Phase 2 Trial of MLN9708 in Patients With Relapsed Multiple Myeloma Not Refractory to Bortezomib


Rochester, Minn., Jacksonville, Fla., Phoenix/Scottsdale, Ariz.

Trial status:
Open for Enrollment
Why is this study being done?

PRIMARY OBJECTIVES: I. To determine the confirmed overall response rate (>= partial response [PR]) of MLN9708 (proteasome inhibitor MLN9708), used as a single agent in patients with relapsed multiple myeloma, who are proteasome inhibitor naive (including bortezomib) naive OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. SECONDARY OBJECTIVES: I. To determine the overall response rate of MLN9708 in combination with dexamethasone, when dexamethasone is added to MLN9708 for lack of response or for progression. II. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 with dexamethasone added for lack of response or progression. OUTLINE: Patients receive MLN9708 orally (PO) on days 1, 8 and 15. Patients with lack of minor response by the end of the second course or lack of partial response by the end of the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 or 12 months for 2 years.

Who is eligible to participate?

Inclusion Criteria: - Calculated creatinine clearance (using Cockcroft-Gault equation) >=30 mL/min - Total bilirubin <= 1.5 x the upper limit of the normal range (ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3x - Absolute neutrophil count >= 1000/mL - Platelet count >= 75000/mL - Hemoglobin >= 8.0 g/dL - Patients with relapsed multiple myeloma who have already received one or more standard treatment regimens - Measurable disease of multiple myeloma as defined by at least ONE of the following: - Serum monoclonal protein >= 1.0 g/dL - >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis - Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2 - Patients should be proteasome inhibitor naïve (including bortezomib) OR have received less than 6 cycles of therapy with a bortezomib containing regimen and were not refractory to the bortezomib based regimen (less than a PR or progression on or within 60 days of discontinuation) - Provide informed written consent - Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only - Willing to return to Mayo Clinic enrolling institution for follow-up - Recovered (ie, < Grade 1 toxicity) from the reversible effects of prior antineoplastic therapy Exclusion Criteria: - Recent prior chemotherapy: - Alkylators (e.g. melphalan, cyclophosphamide) =< 14 days prior to registration - Anthracyclines =< 14 days prior to registration - High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide) =< 7 days prior to registration - Prior therapy with any proteasome inhibitor other than bortezomib - No concomitant high dose corticosteroids other than what is part of treatment protocol (concurrent use of corticosteroids); EXCEPTION: Patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc - Other active malignancy =< 2 years prior to registration; EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer - Any of the following: - Pregnant women or women of reproductive ability who are unwilling to use 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of study drug - Nursing women - Men who are unwilling to use a condom (even if they have undergone prior vasectomy) while having intercourse with any women, while taking the drug and for 30 days after stopping treatment - Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease - Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment - Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period. - Major surgery within 14 days before study registration - Systemic treatment with strong inhibitors of cytochrome P450 1A2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450 3A4 (CYP3A4) (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John's wort) within 14 days before the first dose of MLN9708 - Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months; Note: Prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant - Known human immunodeficiency virus (HIV) positive - Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection - Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol - Known allergy to any of the study medications, their analogues or excipients in the various formulations - Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing - Diarrhea > Grade 1, based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading, in the absence of antidiarrheals

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