Phase
Condition
Multiple Myeloma
Platelet Disorders
Lymphoproliferative Disorders
Treatment
N/AClinical Study ID
Study Summary
Eligibility Criteria
Inclusion
Inclusion Criteria:
ELIGIBILITY CRITERIA FOR PHASE I AND PHASE II
Patients must have RRMM without t(11;14), confirmed by fluorescence in situhybridization (FISH).
RRMM with measurable disease with at least one of the following: M-protein >= 0.5 g/dLin serum or >= 200 mg/24-hour in urine, or serum free light chain (FLC) >= 10 mg/dLwith abnormal serum FLC ratio for subjects without measurable disease by serum proteinelectrophoresis (SPEP) or urine protein electrophoresis (UPEP) criteria.
Prior multiple myeloma (MM) treatment:
Received at least 2 lines of prior therapy (including at least one PI, excludingMLN9708), or
Received 1 prior line of therapy with both a PI (excluding MLN9708) and animmunomodulatory (IMiD) agent.
PI-refractory (only applicable to phase 2, cohort 2): progressing =< 60 days of thelast PI therapy or < 25% response while on therapy.
PI-non-refractory (only applicable to phase 2, cohort 1): not meeting PI-refractorycriteria, i.e., (a) did not progress =< 60 days of the last PI therapy and (b) had >= 25% response while on therapy.
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%).
Absolute neutrophil count (ANC) >= 1,000/mcL (patients may not use growth factorsupport to achieve ANC criteria for eligibility assessment).
Platelets >= 50,000/mcL (patients may not receive a platelet transfusion within 72hours of eligibility assessment).
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN.
Calculated creatinine clearance >= 30 mL/min (measured by either 24-hour urinecollection or calculated using the Cockcroft-Gault formula).
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viralload must be undetectable on suppressive therapy, if indicated.
Patients with a history of hepatitis C virus (HCV) infection must have completedtreatment previously and cured (i.e., undetectable HCV viral load).
Patients with treated brain metastases are eligible if there is no evidence ofprogression for at least 4 weeks after central nervous system (CNS)- directedtreatment, as ascertained by clinical examination and brain imaging (magneticresonance imaging [MRI] or computed tomography [CT] scan) during the screening period.
Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate central nervous system (CNS) specific treatment is not required and isunlikely to be required for at least 4 weeks (or scheduled assessment after the firstcycle of treatment), and a risk-benefit analysis (discussion) by the patient and theinvestigator favors participation in the clinical trial.
The effects of MLN9708 and venetoclax in combination with dexamethasone on thedeveloping human fetus are unknown. For this reason and because corticosteroids likedexamethasone are known to be teratogenic, women of child-bearing potential and menmust agree to use adequate contraception (hormonal or barrier method of birth control;abstinence) prior to study entry, for the duration of study participation, and 3months after completion of the administration of the study agents. Should a womanbecome pregnant or suspect she is pregnant while she or her partner is participatingin this study, she should inform her treating physician immediately.
Ability to understand and the willingness to sign a written informed consent document.
Known human immunodeficiency virus (HIV)-positive patients who meet the followingcriteria will be considered eligible:
CD4 count > 350 cells/mm^3
Undetectable viral load
Maintained on modern therapeutic regimens (utilizing non-CYP-interactive agents)
No history of acquired immunodeficiency syndrome (AIDS)-defining opportunisticinfections.
Exclusion
Exclusion Criteria:
Patients who have been previously treated with MLN9708 or venetoclax or other directBCL2 inhibitor.
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities grade > 1), except for grade 2 peripheral sensoryneuropathy.
Patients who are receiving any other anti-myeloma chemotherapy or radiotherapy,immunotherapy, or investigational agents within 2 weeks or 5 half-lives (whichever islonger and/or applicable) of the start of the trial.
Patients receiving dexamethasone >= 40 mg/day or equivalent of any corticosteroidswithin 2 weeks of the start of the trial.
Patients with non-secretory MM, plasma cell leukemia (i.e., >= 20% plasma cells inperipheral blood differential or >= 2,000/mcL circulating plasma cells), symptomaticprimary light chain (AL) amyloidosis, POEMS syndrome (polyneuropathy, organomegaly,endocrinopathy, monoclonal protein, and skin changes).
Prior allogeneic hematopoietic cell transplantation (HCT) within the last 12 monthsand evidence of active graft-versus-host disease (GVHD).
Prior autologous HCT within the last 3 months.
History of active malignancies other than MM within the last 2 years unless treatedwith curative intent and has no evidence of active disease. Basal cell carcinoma ofthe skin or localized squamous cell carcinoma of the skin are excluded from thiscriterion.
History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to MLN9708, venetoclax, or dexamethasone. This includes boron andboron-containing products.
Patients requiring chronic administration of any medications or substances that arestrong inhibitors or inducers of CYP3A4 enzyme are ineligible. Because the lists ofthese agents are constantly changing, it is important to regularly consult afrequently-updated medical reference. As part of the enrollment/informed consentprocedures, the patient will be counseled on the risk of interactions with otheragents, and what to do if new medications need to be prescribed or if the patient isconsidering a new over-the-counter medicine or herbal product.
Patients with uncontrolled intercurrent illness.
Female patients who are lactating or have a positive serum pregnancy test during thescreening period are excluded from this study because MLN9708 is a proteasomeinhibitor with the potential for embryo-lethal effects, and an unknown but potentialrisk for adverse events in nursing infants secondary to treatment of the mother withMLN9708. Patients must stop breastfeeding while on MLN9708 and until 90 days havepassed since their last dose. These potential risks may also apply to other agentsused in this study.