Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone in Treating Patients with Multiple Myeloma That Has Come Back or Does Not Respond to Treatment

Status: Active

Description

This phase II trial studies the side effects and best dose of daratumumab, ixazomib, pomalidomide, and dexamethasone, and how well they work in treating patients with multiple myeloma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as daratumumab, ixazomib, pomalidomide, and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may work better in treating patients with multiple myeloma.

Eligibility Criteria

Inclusion Criteria

  • Ability to understand and the willingness to sign a written informed consent
  • All study participants must be registered into the mandatory POMALYST REMS program and be willing and able to comply with the requirements of the POMALYST REMS program
  • Confirmed diagnosis of multiple myeloma having received >= 1 and =< 3 prior lines of treatment * Relapsed and/or refractory disease: includes primary refractory patients; refractory = progressive disease (PD) on treatment or within 60 days of last dose of therapy
  • Measurable disease as defined by any of the following: * Serum M-protein level >= 0.5 g/dL, and/or * Urine M-protein >= 200mg/24 hours, and/or * Involved serum free light chain >= 10 mg/dL (>= 100mg/L) AND an abnormal free serum free light chain ratio, and/or * Baseline marrow burden of myeloma of at least 30%
  • Life expectancy of more than 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0,1, or 2
  • No prior progression on pomalidomide
  • All patients (pts) must have received prior lenalidomide therapy and been determined to be relapsed and/or refractory to lenalidomide
  • Bilirubin =< 2 times the upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 times ULN
  • Adequate renal function with creatinine clearance >= 30ml/min
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • Hemoglobin (Hgb) >= 8 g/dL (transfusion permitted)
  • Platelet count >= 75 x 10^9/L (>= 50 x 10^9/L if bone marrow plasma cells are >= 50% of cellularity)
  • Screening ANC should be independent of granulocyte-and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks
  • Patients (Pts) may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, in accordance with institutional guidelines
  • Screening platelet count should be independent of platelet transfusions for at least 2 weeks
  • Women of child-bearing potential and men with partners of child-bearing potential must agree to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity from the time of signing the informed consent form through 120 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
  • Women of childbearing potential have negative pregnancy test within 72 hours of initiating study drug dosing
  • Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study therapy through 120 days after the last dose of study therapy. Females of Child bearing potential must agree to ongoing pregnancy testing. The patient must agree to inform his physician if he has had unprotected sexual contact with a female who can become pregnant or if he thinks for any reason that his sexual partner may be pregnant * Male pts cannot donate semen or sperm while taking pomalidomide and for 28 days after completing the study
  • All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
  • Female of reproductive potential must adhere to the scheduled pregnancy testing as required in the POMALYST REMS program
  • Subjects must agree to take enteric-coated aspirin 81 mg orally daily, or if history of prior thrombotic disease, must be fully anticoagulated with warfarin (international normalized ratio [INR] 2-3) or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism (PE) at the investigator's discretion

Exclusion Criteria

  • Current or anticipated use of other investigational agents
  • Prior daratumumab and ixazomib use
  • Patients who are refractory to pomalidomide
  • Non-secretory or hyposecretory multiple myeloma defined as: * < 0.5 g/dL M-protein in serum * < 200 mg/24 hr urine M-protein
  • POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes) syndrome
  • Plasma cell leukemia (> 2.0 x10^9/L circulating plasma cells by standard differential)
  • Waldenstrom's macroglobulinemia or immunoglobulin (Ig)M myeloma
  • Known central nervous system involvement by multiple myeloma
  • Radiotherapy to multiple sites or immunotherapy within 2 weeks before enrollment (localized radiotherapy to a single site at least 1 week before start is permissible)
  • 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. Non-interventional trials (i.e. observational trials) are permitted at any time point
  • Female patients who are lactating or have a positive serum pregnancy test during the screening period
  • Major surgery within 3 weeks prior to first dose
  • Myocardial infarction within 6 months prior to enrollment, NYHA (New York Heart Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
  • Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort
  • Known or suspected human immunodeficiency virus (HIV) infection, known HIV seropositivity
  • Active hepatitis infection
  • Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
  • 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
  • Patient has >= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period
  • Contraindication to any of the required concomitant drugs
  • Subjects with known or suspected light-chain amyloidosis of any organ
  • Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, daratumumab, or its excipients (refer to investigator's brochure [IB]), or known sensitivity to mammalian-derived products
  • Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal (Note that FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded if FEV1 <50% of predicted normal.)
  • Has known moderate or severe persistent asthma within the past 2 years per asthma guidelines, or currently has uncontrolled asthma of any classification
  • Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance of ixazomib or pomalidomide, including difficulty swallowing

Locations & Contacts

California

San Diego
University of California San Diego
Status: Active
Contact: Caitlin Costello
Phone: 858-822-6600
Email: ccostello@ucsd.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR) including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) of daratumumab, ixazomib, pomalidomide, and dexamethasone (D-IPd) therapy based on International Myeloma Working Group (IMWG) criteria.

II. To evaluate the safety and tolerability of ixazomib in combination with daratumumab, pomalidomide and dexamethasone, which will include treatment-emergent Grade 2-5 adverse events (AEs) defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.03 toxicity criteria attributable to study therapy.

SECONDARY OBJECTIVES:

I. To determine the clinical benefit rate (CBR: minimal response + ORR).

II. To determine Progression Free Survival (PFS), Time to Progression (TTP) and Overall Survival (OS).

III. To determine the percent Minimal Residual Disease (MRD) negativity.

IV. To determine response rates and PFS of patients based on their risk cytogenetics/fluorescence in situ hybridization (FISH) (t[4;14]; t[14;16]; del 17p).

V. To assess the effects of D-IPd on quality of life (QOL) using Cancer Therapy Satisfaction Questionnaire and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Myeloma (MY) 20.

OUTLINE:

Patients receive daratumumab intravenously (IV) for 1.5 to 6.5 hours on days 1, 8, 15, and 22 of courses 1 and 2, on days 1 and 15 of courses 3-6, and on day 1 of subsequent courses, ixazomib orally (PO) on days 1, 8, and 15, pomalidomide PO once daily (QD) on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of California San Diego

Principal Investigator
Caitlin Costello

Trial IDs

Primary ID 180638
Secondary IDs NCI-2018-03193
Clinicaltrials.gov ID NCT03590652