NEWLY- DIAGNOSED MULTIPLE MYELOMA (NDMM) Protocol RV- MM- PI- 0505

Transcription

1 Clinical Trials in Multiple Myeloma at Princess Margaret Cancer Centre (July 2014) NEWLY- DIAGNOSED MULTIPLE MYELOMA (NDMM) 1. An Open- label, Pharmacokinetic Study of Lenalidomide (Revlimid ) and High- dose Dexamethasone induction therapy in previously untreated multiple myeloma (MM) patients with Various Degrees of Renal Dysfunction Validation of Official Dosing Guidelines for Renal Failure. Inclusion criteria Protocol RV- MM- PI Previously untreated, symptomatic multiple myeloma 2. Eligible for autologous stem cell transplantation as per Princess Margaret Hospital criteria. 3. Disease measurable by serum or urine M protein, free light chain assay, bone marrow plasmacytosis or plasmacytoma. 4. No prior myeloma therapy (Exception: up to 480 mg of dexamethasone is allowed within the past 28 days, as well as palliative, localized radiation therapy, without the requirement of a washout period prior enrollment) 5. Laboratory test results within these ranges: Absolute neutrophil count 1,000/mm³ Platelet count 50,000/mm³ (untransfused) Total bilirubin 22 umol/l AST (SGOT) and ALT (SGPT) 2 x ULN or 5 x ULN if hepatic metastases are present.

2 Renal function must be measured by 24hour urine for creatinine clearance (CrCl) any level of CrCl is allowed for eligibility. 6. Able to take aspirin 81mg daily as prophylactic anticoagulation (patients intolerant to ASA may use low molecular weight heparin). Exclusion criteria Patients who fulfill any of the following criteria are not eligible for admission to the study: 1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. 2. Use of any other experimental drug or therapy, except for up to 480 mg of dexamethasone or palliative, localized radiation therapy, without the requirement of a washout period prior enrollment. 3. Known hypersensitivity to thalidomide. 4. Any prior use of lenalidomide. 5. Concurrent use of other anti- cancer agents or treatments. 6. Known positive for HIV or infectious hepatitis, type B or C. 7. Evidence of AL amyloidosis à Open for enrollment ONLY for subjects with renal impairment

3 2. A Phase II Study of using a combination of Busulfan and Melphalan as Conditioning Regimen for Autologous Stem Cell Transplantation (ASCT) in Patients who have received Bortezomib based induction for Newly Diagnosed Multiple Myeloma followed by Lenalidomide Maintenance until Disease Progression Protocol Number: MCRN 001 Inclusion Criteria 1. Age 18 to 75 years, inclusive. 2. Study participants must have a diagnosis of multiple myeloma and are eligible for the planned ASCT. 3. Untreated bone marrow sample was shipped to Princess Margaret Hospital for MRD assay. 4. Must have been treated with a Velcade- based induction regimen. No limit to the number of cycles of induction. 5. Study participants in whom the minimum stem cell dose of 2.0 x 10 6 CD34+ cells/kg has been collected. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of Negative beta- human chorionic gonadotropin (β- HCG) pregnancy test in all women of child- bearing potential (WOCBP). Study participants who are surgically sterile (i.e., have undergone orchidectomy or hysterectomy); female study participants who have been postmenopausal for at least 12 consecutive months; or

4 study participants who agree to remain abstinent or to practice double- barrier forms of birth control from trial screening through 30 days (for females) and 90 days (for males) from the last dose of the study drugs. If employing birth control, two of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device (IUD), birth control pill, birth control implant, condom, or sponge with spermicide. 8. Ability to provide written informed consent prior to initiation of any study- related procedures, and ability, in the opinion of the Principal Investigator, to comply with all requirements of the study. Exclusion Criteria 1. Myeloma progression at any time since starting initial therapy for myeloma. 2. Prior treatment history of ASCT for any medical reason. 3. Prior treatment history of high- dose chemotherapy with stem cell rescue for any medical reason, not limited to myeloma treatment. 4. Prior treatment with busulfan or gemtuzumab ozogamicin for any reason. 5. Systemic amyloidosis. 6. Left ventricular ejection fraction (LVEF) < 45% as measured by either multi- gated acquisition scan (MUGA) or echocardiogram

5 (ECHO) performed within 75 days prior to day of busulfan dose. If cyclophosphamide was used for stem cell harvest, an ECHO or MUGA must be done after the stem cell collection and prior to enrollment to confirm adequate cardiac function. 7. Uncontrolled arrhythmia or symptomatic cardiac disease at the time of screening. 8. Symptomatic pulmonary disease, based on Forced Expiratory Volume in 1 Second (FEV1), Forced Vital Capacity (FVC) or Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) < 50% of predicted (corrected for hemoglobin) measured within 75 days prior to day of busulfan dose. 9. Aspartate transaminase (AST)/alanine transaminase (ALT) 3 x the upper limit of normal (ULN). 10. History of elevated total serum bilirubin >2 mg/dl that had been caused by previous chemotherapy at any point, or total bilirubin > 2.0 mg/dl at the time of screening with the exception of Gilbert s disease. 11. Hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time as International Normalized Ratio (INR) 2.0 at the time of screening. 12. Any previous history of fulminant liver failure, cirrhosis, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, and symptomatic biliary disease. 13. Prior total body irradiation therapy, or radiation therapy directly applied to the liver.

6 14. Patients with a known history of hepatitis B or hepatitis C should be on appropriate anti- viral therapy. Even so, these cases must be discussed with the sponsor and approval obtained prior to screening. 15. Known history of or current HIV infection, or active hepatitis B or c infection or any uncontrolled active infection of any kind at the time busulfan administration. 16. Serum creatinine >177 umol/l at the time of screening. 17. Women who are pregnant or lactating. 18. Current or history of drug and/or alcohol abuse. 19. Use of other investigational therapies within 30 days of enrollment in this study. 20. Clinically significant abnormality in medical history or upon examination that might interfere with the outcomes of the study in the opinion of the investigator. 21. Any patient, who in the opinion of the investigator, should not participate in this study. à Enrollment temporarily on HOLD at PMCC only

7 3. A Phase III, Randomized, Double- Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly- Diagnosed Multiple Myeloma Protocol: C16014 Inclusion Criteria 1. Adult male or female patients 18 years old and above with a confirmed diagnosis of symptomatic multiple myeloma according to standard criteria who have not received prior treatment for symptomatic multiple myeloma 2. Patients for whom lenalidomide and dexamethasone treatment is appropriate and who are not eligible for HDT- SCT for 1 or more of the following reasons: The patient is 65 years of age or older The patient is less than 65 years of age but has significant comorbid condition(s) that are, in the opinion of the investigator, likely to have a negative impact on tolerability of HDT- SCT 3. Patients must have measurable disease defined by at least 1 of the following 3 measurements: Serum M- protein ³ 1 g/dl (³ 10 g/l) Urine M- protein ³ 200 mg/24 hours Serum free light chain assay: involved free light chain level ³ 10 mg/dl (³100 mg/l), provided that the serum free light chain ratio is abnormal 4. Patients must meet the following clinical laboratory criteria: Absolute neutrophil count (ANC) ³1,000/mm3 and platelet count ³ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to randomization

8 Total bilirubin 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3x ULN. Calculated creatinine clearance ³ 30 ml/min 5. ECOG performance status of 0, 1, or Must be able to take concurrent aspirin 70 to 325 mg daily (or enoxaparin 40 mg subcutaneously daily [or its equivalent] if allergic to aspirin), per published standard or institutional standard of care, as prophylactic anticoagulation. NOTE: For patients with prior history of deep vein thrombosis (DVT), low molecular weight heparin (LMWH) is mandatory. Exclusion Criteria 1. Prior treatment for multiple myeloma with either standard of care treatment or investigational regimen NOTE: Prior treatment with corticosteroids or localized radiation is permitted as long as it is below a therapeutic level (maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over a 2- week period 2. Radiotherapy within 14 days before randomization 3. Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection 4. Inability or unwillingness to receive antithrombotic therapy 5. Female patients who are lactating and breastfeeding or have a positive pregnancy test during the screening period 6. Major surgery within 14 days before randomization. NOTE: Kyphoplasty or vertebroplasty is not considered major surgery

9 7. Central nervous system involvement 8. Infection requiring IV antibiotic therapy or other serious infection within 14 days before randomization 9. Diagnosis of Waldenstrom s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months 11. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John s wort within 14 days before randomization in the study 12. Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive. 13. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause). 14. Psychiatric illness/social situation that would limit compliance with study requirements 15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent 16. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or

10 gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment 17. Treatment with any investigational products within 60 days before the first dose of the study drug regimen à Open for enrollment RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM) 1. A Phase I Trial of MK in Combination with Lenalidomide and Dexamethasone in Subjects with Multiple Myeloma Protocol: Merck 023 Inclusion: 1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical research. 2. Be 18 years of age on day of signing informed consent. 3. Has a confirmed diagnosis of multiple myeloma based on standard criteria (see Durie 1986 for criteria [55]). 4. Currently has MM with measurable disease, defined as: a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dl and/or urine monoclonal protein levels of at least 200 mg/24 hours for subjects without measurable serum and urine M- protein levels, an abnormal free light chain ratio (normal value: ) with involved FLC level 10 mg/dl ( 100 mg/l).

11 5. Has relapsed/refractory MM who has failed at least two lines of prior therapy, including bortezomib and an IMiD (thalidomide, pomalidomide, lenalidomide). Relapsed MM defined as disease progression following stabilization or a response to at least one anti- myeloma regimen. Refractory MM defined as meeting one or more of the following: - Nonresponsive to most recent therapy (e.g., stable disease only, or progressive disease while on treatment) - Disease progression within 60 days of discontinuation from most recent therapy 6. Be able to provide archival (if available) and newly obtained bone marrow aspirate/biopsy material for biomarker analysis and disease assessment. 7. Has a performance status of 0 or 1 on the ECOG Performance Scale. 8. Demonstrate adequate organ function. All screening labs should be performed within 7 days of treatment initiation. 9. All subjects must agree to follow the regional requirements for lenalidomide counselling, pregnancy testing, and birth control; and be willing and able to comply with the regional requirements (for example, periodic pregnancy tests, safety labs, etc.). Exclusion The subject must be excluded from participating in the trial if the subject: 1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.

12 2. Has myeloma and a history of repeated infections, primary amyloidosis, hyperviscosity, plasma cell leukemia, POEMS syndrome, Waldenstrom s Macroglobulinemia or IgM myeloma. 3. Has a diagnosis of immunosuppressive disorder or is on any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 4. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 5. Has had prior chemotherapy (including dexamethasone), targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e. Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Subjects with Grade 2 neuropathy are an exception to this criterion and may qualify for the trial. - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. - Note: Toxicity that has not recovered to Grade 1 is allowed if it meets the inclusion requirements for laboratory parameters defined in Table Has been free of additional malignancy for at least 5 years.. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. 7. Has known clinically active CNS involvement. 8. Has an active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use

13 of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen s syndrome will not be excluded from the trial. 9. Has evidence of active, non- infectious pneumonitis. 10. Has an active infection requiring intravenous systemic therapy. 11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre- screening or screening visit through 120 days after the last dose of trial treatment. 13. Has received prior therapy with an anti- PD- 1, anti- PD- L1, anti- PD- L2, anti- CD137, or anti- Cytotoxic T- lymphocyte- associated antigen- 4 (CTLA- 4) antibody (including ipilimumab or any other antibody or drug specifically targeting T- cell co- stimulation or checkpoint pathways). 14. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection. 15. Has a clinically significant coagulopathy per investigator s assessment. 16. Has known symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. 17. Has received an allogenic stem cell transplant. 18. Has received autologous stem cell transplant within 12 weeks before the first infusion. 19. Has received bortezomib, pomalidomide or thalidomide within 2 weeks before the first infusion. 20. Subjects with a prior history of Grade 4 rash associated with thalidomide treatment. 21. Has known hypersensitivity to thalidomide or pomalidomide.

14 22. Is planning for or is eligible for allogenic hematopoietic stem cell transplant. 23. Has known gastrointestinal disease that may significantly alter the absorption of lenalidomide. 24. Is unable or unwilling to undergo antithrombotic prophylactic treatment. 25. Has received a live vaccine within 30 days prior to first dose. à Open for enrollment 2. Phase 1/1b Pharmacokinetics Study of Oral MLN9708 Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients With Normal Renal Function or Severe Renal Impairment Protocol C16015 Inclusion: 1. Male or female patients 18 years or older. 2. MM diagnosed according to standard criteria either currently or at the time of initial diagnosis. Patients in the stable (ie, plateau) phase, defined as myeloma without signs of progression for at least 3 months and with stable paraprotein levels, are eligible for participation. 3. Patients with RRMM after at least 1 prior therapy. A line of therapy is defined as 1 or more cycles of a planned treatment program. This may consist of 1 or more planned cycles of single- agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance, is

15 considered 1 line of therapy. Autologous and allogeneic transplants are permitted. 4. Patients must meet the following clinical laboratory criteria: Absolute neutrophil count (ANC) 1,000/mm3 and platelet count 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to study drug administration. Total bilirubin must be < 1.5 the upper limit of the normal range. Alanine aminotransferase and aspartate aminotransferase must be < 3 the upper limit of the normal range. Calculated CrCl of ³ 90 or < 30 ml/min depending on the group. Patients with severe RI (CrCl < 30mL/min) are eligible. CrCl should be calculated at baseline and prior to each treatment cycle according to the Cockcroft- Gault formula. All measurements should be done within 14 days of starting treatment, with the most recent performed within 1 week of starting treatment. Patients on hemodialysis who are in between dialysis treatments. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence

16 [eg, calendar, ovulation, symptothermal, post- ovulation methods] and withdrawal are not acceptable methods of contraception.) Male patients, even if surgically sterilized (ie, status postvasectomy), who: Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post- ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.) 7. Suitable venous access for the conduct of blood sampling for MLN9708 PK assessments. 8. Voluntary written consent must be given before performance of any study- related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 9. Patient is willing and able to adhere to the study visit schedule and other protocol requirements. Exclusion 1. Female patients who are pregnant or breastfeeding. 2. Failure to have fully recovered (ie, Grade 1 toxicity or less, with the exception of alopecia) from clinically significant effects of prior chemotherapy regardless of the interval since last treatment. 3. Major surgery within 14 days before study drug administration. 4. Radiotherapy within 14 days before study drug administration. 5. Dexamethasone (or equivalent systemic steroid) higher than physiologic dosing within 7 days before study drug administration

17 in Part A. Physiologic dosing of dexamethasone is approximately 1 mg per day (corresponds to mg of prednisone). 6. Central nervous system involvement. 7. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study drug administration. 8. Diagnosis of Waldenstrom s Macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, myeloproliferative syndrome, or primary amyloidosis (with the exception of patients in whom amyloidosis has been documented as a complication of MM, who will be evaluated on a case- by- case basis for trial participation). 9. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 10. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), moderate inhibitors of CYP1A2 (mexiletine, propafenone, and zileuton), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, Voriconazole, ketoconazole, nefazodone, posaconazole), moderate CYP3A inhibitors (amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit- containing products including grapefruit juice, and verapamil), or clinically significant CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, oxcarbazepine, primidone, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John s wort within 14 days before study drug administration in the study. 11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus positive. 12. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere

18 significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, uncontrolled hyperglycemia or peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause). 13. Psychiatric illness/social situation that would limit compliance with study requirements. 14. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 15. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal condition that could interfere with the oral absorption or tolerance of treatment. 16. Diagnosed or treated for another invasive malignancy within 2 years before enrollment or previously diagnosed with another invasive malignancy with current evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. à Open for enrollment 3. A phase I, dose- finding study of the Bromodomain (Brd) inhibitor OTX015 in hematological malignancies. Protocol OTX- 104 Inclusion 1. Signed informed consent must be obtained for all subjects at enrollment into the study, i.e. prior to beginning protocol specific procedures. Patients registered for this trial must be treated and followed at the participating center.

19 2. Histologically or cytologically proven hematological malignancy or confirmed multiple myeloma according to standard diagnosis criteria [Durie, 2006]. For the dose escalation part, any refractory/relapsing hematological malignancy (having failed all standard therapies) will be accepted. For the expansion cohorts, only patients with selected hematological malignancies will be enrolled: At least 4 diseases are foreseen, but additional medical conditions may be decided by the SMC: acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B- cell lymphoma (DLBCL), multiple myeloma (MM). Acute leukemia (AL) is defined according to the WHO 2008 classification [Vardiman, 2009]. Acute myeloblastic leukemia (AML) and B- cell or T- cell acute lymphoblastic leukemia (ALL), de novo, as well as secondary AL (i.e. transformation of a pre- existing myelodysplastic syndrome, chronic myelogenous leukemia or other myeloproliferative neoplasms) may be enrolled. For lymphoma, an archived formaldehyde- fixed paraffin- embedded block must be available. 3. Patient with resistant/refractory disease, having failed all standard therapies or for whom standard treatments are contra- indicated. Multiple myeloma: Patients adequately exposed to at least one alkylating agent, one corticosteroid, one immunomodulatory drug (IMiD) and bortezomib, or for whom one or more of such treatments are contra- indicated. 4. Patients with evaluable disease: - AL patients must have > 5% bone marrow blasts at study entry, without alternative causality (e.g. marrow regeneration), or reappearance of blasts in peripheral blood, or evaluable extramedullary disease [Döhner, 2010]. In case of low marrow blast count (5-10%), relapse should be confirmed by a second myelogram. - Lymphoma patients must have at least one non- irradiated tumor mass > 15 mm (long axis of lymph node) or > 10

20 mm (short axis of lymph node or extranodal lesions) on spiral CT- scan. - Patients with MM must have at least one of the following: serum monoclonal component > 1g/dL (IgG), or > 0.5g/dL (IgA), or Bence- Jones (BJ) proteinuria > 200mg/24h, or measurable plasmacytoma (not previously irradiated). 5. Patients > 18 years old. 6. Life expectancy of at least 3 months 7. ECOG performance status (PS) of 0 to 2 8. Off previous anti- tumor therapy for at least 3 weeks, or 5 half- lives of previously administered drug, whichever is longer, prior to first study treatment administration, except 1) hydroxyurea given to control hyper leukocytosis that should be stopped 48 hours prior to start study medication and 2) rituximab which should be stopped for at least 3 weeks, regardless of half- life. 9. Recovery from the non- hematological toxic effects of prior treatment to grade < 1, according to NCI- CTC classification, except alopecia. 10. Bone marrow function For patients with AL: no limitation For patients with other hematological malignancies: Absolute neutrophil count (ANC) > 1.0 x 109/L, platelets > 50 x 109/L 11. Calculated creatinine clearance > 30mL/min (Cockcroft & Gault formula, or MDRD formula for patients aged > 65 years). 12. Adequate LFTs: Total bilirubin < the institutional upper normal limits (UNL); ALAT/ASAT 3 x UNL (or 5 x UNL in case of liver involvement). 13. Serum albumin > 28g/L 14. Complete baseline disease assessment workup (including bone marrow examination and tumor imaging for lymphomas;

21 bone marrow aspiration for AL, measurement of serum M- component and/or BJ proteinuria, imaging of bone lesions and bone marrow aspiration or biopsy for MM) prior to first study treatment administration. Exclusion 1. History of prior malignancy other than those previously treated with a curative intent more than 5 years ago and without relapse (any tumor) or basal cell skin cancer, in situ cervical cancer, superficial bladder cancer, or high grade intestinal polyps treated adequately, regardless of the disease- free interval. 2. Pregnant or lactating women or women of childbearing potential not using adequate contraception. Male patients not using adequate contraception. 3. Patients with peripheral cytopenias (i.e. auto- immune hemolytic anemia or thrombocytopenia). 4. Patients with acute promyelocytic leukemia or with clinically uncontrolled (i.e. with bleeding) disseminated intravascular coagulation (DIC). 5. MM patients with POEMS syndrome or plasma cell leukemia 6. Patient with chronic graft versus host disease (GVHD) or on immunosuppressive therapy for the control of GVHD 7. Uncontrolled leptomeningeal disease. 8. Uncontrolled disease- related metabolic disorder (e.g. hypercalcemia) 9. Other tumor location necessitating an urgent therapeutic intervention (palliative care, surgery or radiation therapy), such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.) 10. Patients unable to swallow oral medications, or patients with gastrointestinal condition (e.g. malabsorption, resection) deemed to jeopardize intestinal absorption.

22 11. Other serious illness or medical conditions, which, in the investigator s opinion, could hamper understanding of the study by the patient, patient s compliance to study treatment, patient s safety, or interpretation of study results. These conditions include (but are not restricted to): a) Congestive heart failure or angina pectoris except if medically controlled. Previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or arrhythmias. b) Existence of significant neurologic or psychiatric disorders impairing the ability to obtain consent. c) Uncontrolled infection; d) known HIV positivity. 12. Concurrent treatment with other experimental therapies or participation in another clinical trial within 30 days prior to first study treatment administration, or 5 half- lives of previously administered drugs, whichever is longer. 13. Concurrent treatment with any other anticancer therapy, except hydroxyurea to reduced hyper leukocytosis. 14. Concomitant treatment with corticosteroids except chronic treatment with 20 mg of methylprednisolone daily or equivalent dose of other corticosteroids. 15. Patients taking concomitant strong CYP3A4 interacting drugs 16. Patients with prior irradiation on more than 30% of bone marrow reserves (including Total Body Irradiation), regardless of washout period, and patients having received high dose chemotherapy followed by autologous stem cell transplantation less than 90 days prior to first OTX015 dosing. à Open for enrollment

23 3. A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT- 330 in Patients with Advanced Hematological Malignancies Inclusions: 1. Written informed consent in accordance with federal, local, and institutional guidelines 2. Age 18 years 3. Patients with malignancies that are refractory to or who are intolerant of established therapy known to provide clinical benefit for their condition. Patients must not be candidates for anti- tumor regimens known to provide clinical benefit. 4. Histologically confirmed diagnosis, and evidence of disease progression, of Multiple Myeloma (MM), Chronic Lymphocytic Leukemia (CLL), or Waldenstrom s Macroglobulinemia (WM) as described below: Multiple Myeloma (MM): Symptomatic disease previously treated with 3 prior regimens (lines of therapy) that included at least one of each of the following: an alkylating agent, an immunomodulatory drug, a proteasome inhibitor, and a steroid. Patients must have measurable disease as defined by at least one of the following: a) Serum M- protein 0.5 g/dl by serum electrophoresis (SPEP) or for IgA myeloma, by quantitative IgA; or b) Urinary M- protein excretion at least 200 mg/24 hours; or c) Serum Free Light Chain (SFLC) whereby the involved light chain measures 10 mg/dl and with an abnormal ratio

24 Chronic Lymphocytic Leukemia (CLL): advanced, relapsed CLL after having received fludarabine (if appropriate), an alkylating agent, and rituximab as part of one or more of their previous regimens. Waldenström s Macroglobulinemia (WM): relapsed WM after at least 2 prior regimens (lines of therapy) that included at least one proteasome inhibitor and at least one steroid. 5. All patients on this study must have evidence of progressive disease on study entry. Previously untreated patients who are not candidates for chemotherapy on Arm 2 may have Advanced disease (without clear progression). There is no upper limit on the number of prior treatments provided all inclusion/exclusion criteria are met. 6. Dose Escalation Phase: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 Dose Expansion Phase: Eastern Cooperative Oncology Group (ECOG) Performance Status of Adequate hepatic function within 14 days prior to C1D1: total bilirubin <2 times the upper limit of normal (ULN) (except patients with Gilbert s syndrome who must have a total bilirubin of <3 times ULN), aspartate aminotransferase (AST) <2.5 times ULN and alanine aminotransferase (ALT) <2.5 times ULN. In the case of known (radiological and/or biopsy documented) liver metastasis, AST <5.0 times ULN and ALT <5.0 times ULN is acceptable; 8. Adequate renal function within 14 days prior to C1D1: estimated creatinine clearance of 30 ml/min, calculated using the formula of Cockcroft and Gault (140- Age) Mass (kg)/(72 creatinine mg/dl); multiply by 0.85 if female. 9. Female patients of child- bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an

25 effective barrier method of contraception if sexually active with a female of child- bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post- menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose. 10. Arm 1 only: Patients receiving hematopoietic growth factor support including erythropoietin, darbepoetin, G- CSF, GM- CSF, and platelet stimulators can continue to do so, but must be transfusion independent for at least 3 weeks prior to registration in the dose escalation phase of the study. Elective transfusions are permitted for transfusion independent patients during the 3- week period prior to dosing. There are no restrictions on transfusions for enrollment into and during the dose expansion phase of the study. Screening absolute neutrophil count (ANC) should be independent of growth factor support for at least 1 week prior to registration for all patients. 11. Arm 1 only: Adequate hematopoietic function (excluding patients with acute leukemia) within 14 days prior to C1D1: total white blood cell (WBC) count 1,500/mm3, absolute neutrophil count (ANC) 800/mm3, hemoglobin (Hb) 8.0gm/dL, and platelet count 30,000/mm3. Screening ANC should be independent of growth factor support for >1 week for all patients. Exclusions: Patients meeting any of the following exclusion criteria are not eligible to enroll in this study. 1. Patients who are pregnant or lactating; 2. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy 2 weeks prior to cycle 1 day 1 and mitomycin

26 C and radio- immunotherapy 6 weeks prior to cycle 1 day 1. For CLL and NHL palliative steroids for disease related symptoms are allowed up to 3 days prior to starting therapy. For patients in Arm 2, Hydroxyurea may be given prior to, and during the first cycle of treatment with KPT- 330; 3. Patients with active graft versus host disease after allogeneic stem cell transplantation. At least 3 months must have elapsed since completion of allogeneic stem cell transplantation; 4. Major surgery within four weeks before Day 1; 5. Unstable cardiovascular function: symptomatic ischemia, or uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmics are excluded and 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or congestive heart failure (CHF) of NYHA Class 3, or myocardial infarction (MI) within 3 months; 6. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; 7. Known to be HIV seropositive; 8. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen); 9. Patients with active CNS malignancy. Asymptomatic small lesions are not considered active. Treated lesions may be considered inactive if they are stable for at least 3 months. Patient with malignant cells in their cerebrospinal fluid (CSF) without CNS symptom may be included. 10. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea. 11. Grade 2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1). 12. History of seizures, movement disorders or cerebrovascular accident within the past 5 years prior to cycle 1 day 1.

27 13. Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity 14. In the opinion of the investigator, patients who are significantly below their ideal body weight. 15. Serious psychiatric or medical conditions that could interfere with treatment; 16. Participation in an investigational anti- cancer study within 3 weeks prior to Cycle 1 Day 1; 17. Concurrent therapy with approved or investigational anticancer therapeutic other than steroids or hydroxyurea as specified above. à Open for enrollment 4. A Phase 1/2 Trial of ASP7487 (ASP7487 (OSI- 906) in Combination with Bortezomib for the Treatment of Relapsed or Relapsed/Refractory Multiple Myeloma Inclusion Criteria Subject must meet all of the following inclusion criteria to be eligible for participation in this study. 1. Male or female, 18 years or older. 2. A diagnosis of MM and documentation of relapsed or relapse/refractory status following at least 1 prior therapy and a maximum of 4 prior regimens. 3. Patients with measurable disease defined as at least one of the following (these baseline laboratory studies for determining eligibility must be obtained within 21 days prior to enrollment): a. Serum M- protein 0.5 g/dl ( 5 g/l) b. Urine M- protein 200 mg/24 h

28 c. Serum free light chains (FLC) assay: Involved FLC level 10 mg/dl ( 100 mg/l) and an abnormal serum free light chain ratio (< 0.26 or > 1.65) d. Biopsy proven plasmacytoma (should be measured within 28 days of first study drug administration). Prior biopsy is acceptable. e. If the serum protein electrophoresis is unreliable for routine M- protein measurement, quantitative immunoglobulin levels on nephrolometry or turbidometry will be followed. 4. Patient has an ECOG 2 OR Karnofsky 60% 5. Predose mean QTc 450 msec or QTc Fridericia's Correction (QTcF) on Day 1(cycle 1 or cycle 0 if applicable) must be 450 msecq 6. Females of childbearing potential (FCBP): a female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months). Pregnancy status in women of childbearing potential must be confirmed by serum b- hcg at screening. Pregnancy testing is not required for post- menopausal or surgically sterilized women. FCBP must use acceptable forms of birth control or agree to abstain from heterosexual intercourse while participating in the study and for 90 days following the last dose of study drug. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy while participating in the study and for 90 days following the last dose of study drug. 7. Voluntary, written informed consent before performance of any study- related procedure not part of routine medical care

29 with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). 9. Must be able to take and retain oral medications. 10. Inclusion Clinical Laboratories Criteria The following laboratory results must be met within 7 days of first study drug administration: a. Absolute neutrophil count (ANC) 1,000 cells/dl (1.0 x 109/L) (Growth factors cannot be used within 14 days of first study drug administration); b. Platelet count 50,000 cells/dl (50 x 109/L); c. Hemoglobin 8.0 g/dl (4.96 mmol/l); d. Serum AST or ALT within normal limits; e. Total bilirubin within normal limits; f. Creatinine clearance 30 ml/min (Cockcroft- Gault calculation); g. Serum creatinine 1.5 x ULN (correction with hydration and re- testing is permitted)(values 1.5 X ULN may be acceptable if improved with hydration and/or attributable to progressing MM) h. Serum calcium (ionized or corrected for albumin) 2.0 mmol/l (8.0 mg/dl or 1.0 mmol/l ionized calcium) to ULN. Treatment of hypercalcemia or hypocalcemia is allowed and patient may enroll if serum calcium returns to > 2.0 mmols/l to ULN with standard treatment i. Serum potassium, and magnesium within normal limits (correction with supplementation is permitted) j. HgbA1c of 7%

30 k. Fasting glucose of 126 mg/dl (7.0 mmol/l). A diagnosis of Type II diabetes mellitus is permitted if > 8 weeks since diagnosis and well controlled. Concurrent non- insulinotropic antihyperglycemic therapy is permitted if the dose has been stable for 4 weeks. 11. Resolution of prior toxicities associated with a prior treatment to grade 1. Exclusion Criteria Subject who meet any of the following exclusion criteria are not eligible for enrollment. 1. Patients refractory or intolerant to bortezomib are not permitted (Refractory = non- responsive/progressed on therapy or within 60 days of bortezomib) on the Phase 2 part of the study only 2. Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low- risk prostate cancer after curative therapy 3. Patient has received other investigational drugs or chemotherapy within 21 days or approved anti- myeloma therapy including steroid therapy within 14 days prior to first study drug administration 4. History (within the last 6 months) of significant cardiovascular disease unless the disease is well- controlled. Significant cardiac disease includes but is not limited to second/third degree heart block; clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse. History

31 of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment ( grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded 5. Mean QTcF interval > 450 msec at screening 6. Prior autologous, peripheral stem cell transplant within 12 weeks of the first dose of study drug 7. Daily requirement for corticosteroids (except for inhalation corticosteroids) 8. Patients with evidence of mucosal or internal bleeding and/or platelet transfusion refractory (i.e., unable to maintain a platelet count ³ 50,000 cells/dl) 9. Known active infection requiring parenteral or oral anti- infective treatment 10. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow- up evaluation 11. Use of any medical conditions that, in the Investigator s opinion, would impose excessive risk to the patient. Examples of such conditions include any pre- existing kidney disease (acute or chronic, unless renal insufficiency is felt to be secondary to MM), hypertension, active seizure disorder or pulmonary diseases that would impose excessive risk to the patient 12. Patient has hypersensitivity to any of the components of study drugs 13. Known HIV or active hepatitis B or C viral infection 14. Diabetes mellitus currently requiring insulin or insulinotropic therapy or prior history of steroid induced diabetes as described in protocol Appendix 12-10

32 15. History of cerebrovascular accident (CVA) within 6 months prior to registration or that is not stable 16. Prior therapy with an IGF- 1R inhibitor 17. Use of drugs that have a risk of causing QT interval prolongation and/or have a known risk of causing Torsades de Pointes (TdP) before 14 days or the recommended 5 half- life washout period elapses (as indicated in Appendix 12-6) whichever is longer, prior to Cycle 1 Day 1 dosing. Drugs that have a known risk of causing TdP can be found on pros/drug- lists/bycategory.cfm) 18. Use of strong/moderate CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not exclude 19. Gastro- intestinal abnormalities, including bowel obstruction, inability to take oral medication, requirement for intravenous (IV) alimentation, active peptic ulcer or prior surgical procedures or bowel resection or other poorly controlled gastrointestinal disorders that could affect the absorption of study drug (eg, Crohn s disease or ulcerative colitis) 20. Peripheral neuropathy grade Significant liver disease or metastatic disease to the liver 22. History of amyloid, plasma cell leukemia or CNS involvement 23. Prior radiation therapy or major surgical procedure within 4 weeks of the first dose of study treatment (this does not include limited course of radiation used for management of bone pain) à Open for enrollment 5. An Open Label Continuation Study of the Oral AKT

33 Inhibitor GSK in Subjects with Hematologic or Solid Tumor Malignancy. PROTOCOL No. PKB (Rollover) Inclusion Criteria A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Is currently participating in a GSK study (monotherapy or in combination with an approved anti- cancer agent) sponsored by GSK or by another research organization working on behalf of GSK. 2. Currently benefitting from continued treatment and have an acceptable safety profile with GSK as determined by the investigator following previous treatment with GSK either as monotherapy or as part of a combination treatment regimen. 3. Continued ability to swallow and retain orally administered study treatment(s) and does not have any clinically significant GI abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 4. has adequate organ function: Absolute neutrophil count (ANC) 1.0 x 109/L Hemoglobin 8.0 g/dl Platelets 50 x 109/L PT/INR and PTT 1.5x ULN Total bilirubin 1.5x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) AST and ALT 3xULN. If liver involvement is present and ALT and AST levels are>3xunl and<5xuln, enrollment into PKB can occur as long as there is no concurrent bilirubin or INR elevation Serum creatinine OR Calculated creatinine clearance ULN 30 ml/min Ejection Fraction (LVEF) 50% by TTE or MUGA

34 Exclusion criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. Permanent discontinuation of GSK in the parent study due to toxicity or disease progression. 2. Concomitant use of any type of anti- cancer treatment other than studied in the parent protocol. 3. Local access to commercially available GSK Current use of a prohibitive medication(s) as listed in Section 7.2 of the protocol 5. Current use of anticoagulants is only allowed if PTT/INR values fulfill entry criteria. 6. Any unresolved toxicity > Grade 2, except for alopecia, (National Cancer Institute- Common Toxicity Criteria for Adverse Events [NCI- CTCAE], version 4.0) from parent study treatment at the time of transition to this study. 7. History of HIV infection. 8. Peripheral neuropathy Gr>1 9. History of hepatitis B or C infection (subjects with evidence of cleared hepatitis B are permitted). 10. Evidence of severe or uncontrolled systemic diseases (e.g., unstable, or uncompensated respiratory, hepatic, renal, metabolic or cardiac disease). 11. QTcF interval > 500 msecs at the time of transition to this study. 12. Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3 rd degree atrioventricular (AV) block.

35 13. Evidence of current Class II, III, or IV heart failure as defined by the New York Heart Association [NYHA, 1994] functional classification system at the time of transition to this study. 14. Symptomatic or untreated leptomeningeal, CNS or brain metastases or spinal cord compression at the time of transition to this study. NOTE: Subjects are not permitted to receive enzyme- inducing anti- epileptic drugs (EIAEDs). Continued stability of brain metastases must be confirmed with imaging. à Open for enrollment 6. Multicenter, Open- label, Single- arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment with Pomalidomide, Dexamethasone, and Carfilzomib (PdC) in Subjects with Relapsed and Relapsed/ Refractory Multiple Myeloma Protocol: MMRC- 048 Inclusion Criteria 1. Relapsed and relapsed/refractory multiple myeloma requiring systemic therapy. 2. All subjects must have failed 1+ prior treatment, one of which must include lenalidomide therapy and have been determined to be refractory to it. a. Refractory to lenalidomide will be defined as a history of progression on or within

36 60 days of completion of a regimen of a minimum of 2 cycles containing full or maximally tolerated dose of lenalidomide. b. Patients progressing on lenalidomide maintenance in the first line of therapy will be eligible provided that they have received at least 2 cycles of lenalidomide at best tolerated dose or at least 2 cycles of treatment which included lenalidomide at 25mg per dose, or at equivalent renally- adjusted doses respectively. For patients requiring 3rd or higher line of therapy, lenalidomide- refractory status is not required. c. In addition to lenalidomide refractory, subjects refractory to (1) pomalidomide (2) Carfilzomib, or (3) RVD are permitted limited to separate enrollment during Phase II 3. Measurable disease, as indicated by one or more of the following: a. Serum M- protein 0.5 g/dl b. Urine M- protein 200 mg/24 hours c. If serum protein electrophoresis is felt to be unreliable for routine M- protein measurement, then quantitative immunoglobulin levels are acceptable d. Involved serum free light chains 10 mg/dl provided that free light chain ratio is abnormal 4. Males and females 18 years of age 5. Life expectancy of more than 3 months 6. Eastern Cooperative Oncology Group (ECOG) performance status 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

37 platelet count should be independent of platelet transfusions for at least 2 weeks. 9. Calculated or measured creatinine clearance of 30 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) 10. Written informed consent in accordance with federal, local, and institutional guidelines 11. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25mIU/mL within days and again within 24 hours prior to starting Cycle 1 of pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All subjects must be counseled on Day 1 of each cycle (or at a minimum of every 28 days) and at drug discontinuation about pregnancy precautions and risks of fetal exposure. See Appendix: E, F and G 12. Subjects must agree to adhere to all study requirements, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring. Exclusion criteria 1. Non- secretory or hyposecretory multiple myeloma, 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

38 2. Subjects for whom there is the prospect of stem cell transplantation in the next 6 months in the treatment plan are excluded (including subjects for whom the PdC regimen is being considered as pre- transplant cytoreduction). 3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) 4. Plasma cell leukemia 5. Waldenström s macroglobulinemia or IgM myeloma 6. 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) 7. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half- lives (t1/2) prior to first dose, whichever time is greater 8. Refractory to bortezomib, except if meeting criteria for RVD- refractory group (during Phase II) Concurrent Conditions 9. Pregnant or lactating females 10. History of allergy to mannitol or prior hypersensitivity to thalidomide, lenalidomide or pomalidomide 11. Major surgery within 3 weeks prior to first dose, prior peripheral stem cell transplant within 12 weeks of study enrollment, Subject has received any anti- cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with the exception of hormones for thyroid conditions or estrogen replacement therapy [ERT]), or any investigational therapy) within 21 days of enrollment. 12. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure (Appendix B), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities 13. Uncontrolled hypertension or diabetes

39 14. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose 15. Known or suspected HIV infection, known HIV seropositivity 16. Active hepatitis A, B, or C infection 17. Non- hematologic malignancy within the past 3 years except adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix or breast, prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone 18. Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent 19. Significant neuropathy (Grades 3-4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment 20. 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 21. Subjects in whom the required program of PO and IV fluid hydration is contraindicated, e.g., due to pre- existing pulmonary, cardiac, or renal impairment 22. Subjects with known or suspected amyloidosis of any organ 23. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis. à Open for enrollment

40 7. A Phase 2 Study of Sequential Trametinib and GSK in Relapsed or Refractory Multiple Myeloma Protocol: NCI 9460 / PHL- 091 Inclusion Criteria 1 Patients must have histologically or cytologically confirmed Multiple Myeloma. 2 Patients must have measurable disease as defined as at least one of the following: Serum M- protein 0.5 g/dl ( 5 g/l) Urine M- protein 200 mg/24 h Serum free light chains (FLC) assay: Involved FLC level 10 mg/dl ( 100 mg/l) and an abnormal serum free light chain ratio (< 0.26 or > 1.65) Biopsy proven plasmacytoma (should be measured within 28 days of first study drug administration). Prior biopsy is acceptable. If the serum protein electrophoresis is unreliable for routine M- protein measurement, quantitative immunoglobulin levels on nephrolometry or turbidometry will be followed. 3 A diagnosis of MM and documentation of relapsed or relapse/refractory status following at least 2 prior lines of therapy. 4 ECOG performance status 2 (Karnofsky 60%, see Appendix A). 5 Able to swallow and retain orally- administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 6 Patients must have normal organ and marrow function as defined below: Absolute neutrophil count (ANC) 1.0 x109/l

41 Hemoglobin 8 g/dl Platelets 50x109/L Albumin 2.5 g/dl Total bilirubin 1.5x institutional ULN (isolated bilirubin > 1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5x institutional ULN Serum creatinine 1.5 mg/dl OR calculated creatinine clearance (Cockroft- Gault formula) 30 ml/min OR 24- hour urine creatinine clearance 30 ml/min Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) 1.5x institutional ULN Fasting serum glucose < 126 mg/dl (7 mmol/l) 7 Subjects that have been previously diagnosed with Type 2 diabetes or steroid- induced diabetes must also meet the additional following criteria: Diagnosed with diabetes > 6 months prior to enrolment HbAIC < 8% at screening visit Left ventricular ejection fraction institutional lower limit of normal (LLN) by ECHO or MUGA Exclusion Criteria 1 History of another malignancy. Exception: Patients who have been disease- free for 3 years, or patients with a history of completely resected non- melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible. Consult the CTEP Medical Monitor if unsure whether second malignancies meet the requirements specified above. 2 History of interstitial lung disease or pneumonitis.

42 3 Diabetes mellitus currently requiring insulin. Subjects with a history of steroid- induced hyperglycemia may be enrolled provided that HbAIC at screening visit is < 8%. 4 Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy or other approved anti- myeloma therapy without the potential for delayed toxicity within 14 days prior to randomization. 5 Use of other investigational drugs within 28 days (or five half- lives, whichever is shorter, with a minimum of 14 days from the last dose) preceding the first dose of trametinib and during the study. 6 Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. 7 Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) or GSK Current use of a prohibited medication. The following medications or non- drug therapies are prohibited: Other anti- cancer therapy while on study treatment. (note: megestrol [Megace] if used as an appetite stimulant is allowed). Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy. Prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis. Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during thestudy (including, but not limited to, St. John s wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng).

43 9 History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure >21 mm Hg. 10 History or evidence of cardiovascular risk including any of the following: LVEF<LLN. A QT interval corrected for heart rate using the Bazett s formula QTcB 480 msec (> 500 msec for subjects with bundle branch block) History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for >30 days prior to randomization are eligible). Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block. Subject with intra- cardiac defribillators or pacemakers. History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization. History or evidence of current Class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system Treatment- refractory hypertension defined as a blood pressure of systolic >140 mmhg and/or diastolic >90 mmhg which cannot be controlled by antihypertensive therapy. Known cardiac metastases.

44 11 Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection, which will be allowed). 12 HIV- positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with trametinib and/or GSK In addition, these patients are at increased risk of lethal infections when treated with marrow- suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. à Open for Enrollment