested to proceed to ASCT. (Refer to section 6.4)  
3. Measurable disease, prior to initial treatment as indicated by one or more of the following:
- Serum M-protein ≥ 0.5 g/dL - Urine M-protein ≥ 200 mg/24 hours - If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable
Demographic:
4. Males and females ≥ 18 years of age  
5. Life expectancy of more than 3 months 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix C)
Laboratory  
7. Adequate hepatic function, with bilirubin < 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times ULN
8. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L. Screening platelet count should be independent of platelet transfusions for at least 2 weeks.  
9. Calculated or measured creatinine clearance of ≥ 50 mL/minute, calculated using the following formula of Cockcroft and Gault:
(140 - age) x mass (kg) x 0.85 (if female) 72 x creatinine (mg/dL) Or creatinine below 2 g/dl
clinical study protocol
ethical/other

10. Written informed consent in accordance with federal, local, and institutional guidelines  
11. Females of childbearing potential (FCBP) [defined as sexually mature females who: 1)
have not undergone a hysterectomy or bilateral oophorectomy; or 2) have not been
naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months)] must agree to ongoing pregnancy testing.  
12. FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before Day 1 Cycle 1 and the second pregnancy test must be performed within 24 hours of Day 1 Cycle 1. The subject may not receive lenalidomide until the Treating Investigator has verified that the results of these pregnancy tests are negative, and must agree to ongoing pregnancy tests as outlined in the protocol. *For patients already on Revlimid, continuation* of current testing schedule is permitted as long as it is not interrupted during the transition to CRd therapy.  
13. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The 2 methods of reliable contraception must include a highly effective method (ie, intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and an additional effective (barrier) method (ie, latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed.  
14. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.  
15. Male subjects must agree to inform his physician if he has had unprotected sexual contact with a female who can become pregnant or if he thinks for any reason that his sexual partner may be pregnant.  
16. Male subjects must agree not to donate semen or sperm while taking lenalidomide and/or carfilzomib and 28 days after the last Lenalidomide/Carfilzomib dose.  
17. All study participants enrolled in the United States must be registered into the mandatory REVLIMID Rems ® program and be willing and able to comply with the requirements of REVLIMID Rems®.
18. The ability to take aspirin or other appropriate VTE prophylaxis 19. Subjects must agree to adhere to all study requirements, including birth control measures and pregnancy testing, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring.
clinical study protocol
3.7 exclusion criteria disease-related

1. Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as
<0.5 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, or disease only measured by serum free light chain 2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
3. Waldenström's macroglobulinemia or IgM myeloma 4. Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
5. Participation in an investigational therapeutic study within 3 weeks or within 5 drug halflives (t1/2) prior to first dose, whichever time is greater 6. Participation in another clinical trial unless approved by the Lead Principal Investigator Concurrent Conditions 7. Pregnant or lactating females 8. History of allergy to mannitol 9. Major surgery within 3 weeks prior to first dose 10. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities 11. Uncontrolled hypertension or diabetes 12. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose 13. Known or suspected HIV infection, known HIV seropositivity 14. Active hepatitis A, B, or C infection  
15. Non-hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone 16. Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent 17. Significant neuropathy (Grades 3-4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment
18. Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (eg, lansoprazole), enteric-coated aspirin, allopurinol or if a history of prior thrombotic disease, warfarin or low molecular weight heparin 19. Subjects in whom the required program of PO and IV fluid hydration is contraindicated, eg, due to pre-existing pulmonary, cardiac, or renal impairment 20. Subjects with known or suspected amyloidosis of any organ 21. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis. 22. For subjects enrolled in the United States, no coverage or not-acceptable by patient co-pay for Lenalidomide.
clinical study protocol
4 subject enrollment 4.1 patient

Patient registration for this trial will be centrally managed by the designated University of Chicago Clinical Research Associate (CRA). A potential study subject who has been screened for the trial and who has signed the Informed Consent document will be initially documented by the participating site on the Screening and Enrollment Log provided by the University of Chicago. It is the responsibility of the site Treating Investigator to determine patient eligibility prior to submitting a patient registration request to the lead site. After patient eligibility has been determined, a copy of the completed Eligibility Worksheet together with all the pertinent source documents will be submitted by the requesting site to the University of Chicago CRA, either by fax or by email between the hours of 9 am and 5 pm CST. The University of Chicago CRA, who acts as the registrar, will review the submitted documents and process the registration. Sites should inform the CRA of a potential registration by 5 p.m. Central Time at least 72 hours prior to the anticipated Cycle 1 Day 1. Same day registrations cannot be guaranteed. Subsequently, an email will be sent by the University of Chicago CRA to the requesting site registrar to confirm patient registration and to provide the study identification number that has been assigned to the patient. In addition, a copy of the completed eligibility worksheet signed and dated by the registrar, will be faxed back to the requesting site registrar. Following completion of the induction therapy, patients proceeding to ASCT will be considered "off study." Prior to beginning consolidation, subjects must meet treatment parameters including ANC ≥ 1.0 x 109/L, Platelet count ≥ 50 x 109/L, serum uric acid and creatinine levels returned to baseline and resolution of all transplant-related toxicities (Section 5.3). Patients found to be ineligible for participation after being consented will be considered screen failures, and documented as such in the Screening and Enrollment Log. These patients will not have study identification number assigned to them, and will not receive study treatment.
clinical study protocol
5 treatment 5.1 general procedures

Individual Subject Treatment After screening, eligibility determination, and enrollment, subjects will receive carfilzomib, lenalidomide, and dexamethasone. All subjects are planned to receive 4 cycles of CRd induction. Patients who achieve confirmed CR/nCR prior to completion of 4 cycles can proceed to SCC earlier but then resume treatment for a total of 4 induction cycles. After completion of induction, all patients will proceed to stem cells harvest followed by ASCT. Following ASCT (3 months post-AST; 70-90 days but not more than 120), subjects will continue with CRd consolidation (cycles 5-8). Of note, 30 days following the last dose of CRd, (i.e. Cycle 4 Day 22), or at the start of stem cell collection (whichever occurs first), and during ASCT period, patients will be considered to be off-study so no toxicities will be recorded for this period unless considered directly related to treatment with CRd. The CRd maintenance phase will commence at the start of cycle 9 and continue through cycle 18. For patients enrolled into CRd induction, consolidation, and maintenance the protocol treatment will last for a total of 18 cycles (4 cycles prior to ASCT + 4 cycles post ASCT consolidation + 10 cycles of CRd maintenance). After completion of CRd treatment, patients will then move to a recommended single-agent lenalidomide maintenance therapy off protocol, as long as it is tolerated and there is no evidence of progressive disease. An individual subject will be considered off-treatment following a 30-day safety follow-up period after the last CRd cycle of treatment. Subjects who have not progressed upon completion or discontinuation of the study will be followed for up to 5 years from the safety follow-up visit for disease progression. All subjects will be followed for survival and development of new cancers at least every 3 months.
clinical study protocol
5.2 drug administration

5.2.1 **PRETREATMENT PREPARATION**
Two days before Day 1 of Cycle 1, the following **required** concomitant medication should be started:
- **Oral hydration** 30 mL/kg/day (approximately 6 to 8 cups of liquid per day) and before each dose of carfilzomib. Compliance must be assessed before initiating treatment; treatment is to be delayed if PO hydration is not adequate.  
The following required treatments will be started on Cycle 1 Day 1 or up to 24 hours prior to Cycle 1 Day 1:
- **Valacyclovir** 500 mg PO QD or equivalent HZV prophylaxis, continuing for the duration of treatment. Additional prophylaxis is at the Treating Investigator's discretion.  
- **Aspirin** (enteric-coated) 325 mg PO QD for the duration of treatment. (Subjects with known high thrombotic risk, eg, prior thrombosis, DVT, etc) should receive full anticoagulation at the Treating Investigator's discretion.)
The following may be given at Treating Investigator's discretion  
- **Lansoprazole** (Prevacid ) 15 mg PO QD, or other PO proton-pump inhibitor or H1 blocker to prevent peptic disease for the duration of treatment
clinical study protocol
- mycostatin or nystatinto prevent

Serum chemistries and hematology must be obtained and reviewed prior to carfilzomib dosing on Days 1, 8, 15 during Cycle 1-8 and on Days 1 and 15 of Cycles 9-18. Clinically significant electrolyte abnormalities (ie, ≥ Grade 2) should be corrected before carfilzomib dosing. Serum chemistries on Day 2, 9, 16 are optional if Tumor Lysis Syndrome is suspected or at the discretion of the treating investigator.
clinical study protocol
- on day 1

o Dexamethasone (IV or PO) is given between 30 minutes and 4 hours before carfilzomib.  
o IV hydration will be given immediately before each carfilzomib dose during Cycle 1. This will consist of 125 to 500 mL normal saline or other appropriate IV fluid. If
LDH or uric acid is elevated (and/or in subjects considered still at risk for tumor lysis syndrome) at Cycle 2, Day 1, then the recommended IV hydration should be given additionally before each dose in Cycle 2. The goal of the hydration program is to maintain robust urine output (comparable to fluid intake). Subjects should be monitored closely during this period for evidence of fluid overload and diuretics should be used if patients have positive fluid balance of more than 1litre or weight gain of more than 1 kg.  
o Subjects should have a dedicated line for carfilzomib administration. Before and after administration, the line must be flushed with 20 mL of normal saline. If a dedicated line is not possible, the existing line must be flushed with a minimum of 20 mL of normal saline before and after drug administration.
clinical study protocol
5.2.2 dexamethasone

Dexamethasone will be administered between 30 minutes and 4 hours preceding the carfilzomib (on days that they coincide), as follows: - Cycles 1 - 4 (induction): 40 mg PO or IV per dose Days 1, 8, 15 and 22  
- Cycles 5 - 8 (consolidation): 20 mg (or last tolerated dose) PO or IV per dose Days 1, 8, 15 and 22
- Cycles 9 - 18 (maintenance): 20 mg (or last tolerated dose) PO or IV per dose Days 1, 8, 15 and 22
During Cycle 1, dexamethasone may administered as a split schedule PO or IV pre-Carfilzomib on days 1, 2, 8, 9, 15, 16 as well as Day 22, 23 in patients with high tumor burden or risk for cytokine release syndrome. This means that a patient assigned 40mg dexamethasone on days 1, 8, 15, 22 may receive 20 mg on days 1,2, 8, 9, 15, 16, 22, 23 (20/20) or 36 mg on Day 1, 8, 15, 22 and 4 mg on Days 2, 9, 16, 23 (36/4). It is recommended that patients should return to one dose of 40mg/week in Cycle 2+ however a split schedule may be implemented after discussion with the Lead Principle Investigator. Dexamethasone given on days without carfilzomib (on Days 22 of Cycles 1-8) may be selfadministered by the subject on an outpatient basis. Missed doses of dexamethasone will not be made up. Procedures for dose reductions and delays are summarized in Section 5.4 (Table 5.3)
clinical study protocol
5.2.3 carfilzomib

Carfilzomib will be administered after dexamethasone as follows:  
- Cycle 1 Days 1 and 2: 20 mg/m2 IV over 10 minutes but may be administered over 30 minutes according to institutional guidelines o For patients at high risk for Tumor Lysis Syndrome, step-up dosing to 27 mg/m2 on Day 8, 9 and to 36 mg/m2 on Days 15, 16 may be used.  
- Induction Cycles 1-4 (starting with Cycle 1 Day 8) 36 mg/m2 IV as a 30 minute infusion Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle
- CRd Consolidation Cycles 5-8: Last tolerated dose prior to ASCT as IV infusion Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle
- CRd Maintenance Cycles 9-18: Last tolerated dose as IV infusion Days 1, 2, 15, and 16 of a 28-day cycle
The dose will be calculated using the subject's actual body surface area (BSA) at baseline.  
Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. For weight changes
>10%, carfilzomib dose should be recalculated. Carfilzomib for Injection will be given as an IV infusion. The dose will be administered at a facility capable of managing hypersensitivity reactions. Subjects will remain at the clinic for at least 1 hour following each dose of carfilzomib for clinical observation during each dose in Cycle 1 and for Day 1 of Cycle 2. Doses of carfilzomib may be rescheduled by up to 2 days, In the event that there is a one day break in between Carfilzomib dosing (i.e. Carfilzomib administered on Day 1 and 3, for example, due to a holiday) then 4mg of dexamethasone should be administered prior to the second day of dosing. Anticipated delays of carfilzomib dosing should be discussed with the Lead Principal Investigator. Missed doses will not be replaced during a cycle. Procedures for carfilzomib dose reductions and delays are summarized in Section 5.4, along with the criteria that must be met for re-treatment with study drug. Carfilzomib for Injection is supplied both as a lyophilized parenteral product in single-use vials; the lyophilized product is supplied in 25-mg and 60-mg vials. Prior to use, the lyophilized product is reconstituted with Water for Injection. See Section 10.1 for details on carfilzomib description, formulation, preparation, storage, and accountability.
clinical study protocol
5.2.4 lenalidomide

Subjects will receive lenalidomide as follows: - Induction Cycles 1-4: Lenalidomide 25 mg PO once daily on Days 1-21 of each 28-day cycle.  
- CRd Consolidation Cycles 5-8 and CRd maintenance Cycles 9-18: Last tolerated dose prior to ASCT on Days 1-21 of each 28-day cycle. The first cycle of consolidation, Cycle 5, must start at last tolerated dose prior to ASCT but not higher than 15 mg per dose.
In discussion with the Lead Principal Investigator and on a case-by-case basis, provisions may be made to start at a lower than 15 mg dose of lenalidomide for participants with inadequate hematologic parameters following ASCT. The dose of lenalidomide should be re-escalated up to 25 mg per dose (or best tolerated dose prior to transplant) after completion of 1 cycle of CRd consolidation for participants with adequate hematologic parameters. On days coinciding with carfilzomib administration, lenalidomide should be taken at least 4 hours after the carfilzomib dose and may be self-administered at home by the subject. On days on which carfilzomib is not administered, lenalidomide should be taken at approximately the same time each day. Missed doses of lenalidomide will not be made up. Subjects should be instructed to never take lenalidomide past Day 21 of each cycle.  
Lenalidomide is taken with water on a full or empty stomach. Subjects should not break, chew or open capsules. Late doses of lenalidomide should if possible be taken on the assigned day but should not be made up the next day. Vomited doses will not be made up. No intra-subject dose escalation of lenalidomide will be permitted. For all subjects enrolled in the United States, Lenalidomide (Revlimid®) will be used as commercial drug covered by patients insurance in accordance with the Revlimid REMS® program of Celgene Corporation. In accordance with Revlimid REMS® requirements, all participating investigators and subjects must be registered in and must comply with all requirements of the program. Prescriptions must be filled within 7 days and will only be filled for one cycle at a time, for 21 days of treatment. All subjects and investigators must comply with lenalidomide prescribing requirements. Procedures for dose reductions and delays are summarized in Section 5.4. Information on lenalidomide description, formulation, storage, and accountability may be found in Section 10.2.
clinical study protocol
5.2.5 treatment compliance

Research center personnel will review the dosing instructions with subjects. Subjects will be asked to maintain a diary to record drug administration. Subjects will be asked to bring any unused drug and empty drug containers to the research center at their next visit. Research personnel will count and record the number of used and unused drug at each visit and reconcile with the patient diary.  
Page 47
clinical study protocol
5.3 instructions for initiation of

NOTE: to initiate consolidation therapy following ASCT, the patient must be recovered from all transplant-related toxicities as well as meet the treatment parameters described below: The following guidelines refer to a new course of treatment following cycle 1 induction or after the first consolidation cycle. Patients who do not proceed to ASCT and continue on CRd therapy may proceed as noted below. A new course of treatment may begin on the scheduled Day 1 of a new cycle if all of the following are met:
- ANC ≥ 1.0 x 109/L - Platelet count ≥ 50 x 109/L, unless attributed to myeloma involvement of > 50% in the bone marrow, in which case platelets must be > 30 x 109/L to initiate the next cycle
- Any other study drug-related adverse event must have resolved to grades as specified in protocol (see Section 5.4) - Serum uric acid and creatinine levels must return to baseline prior to carfilzomib doses during Cycles 1 and 2 If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly, and a new treatment cycle will not be initiated until the toxicity has resolved, as described above. If either lenalidomide or carfilzomib are held for the remainder of the previous cycle or the new cycle is delayed due to residual toxicity on the planned Day 1 of the next cycle, then the new cycle will be started at 1 dose decrement. (see Section 5.4)
clinical study protocol
5.4 dose modification guidelines

The following sections and tables summarize dosing modifications of carfilzomib, lenalidomide, and dexamethasone to manage possible toxicity. Dose modifications different from those stated in the protocol should be discussed with the Lead Principal Investigator. Administration of carfilzomib and lenalidomide will be discontinued in the event of any other toxicity that, in the opinion of the Lead or Treating Investigator, warrants discontinuation. Dose reduction levels of carfilzomib and lenalidomide for toxicity management of individual subjects are provided below:  
| Nominal          | Reduced Carfilzomib Doses   |          |          |          |
|------------------|-----------------------------|----------|----------|----------|
| Carfilzomib Dose | Dose -1                     | Dose -2  | Dose -3  | Dose -4  |
| 36 mg/m2         | 27 mg/m2                    | 20 mg/m2 | 15 mg/m2 | 11 mg/m2 |  
| Nominal  Lenalidomide  Dose   | Reduced Lenalidomide Doses Dose -3   | Dose -4   |       |      |
|-------------------------------|--------------------------------------|-----------|-------|------|
| Dose -1                       | Dose -2                              |           |       |      |
| 25 mg                         | 20 mg                                | 15 mg     | 10 mg | 5 mg |  
In addition to dose reductions, administration of carfilzomib and lenalidomide will be held temporarily in the event of a treatment-related toxicity at the Treating Investigator's discretion. Study treatment may be reintroduced if resolution of the event to the baseline value or to ≤ Grade 1 within 21 days; otherwise study drug will be permanently discontinued, unless approved by the Lead Principal Investigator. Two dose reduction levels of dexamethasone are defined for the 2 protocol-stipulated dose levels (40 mg for Cycles 1-4 and 20 mg for Cycles 5-18), as illustrated in Table 5-3. Dexamethasone delay should be performed as clinically indicated at the discretion of the treating investigator however the dexamethasone dose must be administered as part of the premedication for carfilzomib on Days 1, 8, 15.Refer to section 5.5.2 for further guidance on dexamethasone administration.  
| Nominal  Dexamethasone  Dose   | Reduced Dexamethasone Doses Dose -1 Dose -2 Dose -3   | Dose -4   |
|--------------------------------|-------------------------------------------------------|-----------|
| Confidential                   | 5 OCT 2016                                            |           |  
Page 49  
| 40 mg   | 30 mg   | 20 mg   | 15 mg   | 10 mg   |
|---------|---------|---------|---------|---------|
| 20 mg   | 15 mg   | 10 mg   | N/A     | N/A     |
clinical study protocol
5.4.1 hematologic toxicity

Guidelines for the management of hematologic toxicities (thrombocytopenia and neutropenia) are summarized in Table 5-4.
clinical study protocol
5.4.2 non-hematologic toxicity

Guidelines for the management of non-hematologic toxicities are summarized in Table 5-5.
clinical study protocol
table 5-4. dose reduction guidelines

| Thrombocytopenia1 Recommended Action                                                                                                                                             |                                                                                                                                                                                                                                                                                         |                                                                                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|
| When Platelets:                                                                                                                                                                  | Lenalidomide                                                                                                                                                                                                                                                                            | Carfilzomib                                                                            |
| Hold carfilzomib, follow CBC  weekly. Hold prophylactic anti                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                         |                                                                                        |
| coagulation until platelets return to  30 x 109 /L                                                                                                                               |                                                                                                                                                                                                                                                                                         |                                                                                        |
| Return to ≥ 30 x 109 /L                                                                                                                                                          | Resume lenalidomide at full dose                                                                                                                                                                                                                                                        | Resume carfilzomib at full dose.                                                       |
| Subsequently drop to < 30 x                                                                                                                                                      | Hold lenalidomide and follow                                                                                                                                                                                                                                                            | Hold carfilzomib and follow CBC                                                        |
| 109 /L                                                                                                                                                                           | CBC weekly                                                                                                                                                                                                                                                                              | weekly                                                                                 |
| Hold lenalidomide, follow CBC  weekly. Hold prophylactic ant                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                         |                                                                                        |
| coagulation until platelets return to  30 x 109 /L                                                                                                                               |                                                                                                                                                                                                                                                                                         |                                                                                        |
| Fall to < 30 x 109 /L                                                                                                                                                            | Resume carfilzomib at one dose  decrement if cyclical  thrombocytopenia is still below  levels considered safe by the  Treating Investigator at one dose  decrement (i.e., dose decrease only  if Treating Investigator judgment is  that Carfilzomib contributed to  thrombocytopenia) |                                                                                        |
| 1Platelet transfusions should also be considered for the management of thrombocytopenia as clinically indicated Neutropenia Recommended Action When ANC Lenalidomide Carfilzomib |                                                                                                                                                                                                                                                                                         |                                                                                        |
| Falls to < 0.5 x 109 /L or to <                                                                                                                                                  | Hold lenalidomide,                                                                                                                                                                                                                                                                      |                                                                                        |
| 1.0 x 109 /L with fever                                                                                                                                                          | add filgrastim if Grade 3 with fever  or Grade 4, follow CBC weekly                                                                                                                                                                                                                     |                                                                                        |
| Return to ≥ 30 x 109 /L                                                                                                                                                          | Resume lenalidomide at 1 dose  decrement                                                                                                                                                                                                                                                | Hold carfilzomib, add filgrastim if  Grade 3 with fever or Grade 4,  follow CBC weekly |  
| Returns to 1.0 x 109 /L (if  neutropenia was the only  toxicity noted)   | Resume lenalidomide at full dose                                                         | Resume carfilzomib at full dose                                               |
|--------------------------------------------------------------------------|------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------|
| Return to 1.0 x 109 /L (if                                               | Resume lenalidomide at 1 dose                                                            | Resume carfilzomib at full dose                                               |
| other toxicity noted)                                                    | decrement                                                                                | unless marked cyclical                                                        |
| thrombocytopenia is present, then  reduce by 1 dose decrement            |                                                                                          |                                                                               |
| Subsequently drops to < 0.5 x  109 /L or to < 1.0 x 109 /L with  fever   | Hold lenalidomide treatments                                                             | Hold carfilzomib treatments                                                   |
| Returns to 1.0 x 109 /L                                                  | Resume lenalidomide at 1 dose                                                            | Resume carfilzomib previous dose at 1  dose decrement (dose decrease required |
| decrement                                                                | only if treating investigator judgment is  that Carfilzomib contributed to  neutropenia) |                                                                               |  
| Table 5-5. Dose Modifications for Non-hematologic Toxicity Recommended Action   |                                                                                                                                                                                                              |                                                                                                                              |
|---------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|
| Toxicity                                                                        | Lenalidomide                                                                                                                                                                                                 | Carfilzomib                                                                                                                  |
| Non-Blistering Rash Grade 3                                                     | Hold lenalidomide dose; follow  weekly If the toxicity resolves to ≤ Grade  1 prior to Day 21 of the current  cycle, restart at 1 dose decrement  and continue the cycle until Day  21 of the current cycle. | Hold (if Treating Investigator's  opinion is possibly related to  Carfilzomib) until ≤ Grade 1,  reinstitute at current dose |
| Grade 4                                                                         | Discontinue lenalidomide study                                                                                                                                                                               | Hold until ≤ Grade 1, reinstitute at                                                                                         |
| drug.                                                                           | current dose.                                                                                                                                                                                                |                                                                                                                              |
| Desquamating (blistering)  rash  - any grade                                    | Discontinue lenalidomide study                                                                                                                                                                               | Hold until ≤ Grade 1, reinstitute at                                                                                         |
| drug.                                                                           | current dose.                                                                                                                                                                                                |                                                                                                                              |
| Erythema multiforme ≥                                                           | Discontinue lenalidomide study                                                                                                                                                                               | Hold until ≤ Grade 1, reinstitute at                                                                                         |
| Grade 3                                                                         | drug.                                                                                                                                                                                                        | current dose.                                                                                                                |
| Sinus bradycardia/ other  cardiac arrhythmia                                    |                                                                                                                                                                                                              |                                                                                                                              |  
| Table 5-5. Dose Modifications for Non-hematologic Toxicity Recommended Action                                                                                         |                                                                                                                                                                                  |                                                     |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------|
| Toxicity                                                                                                                                                              | Lenalidomide                                                                                                                                                                     | Carfilzomib                                         |
| ≤ Grade 2                                                                                                                                                             | Hold lenalidomide dose. Follow  at least weekly. If the toxicity resolves to ≤ Grade  1 prior to Day 21, restart at 1 dose  decrement and continue the cycle  until Day 21.      | Hold until ≤ Grade 1, reinstitute at  current dose. |
| ≥ Grade 3                                                                                                                                                             | Discontinue lenalidomide study                                                                                                                                                   | Hold until ≤ Grade 1, reinstitute at                |
| drug                                                                                                                                                                  | current dose.                                                                                                                                                                    |                                                     |
| Allergic                                                                                                                                                              |                                                                                                                                                                                  |                                                     |
| reaction/hypersensitivity Grade 2 - 3                                                                                                                                 | Hold lenalidomide dose. Follow  at least weekly. If the toxicity resolves to ≤ Grade  1 prior to Day 21, restart at 1 dose  decrement and continue the cycle  until Day 21.      | Hold until ≤ Grade 1, reinstitute at  current dose. |
| Grade 4                                                                                                                                                               | Discontinue                                                                                                                                                                      | Discontinue                                         |
| Tumor lysis syndrome                                                                                                                                                  |                                                                                                                                                                                  |                                                     |
| (≥ 3 of the following: ≥ 50%  increase in creatinine,  uric acid, or phosphate;≥  30% increase in  potassium;≥ 20%  decrease in calcium; or ≥  2-fold increase in LDH | Hold lenalidomide until all  abnormalities in serum  chemistries have resolved. Reinstitute at full doses.                                                                       | Hold carfilzomib until all                          |
| abnormalities in serum chemistries  have resolved. Reinstitute at full doses.                                                                                         |                                                                                                                                                                                  |                                                     |
| Infection Grade 3 or 4                                                                                                                                                | Hold lenalidomide until systemic  treatment for infection is  completed. If no neutropenia,  restart both drugs at full dose. If  neutropenic, follow neutropenic  instructions. | Hold carfilzomib until systemic                     |
| treatment for infection is completed  If no neutropenia, restart both drugs  at full dose. If neutropenic, follow  neutropenic instructions.                          |                                                                                                                                                                                  |                                                     |
| Herpes zoster or simplex of                                                                                                                                           | Hold lenalidomide until lesions                                                                                                                                                  |                                                     |
| any grade                                                                                                                                                             | are dry.                                                                                                                                                                         |                                                     |
| Reinstitute at full doses.                                                                                                                                            | Hold carfilzomib until lesions are  dry. Reinstitute at full doses.                                                                                                              |                                                     |
| Confidential                                                                                                                                                          | 5 OCT 2016                                                                                                                                                                       |                                                     |
| Page 52 of 121                                                                                                                                                        |                                                                                                                                                                                  |                                                     |  
| Table 5-5. Dose Modifications for Non-hematologic Toxicity Recommended Action   |                                                                                  |                                   |
|---------------------------------------------------------------------------------|----------------------------------------------------------------------------------|-----------------------------------|
| Toxicity                                                                        | Lenalidomide                                                                     | Carfilzomib                       |
| Grade 2 neuropathy with  pain or any Grade 3  neuropathy                        | Hold until resolved to ≤ Grade 2.  Then restart carfilzomib at 1 dose  decrement |                                   |
| Grade 4 neuropathy                                                              | Discontinue                                                                      | Discontinue                       |
| Hold until ≤ Grade 2.                                                           |                                                                                  |                                   |
| Then restart lenalidomide at 1  dose decrement                                  |                                                                                  |                                   |
| Renal dysfunction                                                               |                                                                                  |                                   |
| Serum creatinine > 2 mg/dL                                                      | Base dose reduction on calculated                                                | Base dose reduction on calculated |
| GFR (below)                                                                     | GFR (below)                                                                      |                                   |
| CrCl>50 mL/min                                                                  | Full dose                                                                        | Full dose                         |
| CrCl <50 mL/min                                                                 | Reduce lenalidomide to 10 mg                                                     |                                   |
| > 30 mL/min                                                                     | every 24 h; may reinstate prior  dose if, after 2 cycles, CrCl  normalizes       | Full dose                         |
| CrCl< 30 mL/min                                                                 | Reduce lenalidomide to 15 mg                                                     | Hold carfilzomib until CrCl> 30   |
| every 48 h                                                                      | mL/min; restart at 1 dose decrement                                              |                                   |
| CrCl< 30 mL/min requiring                                                       | 5 mg. Once daily. On dialysis                                                    |                                   |
| dialysis                                                                        | days the dose should be                                                          |                                   |
| administered following dialysis.                                                | Hold until resolved to ≤ Grade 2.  Then restart carfilzomib at 1 dose  decrement |                                   |  
| Table 5-5. Dose Modifications for Non-hematologic Toxicity Recommended Action                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                         |                                                                            |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|
| Toxicity                                                                                                                                                                                                                                                                                 | Lenalidomide                                                                                                                                                                                                                                                                                                                            | Carfilzomib                                                                |
| Venous                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                         |                                                                            |
| thrombosis/embolism ≥ Grade 3                                                                                                                                                                                                                                                            | Hold lenalidomide dose and                                                                                                                                                                                                                                                                                                              |                                                                            |
| adjust anticoagulation regimen;  re-start at Treating Investigator's  discretion at full dose                                                                                                                                                                                            | No adjustment required                                                                                                                                                                                                                                                                                                                  |                                                                            |
| Hyperthyroidism or                                                                                                                                                                                                                                                                       | Omit lenalidomide for remainder                                                                                                                                                                                                                                                                                                         |                                                                            |
| hypothyroidism                                                                                                                                                                                                                                                                           | of cycle, evaluate, and initiate  appropriate therapy.                                                                                                                                                                                                                                                                                  |                                                                            |
| Restart lenalidomide next cycle at  1 dose decrement                                                                                                                                                                                                                                     | No adjustment required                                                                                                                                                                                                                                                                                                                  |                                                                            |
| Congestive heart failure                                                                                                                                                                                                                                                                 | Any subject with symptoms of                                                                                                                                                                                                                                                                                                            |                                                                            |
| (CHF)                                                                                                                                                                                                                                                                                    | CHF, whether or not                                                                                                                                                                                                                                                                                                                     |                                                                            |
| lenalidomide related, must have  the dose held until resolution or  return to baseline. If CHF was  felt to be lenalidomide related,  reinstate by one dose decrement  after return to baseline. If no  resolution of CHF after 2 weeks,  the subject will be withdrawn  from the study. | Any subject with symptoms of CHF,  whether or not carfilzomib related,  must have the dose held until  resolution or return to baseline. If CHF was felt to be carfilzomib  related, reinstate by one dose  decrement after return to baseline. If  no resolution of CHF after 2 weeks,  the subject will be withdrawn from  the study. |                                                                            |
| Hypertension including                                                                                                                                                                                                                                                                   | ≥ Grade 3: Carfilzomib attribution,                                                                                                                                                                                                                                                                                                     |                                                                            |
| Hypertensive Crises                                                                                                                                                                                                                                                                      | NA                                                                                                                                                                                                                                                                                                                                      | hold drug until resolved to ≤ Grade 2.  Resume at one level dose reduction |
| Heart problems, including  rapid, strong, or irregular  heartbeat Heart attack, reduced  blood flow to the heart,  abnormal amount of fluid  between the heart and  lining around the heart,  and swelling/irritation of  the lining around the heart                                    | ≥ Grade 3: Carfilzomib attribution,                                                                                                                                                                                                                                                                                                     |                                                                            |
| hold drug until resolved to ≤ Grade 1.  Resume at one level dose reduction                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                         |                                                                            |
| NA                                                                                                                                                                                                                                                                                       | ≥ Grade 3: Carfilzomib attribution,                                                                                                                                                                                                                                                                                                     |                                                                            |
| Pericardial Effusion                                                                                                                                                                                                                                                                     | NA                                                                                                                                                                                                                                                                                                                                      | hold drug until resolved to Grade 1.  Resume at one level dose reduction   |
| Pericarditis                                                                                                                                                                                                                                                                             | ≥ Grade 3: Carfilzomib attribution,                                                                                                                                                                                                                                                                                                     |                                                                            |
| NA                                                                                                                                                                                                                                                                                       | hold drug until resolved to Grade 1.  Resume at one level dose reduction                                                                                                                                                                                                                                                                |                                                                            |
| Confidential                                                                                                                                                                                                                                                                             | 5 OCT 2016                                                                                                                                                                                                                                                                                                                              |                                                                            |
| Page 54 of 121                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                         |                                                                            |  
| Table 5-5. Dose Modifications for Non-hematologic Toxicity Recommended Action                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                             |                                                                          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|
| Toxicity                                                                                                                                                                                                                                                        | Lenalidomide                                                                                                                                                                                                                                                                                | Carfilzomib                                                              |
| Pulmonary Hypertension                                                                                                                                                                                                                                          | = Grade 2: Carfilzomib attribution,  Reduce drug: one level dose  reduction                                                                                                                                                                                                                 |                                                                          |
| NA                                                                                                                                                                                                                                                              | ≥ Grade 3: Carfilzomib attribution,  hold drug until resolved to ≤Grade 2.  Resume at one level dose reduction                                                                                                                                                                              |                                                                          |
| Pulmonary Toxicities:                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                             |                                                                          |
| Interstitial Lung Disease  (inc. pneumonitis), Acute  Respiratory Failure, and  Adult Respiratory Distress  Syndrome (ARDS), cough  and cough with phlegm                                                                                                       | ≥ Grade 2 for Pneumonitis ≥ Grade 3 for ARDS ≥ Grade 4 for Respiratory Failure                                                                                                                                                                                                              |                                                                          |
| NA                                                                                                                                                                                                                                                              | Carfilzomib attribution, hold drug  until resolved to ≤Grade 1. Resume  at one level dose reduction                                                                                                                                                                                         |                                                                          |
| NA                                                                                                                                                                                                                                                              | ≥ Grade 3: Carfilzomib attribution,  hold drug until resolved to ≤ Grade 1.  Resume at one level dose reduction                                                                                                                                                                             |                                                                          |
| Blood clot in the lungs,                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                             |                                                                          |
| fluid in the lungs, bleeding  in the lungs                                                                                                                                                                                                                      | ≥ Grade 3: Carfilzomib attribution,                                                                                                                                                                                                                                                         |                                                                          |
| Gastrointestinal  Perforation                                                                                                                                                                                                                                   | NA                                                                                                                                                                                                                                                                                          | hold drug until resolved to Grade 1.  Resume at one level dose reduction |
| Hold drug until resolved to                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                             |                                                                          |
| ≤Grade 1 or baseline. Resume at  the same dose or reduced dose as  appropriate. If tolerated, the  reduced dose may be escalated to  the previous dose at the discretion  of the physician. Frequent  monitoring of liver function  should then be implemented. | Hold drug until resolved to ≤Grade 1  or baseline. Resume at the same dose  or reduced dose as appropriate. If  tolerated, the reduced dose may be  escalated to the previous dose at the  discretion of the physician. Frequent  monitoring of liver function should  then be implemented. |                                                                          |
| Hepatic Toxicities (≥ Grade  3 elevation of AST or ALT,  Bilirrubin, or other  ≥ Grade 3 liver  abnormalities)                                                                                                                                                  | Full dose                                                                                                                                                                                                                                                                                   |                                                                          |
| Other non-hematologic  toxicity assessed as  lenalidomide-related  ≥ Grade 3                                                                                                                                                                                    | Hold lenalidomide dose. Follow  at least weekly. If the toxicity ≤ Grade 1 before  Day 21 of the current cycle,  restart at 1 dose decrement and  continue until Day 21 of the  current cycle                                                                                               |                                                                          |  
| Table 5-5. Dose Modifications for Non-hematologic Toxicity Recommended Action   |                                                                                                      |                                                                                                       |
|---------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|
| Toxicity                                                                        | Lenalidomide                                                                                         | Carfilzomib                                                                                           |
| Other non-hematologic  toxicity assessed as  carfilzomib-related  ≥ Grade 3     | Full dose                                                                                            | Hold carfilzomib dose until toxicity  resolves to ≤ Grade 1 or baseline.  Restart at 1 dose decrement |
| Other non-hematologic  toxicity assessed as drugrelated ≥ Grade 3                                                                                 | Hold treatment and restart at 1                                                                      |                                                                                                       |
| dose decrement when toxicity has  resolved to ≤ Grade 1 or baseline             | Hold treatment and restart at 1 dose  decrement when toxicity has resolved  to ≤ Grade 1 or baseline |                                                                                                       |  
| Body System                 | Symptom                                                                                                                                                                                                                                                                                                         | Recommended Action                                                                                                                                                 |
|-----------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Gastrointestinal            | Dyspepsia, gastric or  duodenal ulcer, gastritis  Grade 1-2 (requiring  medical management)                                                                                                                                                                                                                     | Treat with H2 blockers, sucralfate, or omeprazole. If symptoms persist  despite above measures, decrease dexamethasone dose by  1 dose level.                      |
| Gastrointestinal            | ≥ Grade 3 (requiring                                                                                                                                                                                                                                                                                            | Hold dexamethasone until symptoms adequately controlled. Restart at                                                                                                |
| hospitalization or surgery) | 1 dose decrement along with concurrent therapy with H2 blockers,  sucralfate, or omeprazole. If symptoms persist despite above  measures, discontinue dexamethasone permanently.                                                                                                                                |                                                                                                                                                                    |
| Gastrointestinal            | Acute pancreatitis                                                                                                                                                                                                                                                                                              | Discontinue dexamethasone permanently.                                                                                                                             |
| Cardiovascular              | Edema ≥ Grade 3 (limiting function  and unresponsive to therapy  or anasarca) Diuretics as needed, and restart dexamethasone at 1 dose decrement;  if edema persists despite above measures, decrease dose another level.  Discontinue dexamethasone permanently if symptoms persist despite  second reduction. |                                                                                                                                                                    |
| Neurology                   | Confusion or mood  alteration  > Grade 2 (interfering with  function +/- interfering with  activities of daily living) Hold dexamethasone until symptoms resolve. Restart at 1 dose  decrement. If symptoms persist despite above measures, discontinue  dexamethasone permanently.                             |                                                                                                                                                                    |
| Musculoskeletal             | Muscle weakness > Grade 2  (symptomatic and  interfering with function +/- interfering with activities of  daily living) Decrease dexamethasone by 1 dose level. If weakness persists,  decrease dose by 1 more dose level. Discontinue dexamethasone  permanently if symptoms persist.                         |                                                                                                                                                                    |
| Metabolic                   | Hyperglycemia ≥ Grade 3                                                                                                                                                                                                                                                                                         | Treatment with insulin or PO hypoglycemic agents as needed. If  uncontrolled despite above measures, decrease dose by 1 dose level  until levels are satisfactory. |
clinical study protocol
5.4.3 conditions not requiring dose

The following conditions are exceptions to the above guidelines. Carfilzomib does not need to be held in the following cases: - Grade 3 nausea, vomiting, or diarrhea (unless persisting more than 3 days with adequate treatment of antiemetics or antidiarrheal agents)
- Grade 3 dexamethasone-related hyperglycemia - Grade 1-3 lenalidomide-induced rash  
- Grade 3 fatigue (unless persisting for > 14 days) - Alopecia