ixazomib and Nausea

Topics: Antineoplastic Agents; Boron Compounds; Constipation; Diarrhea; Glycine; Humans; Multiple Myeloma; Nausea; Proteasome Inhibitors; Vomiting

The oral proteasome inhibitor ixazomib is approved in multiple countries in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Two oral capsule formulations of ixazomib have been used during clinical development. This randomized, 2-period, 2-sequence crossover study (Clinicaltrials.gov identifier NCT01454076) assessed the relative bioavailability of capsule B in reference to capsule A in adult patients with advanced solid tumors or lymphoma. The study was conducted in 2 parts. In cycle 1 (pharmacokinetic cycle), patients received a 4-mg dose of ixazomib as capsule A or capsule B on day 1, followed by a 4-mg dose of the alternate capsule formulation on day 15. Pharmacokinetic samples were collected over 216 hours postdose. After the pharmacokinetic cycle, patients could continue in the study and receive ixazomib (capsule B only) on days 1, 8, and 15 of each 28-day cycle. Twenty patients were enrolled; of these, 14 were included in the pharmacokinetic-evaluable population. Systemic exposures of ixazomib were similar after administration of capsule A or capsule B. The geometric least-squares mean ratios (capsule B versus capsule A) were 1.16 for C

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Biological Availability; Boron Compounds; Capsules; Chemistry, Pharmaceutical; Cross-Over Studies; Fatigue; Female; Glycine; Humans; Lymphoma; Male; Middle Aged; Nausea; Proteasome Inhibitors

The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double-blind, placebo-controlled Phase III TOURMALINE-MM1 study of ixazomib-Rd (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression-free survival versus placebo-Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo-Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long-term IRd treatment. Safety data from TOURMALINE-MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Dexamethasone; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Eruptions; Follow-Up Studies; Glycine; Hematologic Diseases; Humans; Lenalidomide; Leukocyte Count; Male; Middle Aged; Multiple Myeloma; Nausea; Peripheral Nervous System Diseases; Platelet Count; Thalidomide; Vomiting

Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Boron Compounds; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Drugs, Investigational; Fatigue; Female; Glycine; Humans; Male; Middle Aged; Multiple Myeloma; Nausea; Neoplasm Recurrence, Local; Proteasome Inhibitors; Remission Induction; Thrombocytopenia; Treatment Outcome; Vomiting

Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade ≥3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.

Topics: Administration, Oral; Aged; Aged, 80 and over; Area Under Curve; Boron Compounds; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Exanthema; Fatigue; Female; Glycine; Humans; Male; Middle Aged; Multiple Myeloma; Nausea; Neoplasm Recurrence, Local; Proteasome Inhibitors; Thrombocytopenia; Treatment Outcome