Pomalidomide and Dexamethasone With or Without Ixazomib in Treating Patients With Relapsed Multiple Myeloma
Pomalidomide and Dexamethasone With or Without Ixazomib in Treating Patients With Relapsed Multiple Myeloma
This randomized phase I/II trial studies the side effects and best dose of pomalidomide and
 ixazomib when given together with dexamethasone and to see how well pomalidomide and
 dexamethasone with or without ixazomib works in treating patients with multiple myeloma that
 has come back. Biological therapies, such as pomalidomide and dexamethasone, may stimulate
 the immune system in different ways and stop cancer cells from growing. Ixazomib may stop the
 growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet
 known whether pomalidomide and dexamethasone are more effective with or without ixazomib in
 treating multiple myeloma.
PRIMARY OBJECTIVES:

 I. To establish the maximum tolerated dose (MTD) for combination therapy
 pomalidomide/dexamethasone/ixazomib. (Phase I) II. To assess whether the combination of
 pomalidomide/dexamethasone/ixazomib improves progression-free survival (PFS) relative to
 pomalidomide/dexamethasone. (Phase II)

 SECONDARY OBJECTIVES:

 I. To determine dose-limiting toxicities (DLTs). (Phase I) II. To analyze type and grade of
 all serious adverse events (SAEs). (Phase I) III. To analyze type and grade of all adverse
 events (AEs). (Phase I) IV. To analyze the reason for and incidence of dose
 modifications/omissions/delays. (Phase I) V. To assess preliminary evidence of clinical
 efficacy. (Phase I) VI. To assess whether the overall response rate (ORR), partial response
 (PR), very good partial response (VGPR), complete response (CR) or stringent CR (sCR) rate
 differ with respect to treatment regimen. (Phase II) VII. To assess the clinical benefit rate
 (CBR: minimal response [MR] + ORR) for pomalidomide/dexamethasone/ixazomib compared to
 pomalidomide/dexamethasone. (Phase II) VIII. To assess the disease control rate (DCR: stable
 disease [SD] + CBR) for pomalidomide/dexamethasone/ixazomib compared to
 pomalidomide/dexamethasone. (Phase II) IX. For those patients achieving a PR or better, we
 will assess whether the combination of pomalidomide/dexamethasone/ixazomib increases the
 duration of response (DOR) compared to pomalidomide/dexamethasone. (Phase II) X. To assess
 whether the combination of pomalidomide/dexamethasone/ixazomib improves overall survival (OS)
 compared to those taking pomalidomide/dexamethasone alone. (Phase II) XI. To assess time to
 next treatment (TNT) for patients taking pomalidomide/dexamethasone/ixazomib compared to
 those on pomalidomide/dexamethasone. (Phase II) XII. To evaluate the safety of
 pomalidomide/dexamethasone/ixazomib compared with pomalidomide/dexamethasone. (Phase II)
 XIII. For patients on the pomalidomide/dexamethasone arm who opt to cross-over to the
 pomalidomide/dexamethasone/ixazomib arm, assessment of response rate (ORR, CBR, DCR), DOR,
 TNT, PFS and OS will be evaluated from date of cross-over. (Phase II) XIV. To determine if
 baseline level of perceived fatigue and overall quality of life (QOL) is associated with OS.
 (Phase II)

 OUTLINE: This is a phase I, dose-escalation study of pomalidomide and ixazomib followed by a
 phase II study.

 After completion of study treatment, patients are followed up every 4 weeks until disease
 progression and then every 3 months for 3 years.
-  Histologically confirmed diagnosis of symptomatic multiple myeloma; relapsed disease
 is myeloma that has previously responded to prior therapy (MR or better) and
 subsequently progressed

 -  Patient must have measurable disease or non-measurable disease, defined as one or more
 of the following holding true:

 -  Measurable disease:

 -  Serum M-protein >= 1.0 g/dL (>= 0.5 g/dL for IgA or IgM myeloma) and/or

 -  Urine M-protein >= 200 mg/24 hours and/or

 -  Involved serum free light chain level >= 10 mg/dL AND an abnormal serum free
 light chain ratio

 -  For non-measurable disease:

 -  Baseline marrow burden of myeloma of at least 30%

 -  Progression on lenalidomide as part of first line therapy (lenalidomide-refractory
 disease)

 * Lenalidomide-refractory disease is defined as disease progression on or progression
 within 60 days of the last dose of a lenalidomide-based treatment; patients should
 have received at least 2 cycles of a lenalidomide-based regimen to be evaluable for
 refractoriness; examples: 1) progression on lenalidomide maintenance therapy after
 initial induction +/- consolidation; 2) initial response followed by progression on
 continuous lenalidomide-dexamethasone +/- elotuzumab or daratumumab

 -  Pomalidomide naive disease

 -  Proteasome inhibitor naive or sensitive disease; proteasome inhibitor sensitive
 disease is defined as a PR or better to prior proteasome inhibitor-based therapy that
 is maintained for >= 60 days from the last dose of the proteasome inhibitor

 * A patient who receives induction therapy with lenalidomide, bortezomib and
 dexamethasone and achieves a PR or better but subsequently progresses on continued
 lenalidomide or lenalidomide-dexamethasone would be eligible provided the progression
 occurs 60 days or more after discontinuation of the bortezomib; similarly, ixazomib
 exposure is allowed provided they meet the definition of proteasome inhibitor
 sensitive disease

 -  1 prior line of systemic therapy for multiple myeloma, where a line of therapy for
 myeloma is defined as 1 or more planned cycles of single agent or combination therapy,
 as well as a planned series of treatment regimens administered in a sequential manner
 (e.g. lenalidomide, bortezomib and dexamethasone induction therapy for 4 cycles
 followed by autologous stem cell transplantation and then lenalidomide maintenance
 therapy would be considered 1 line of prior therapy); a new line of therapy begins
 when a planned therapy is modified to include other treatment agents (alone or in
 combination) as a result of disease progression, disease relapse or treatment-related
 toxicity (e.g. a patient is progressing in the face of lenalidomide maintenance
 therapy and has bortezomib and dexamethasone added into their regimen); a new line of
 therapy also begins when a planned treatment-free interval is interrupted by the need
 to start treatment due to disease relapse/progression (e.g. a patient with relapsed
 myeloma achieves a partial response after a planned 8 cycles of cyclophosphamide,
 bortezomib and dexamethasone, enjoys an 8-month period off therapy but then
 experiences disease progression requiring re-initiation of therapy)

 -  Allogeneic stem cell transplantation is allowed provided the patient is >= 1 year from
 transplant at time of registration, is not on immunosuppressive therapy to
 treat/prevent graft-versus-host disease, has no evidence of active graft versus host
 disease, and no evidence of active infection

 -  No other chemotherapy or radiation therapy within 14 days prior to registration

 -  No investigational therapy within 14 days prior to registration

 -  No major surgery within 28 days prior to registration

 -  No G-CSF (filgrastim) or GM-CSF (sargramostim) within 7 days of registration or
 pegfilgrastim within 14 days of registration to meet eligibility criteria

 -  No platelet transfusions within 7 days of registration to meet eligibility criteria;
 Note: red blood cell transfusions are allowed at any time

 -  A female of childbearing potential is a sexually mature female who: 1) has not
 undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
 postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in
 the preceding 24 consecutive months)

 -  Women of childbearing potential:

 -  Must have a negative serum or urine pregnancy test with a sensitivity of at
 least 25 mlU/ml no more than 14 days prior to registration and must agree to
 repeat this test within 24 hours of starting pomalidomide

 -  Must either commit to complete abstinence from heterosexual contact or begin
 TWO acceptable methods of birth control, one highly effective method and one
 additional effective (barrier) method, AT THE SAME TIME, before starting
 pomalidomide

 -  Must agree to ongoing pregnancy testing

 -  Must agree to not become pregnant or breast feed a child during treatment on
 this protocol

 -  Men must practice complete abstinence or agree to use a condom during sexual
 contact with a female of childbearing potential, even if they have had a
 successful vasectomy

 -  Note: All participants must be counseled at a minimum of every 28 days about
 pregnancy precautions and risks of fetal exposure

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

 -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

 -  Platelet count >= 50 x 10^9/L

 -  Calculated (Calc.) creatinine clearance >= 30 mL/min; calculated utilizing the
 Cockcroft-Gault formula or 24-hour urine collection

 -  Total bilirubin < 1.5 x upper limits of normal (ULN)

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper
 limits of normal (ULN)

 -  Note: G-CSF and platelet transfusions cannot be used to increase counts to meet
 eligibility criteria

 -  Patients cannot have:

 -  Central nerve system involvement

 -  Primary refractory multiple myeloma, where primary refractory multiple myeloma is
 defined as disease that is nonresponsive - patients who have never achieved a
 minimal response (MR) or better - with any therapy over the course of their
 disease; it includes patients who never achieve MR or better in whom there is no
 significant change in M-protein and no evidence of clinical progression as well
 as patients who meet criteria for true progressive disease (PD)

 -  Primary or secondary plasma cell leukemia

 -  Light-chain (AL) amyloidosis or polyneuropathy, organomegaly, endocrinopathy,
 monoclonal gammopathy, and skin changes (POEMS) syndrome

 -  Known active hepatitis C based on:

 -  +hepatitis C virus (HCV) antibody (confirmed)

 -  +HCV RNA

 -  Liver disease with history of positive serology

 -  Note: patients with a prior history of hepatitis C that has been
 successfully eradicated with antiviral therapy are eligible

 -  Known hepatitis B surface antigen positivity

 -  Previous hypersensitivity to any of the components of the study treatment

 -  Prior history of erythema multiforme with thalidomide or lenalidomide treatment

 -  =< grade 2 peripheral neuropathy

 -  Adequate cardiac function, defined as:

 -  No electrocardiogram (EKG) evidence of acute ischemia

 -  No EKG evidence of active, clinically significant conduction system abnormalities

 -  No EKG evidence of > grade 2 (> 480 ms) corrected QT (QTc) prolongation

 -  Prior to study entry, any EKG abnormality at screening not felt to put the
 patient at risk has to be documented by the investigator as not medically
 significant

 -  No uncontrolled angina or severe ventricular arrhythmias

 -  No clinically significant pericardial disease

 -  No history of myocardial infarction within 6 months prior to registration

 -  No class 3 or higher New York Heart Association congestive heart failure

 -  No strong inducers of cytochrome P450 (CYP) 3A4 or CYP1A2 or strong inhibitors of
 CYP3A4 or CYP1A2 within 14 days prior to registration

 -  Note: Ixazomib is a substrate of CYP3A4 and CYP1A2

 -  Patients with human immunodeficiency virus (HIV) infection are eligible, provided they
 meet the following:

 -  No history of acquired immunodeficiency syndrome (AIDS)-defining conditions or
 other HIV related illness

 -  Cluster of differentiation (CD)4+ cells nadirs > 350/mm^3 within 28 days prior to
 registration

 -  Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50
 copies/mm^3 within 28 days prior to registration

 -  Note: HIV+ patients who enroll on this study and are assigned to treatment with
 ixazomib may need to modify their anti-retroviral therapy prior to receiving
 protocol therapy if they are on strong inducers or potent inhibitors of
 cytochrome P450 3A4

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Patients randomized to Arm 1 may opt to
 switch to the 3-drug regimen following disease progression; these patients must be
 re-registered to the study and meet the eligibility criteria below

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Patient must have measurable disease or
 non-measurable disease after progression on pomalidomide + dexamethasone, defined as
 one or more of the following holding true:

 * Measurable disease:

 -  Serum M-protein >= 0.5 g/dL and/or

 -  Urine M-protein >= 200 mg/24 hours and/or

 -  Involved serum free light chain level >= 10 mg/dL AND an abnormal serum free
 light chain ratio

 * For non-measurable disease:

 -  Marrow burden of myeloma of at least 30%

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2):

 -  Women of childbearing potential:

 ** Must have a negative serum or urine pregnancy test within 72 hours prior to
 re-registration

 ** Must either commit to complete abstinence from heterosexual contact or begin
 TWO acceptable methods of birth control, one highly effective method and one
 additional effective (barrier) method, AT THE SAME TIME, before starting
 pomalidomide

 ** Must agree to ongoing pregnancy testing

 ** Must agree to not become pregnant or breast feed a child during treatment on
 this protocol

 -  Men must practice complete abstinence or agree to use a condom during sexual
 contact with a female of childbearing potential, even if they have had a
 successful vasectomy

 -  Note: All participants must be counseled at a minimum of every 28 days about
 pregnancy precautions and risks of fetal exposure

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): ECOG performance status 0-2

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Absolute neutrophil count (ANC) >= 1.0
 x 10^9/L

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Platelet count >= 50 x 10^9/L

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Calc. creatinine clearance >= 30 mL/min

 * Calculated utilizing the Cockcroft-Gault formula or 24-hour urine collection

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Total bilirubin < 1.5 x upper limits of
 normal (ULN)

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): AST and ALT < 2.5 x upper limits of
 normal (ULN)

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Note: G-CSF and platelet transfusions
 cannot be used to increase counts to meet eligibility criteria

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): =< grade 2 peripheral neuropathy

 -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): No strong inducers of cytochrome P450
 (CYP) 3A4 or CYP1A2 or strong inhibitors of CYP3A4 or CYP1A2 * Note: Ixazomib is a
 substrate of CYP3A4 and CYP1A2