An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Form of MLN9708, a Second-Generation Proteasome Inhibitor, in Adult Patients with Relapsed and/or Refractory Multiple Myeloma
The goal of this clinical research study is learn the highest tolerable dose of MLN9708 that can be given to patients with MM. Researchers also want to learn more about how MLN9708 works in the body. The safety of this drug will also be studied.
Disease Group: Myeloma
Treatment Agent: MLN9708
Treatment Location: Both at MD Anderson & outside MD Anderson at one or more Collaborating Sites or Institutions
Estimatated Length of Stay in Houston: none
Sponsor: Millennium Pharmaceuticals, Inc.
Return Visit: Patients will be administered MLN9708 orally on Days 1, 4, 8, and 11 during a 21-day treatment cycle.
Home Care: no home care
Primary Objectives: • To determine the safety profile, tolerability, and maximum tolerated dose (MTD) of MLN9708 administered orally in patients with relapsed and/or refractory multiple myeloma • To inform the recommended phase 2 dose of MLN9708 Secondary Objectives: • To characterize the pharmacokinetics (PK) in plasma of MLN9708 administered orally • To characterize the pharmacodynamic effect on 20S proteasome activity in blood of MLN9708 administered orally • To determine the overall response rate (CR + PR) and CR + PR + MR rate of MLN9708 in patients with relapsed and/or refractory multiple myeloma • To determine overall response rate (CR + PR) and the response rate of CR + PR + MR of MLN9708 in patients with relapsed or refractory multiple myeloma who are either proteasome inhibitor-naïve, have relapsed after VELCADE, or who have recently been treated with carfilzomib. Exploratory Objectives: • To assess the downstream effects of MLN9708, such as modulation of activating transcription factor-3 (ATF-3) expression, in multiple myeloma cells • To assess for candidate biomarkers of responsiveness to treatment with MLN9708 such as p52 and p65, in multiple myeloma cells • To assess potential relationships between MLN9708 treatment and electrocardiogram (ECG) parameters • To assess potential relationships between polymorphic variations in genes encoding CYPs and drug transporters and the PK and clinical effects of MLN9708
IRB Review and Approval Date: 05/24/2010
Recruitment Status: Not Accepting
Projected Accrual: 70
1) Male or female patients 18 years or older
2) Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis
3) Patients with multiple myeloma who have relapsed following at least 2 lines of therapy, that must include VELCADE, thalidomide (or lenalidomide), and corticosteroids. Patients enrolled in the MTD expansion cohort must also be refractory to their most recent therapy as evidenced by PD while on therapy or within 60 days after their last dose of therapy.Patients enrolled in the Carfilzomib expansion cohort must meet requirements for MTD expansion and must have previously received carfilzomib and have relapsed or are refractory to their most recent therapy as evidenced by PD while on therapy or within 60 days after their last dose of therapy.
4) Continuation of Inclusion #3: Patients enrolled in the proteasome inhibitor-naive expansion cohort must have multiple myeloma and be relapsed or refractory after >/= 1 prior therapy which must include thalidomide (or lenalidomide), and corticosteroids, but never have received a proteasome inhibitor. Patients enrolled in the VELCADE-relapsed expansion cohort must have multiple myeloma and be relapsed or refractory after >/= 1 prior therapy, but must have relapsed after previous VELCADE exposure and not have been treated with any other proteasome inhibitor.
5) Patients must have measurable disease defined by at least 1 of the following 2 measurements: Serum M-protein >/= 1 g/dL (>/= 10 g/L) [Note: For dose escalation cohorts only, patients with serum M-protein >/= 0.5 g/dL (>/=5 g/L) is acceptable.] , Urine M-protein >/= 200 mg/24 hours
6) ECOG performance status of 0 to 2
7) Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
8) Continuation of Inclusion # 7: Male patients, even if surgically sterilized (ie, status postvasectomy), who: Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, OR Agree to completely abstain from heterosexual intercourse.
9) Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
10) Suitable venous access for the study-required blood sampling, including PK and pharmacodynamic sampling. Central venous access is not required.
11) Clinical laboratory values as specified below within 3 days before the first dose of study drug: Absolute neutrophil count (ANC) >/= 1,000/mm^3 and platelet count >/= 75,000/mm^3. Total bilirubin must be </= 1.5 × the upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be </= 2.5 × ULN. Creatinine clearance or calculated creatinine clearance >/= 20 mL/minute
12) Recovered (ie, </= Grade 1 toxicity) from the reversible effects of prior antineoplastic therapy.
1) Peripheral neuropathy >/= Grade 2 on clinical examination during
the Screening period.
2) Female patients who are lactating or have a positive serum pregnancy test during the Screening period.
3) Major surgery within 14 days before the first dose of study drug.
4) Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment.
5) Life-threatening illness unrelated to cancer.
6) Diarrhea > Grade 1, based on the NCI CTCAE categorization.
7) Patient must have recovered from the side effects of previous systemic antineoplastic therapy given within 21 days before the first dose of study treatment.
8) Radiotherapy within 14 days before the first dose of study treatment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708.
9) Treatment with any investigational products within 21 days before the first dose of study treatment.
10) Treatment with any investigational proteasome inhibitor, except carfilzomib. Patients previously treated with carfilzomib may be eligible for the Dose Escalation cohorts if the last dose of carfilzomib was >/= 60 days before the first dose of MLN9708, the Relapsed Refractory MTD expansion cohort if they have refractory disease, or the Carfilzomib cohort regardless of the time since the last dose of carfilzomib.
11) Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) within 14 days before the first dose of MLN9708.
12) Ongoing therapy with corticosteroids greater than 10 mg of prednisone or its equivalent per day. Inhaled and topical steroids are permitted
13) Central nervous system (CNS) involvement.
14) Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months.
15) QTc > 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
16) Known human immunodeficiency virus (HIV) positive.
17) Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
18) Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
19) Known allergy to boron or excipients in the formulation.
20) Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing.
Information and next steps
Phase I/Phase II
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