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?
I. To determine the confirmed overall response rate (>= partial response [PR]) of MLN9708 (ixazomib), used as a single agent in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (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.
II. To determine the confirmed overall response rate (>=PR) of MLN9708 at a 4 mg dose level in combination with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naïve 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.
III. To determine the confirmed overall response rate (>=PR) of MLN9708 at a 5.5 mg dose level in combination with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naïve 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.
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.
III. To determine the overall response rate of MLN9708 at two different doses, in combination with dexamethasone.
IV. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 at two different doses, in combination with dexamethasone.
Patients receive ixazomib 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 or if there is disease progression also receive dexamethasone PO on days 1, 8 and 15. 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?
- Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min
- Absolute neutrophil count >= 1000/mL
- Untransfused platelet count >= 75000/mL
- Hemoglobin >= 8.0 g/dL
- Total bilirubin =< 1.5 x the upper limit of the normal range (ULN)
- Aspartate aminotransferase (AST) =< 3 x ULN
- 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 institution for follow-up during the Active Monitoring Phase of the study; Note: during the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
- Recovered (ie, < grade 1 toxicity) from the reversible effects of prior antineoplastic therapy
- 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
- 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
- Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
- 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 90 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, family 1, subfamily A, polypeptide 2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (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