Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Pomalidomide and Dexamethasone with or without Ixazomib in Treating Patients with Refractory Multiple Myeloma

Protocol: ALLIANCE-A061202

Full Title

A Phase I/II Study Of Pomalidomide, Dexamethasone And Ixazomib Vs. Pomalidomide And Dexamethasone For Patients With Multiple Myeloma Refractory To Lenalidomide And Proteasome Inhibitor-Based Therapy

Purpose

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 does not respond to treatment. 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.

Study Objective

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 evaluate the overall response rate (ORR), partial response (PR), very good partial response (VGPR), complete response (CR) and stringent CR (sCR) rate for pomalidomide/dexamethasone/ixazomib compared to pomalidomide/dexamethasone. (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)

TERTIARY OBJECTIVES:

I. To determine the extent to which cereblon expression (via quantitative polymerase chain reaction [PCR] and immunohistochemistry [IHC]) is associated with therapeutic response. (Phase II)

II. To examine whether PFS or OS differs with respect to cereblon expression levels. (Phase II)

III. To examine whether therapeutic response, PFS, and OS differs with respect to either the percentage of interferon regulatory factor 4 (IRF-4) or v-myc myelocytomatosis viral oncogene homolog (avian) (c-Myc) positivity in plasma cells or IHC staining intensity in plasma cells at baseline. (Phase II)

IV. To examine whether resistance mutations in the immunomodulatory drug (IMiD) binding domain of cereblon emerge in patients with an initial response to therapy (MR or better) who then progress. (Phase II)

V. To examine the percent agreement between cereblon expression levels at baseline and progression as well as the percentage of patients with expression gain or loss. (Phase II)

VI. To examine whether reduced expression of Ikaros (IKZF1) and/or Aiolos (IKZF3) transcription factors is associated with inferior clinical efficacy (ORR, PFS, OS). (Phase II)

VII. To determine whether resistance mutations in Ikaros and Aiolos develop in patients with an initial response to therapy (MR or better) who then progress. (Phase II)

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

PHASE I: Patients receive pomalidomide orally (PO) once daily (QD) on days 1-21, dexamethasone PO QD on days 1, 8, 15, and 22, and ixazomib PO QD on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pomalidomide PO QD on days 1-21 and dexamethasone PO QD on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression may cross over to Arm II.

ARM II: Patients receive pomalidomide, dexamethasone, and ixazomib as in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 weeks until disease progression and then every 3 months for 3 years.

Are you eligible?

Inclusion Criteria:

Histologically confirmed diagnosis of symptomatic multiple myeloma; relapsed disease is myeloma that has previously responded to prior therapy (MR or better) and subsequently progressed

Measurable disease

Serum myeloma protein (M-protein) >= 1.0 g/dL (>= 0.5 g/dL for immunoglobulin A [IgA] 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 and/or

Baseline marrow burden of myeloma of at least 30%

Please note: for patients participating in the phase II portion of the study who elect to cross-over from treatment Arm 1 to treatment Arm 2 at the time of disease progression, the serum M protein should be 0.5 g/dL or more if that is the parameter being followed to measure response

Previously treated symptomatic multiple myeloma

Lenalidomide AND proteasome inhibitor-refractory multiple myeloma (dual refractory disease):

Please note: lenalidomide and proteasome inhibitor-refractory disease is defined as disease progression on or progression within 60 days of the last dose of a lenalidomide- AND proteasome inhibitor-based treatment; patients should have received at least 2 cycles of a lenalidomide- or proteasome inhibitor-based regimen at standard doses to be evaluable for refractoriness; patients can be refractory to any proteasome inhibitor–they do NOT need to be refractory to all available proteasome inhibitors; in addition, patients can be refractory to lenalidomide and proteasome inhibitors given sequentially as part of different lines of therapy OR therapy that includes a combination of lenalidomide and a proteasome inhibitor; please see the International Myeloma Working Group (IMWG) response criteria for progressive disease (PD)

At least 2 or more prior lines of systemic therapy for multiple myeloma

Please note: 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, is not on immunosuppressive therapy to treat/prevent graft-versus-host disease, has no evidence of active graft versus host disease, no evidence of active infection and meets all other criteria for participation

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

No investigational agent within 21 days prior to registration

Pomalidomide naive and pomalidomide sensitive disease are allowed during phase I and phase II

Please note: Sensitivity to pomalidomide is defined as an MR or better to prior pomalidomide-based therapy that is maintained for >= 60 days from the last dose of therapy

No concurrent investigational therapy

No major surgery within 28 days prior to registration

Patients cannot have received G-CSF (filgrastim) or GM-CSF (sargramostim) within 1 week of screening or pegfilgrastim within 2 weeks of screening to meet eligibility criteria

Patients cannot have received a platelet transfusion within 7 days of screening to meet eligibility criteria; red blood cell transfusions are allowed at any time

Non-pregnant and non-nursing:

A female of childbearing potential is a sexually mature female who:

  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • 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); please note the information below is strictly for eligibility purposes

Therefore, 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 therapy and repeated again within 24 hours of starting pomalidomide and 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; females of childbearing potential must also agree to ongoing pregnancy testing; 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; all participants must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure; participating women cannot be pregnant or nursing

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 >= 50 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)

Patients cannot have:

Central nerve system involvement

Primary refractory multiple myeloma

  • Note: primary refractory multiple myeloma is defined as disease that is nonresponsive-patients who have never achieved an 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

Patients cannot have:

Known active hepatitis C based on:

+Hepatitis C virus (HCV) antibody (confirmed)

+HCV ribonucleic acid (RNA)

Liver disease with history of positive serology

Known hepatitis B surface antigen positivity

Patients cannot have had previous hypersensitivity to any of the components of the study treatment

Patients cannot have had a 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 the last 6 months

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

Patients cannot be on strong inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450 family 1, subfamily A, polypeptide 2 (CYP1A2) or strong inhibitors of CYP3A4 or CYP1A2

Note: Ixazomib is a substrate of CYP3A4 and CYP1A2

Chronic concomitant treatment with strong CYP3A4 inducers is not allowed (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort); please note that drugs that strongly induce or inhibit CYP3A4 are not allowed; because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians’ Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

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

Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50 copies/mm^3

Please 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

Multiple Myeloma