IXAZOMIB

 

Ixazomib (NinlaroŽ) is an oral proteasome inhibitor. It is a reversible boronate dipeptide PI.

Approved by the FDA in 2015, with the indication of use with lenalidomide and dexamethasone after at least one prior therapy. Produced by Takeda Pharmaceuticals.

Supplied as capsules of 2.3, 3, and 4 mg.

Dose: 4 mg PO once a week on days 1, 8, 15 every 28 days.

It rapidly hydrolyzes in plasma into its biologically active form, MLN2238.
It preferentially binds to and inhibits the beta5 subunit (chymotrypsin-like activity) of the 20S proteasome.

Most common adverse reactions:
 - Thrombocytopenia
 - Nausea, vomiting
 - Diarrhea, constipation
 - Peripheral edema
 - Peripheral neuropathy
 

 

Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study.
Lancet Oncol. 2014 Dec;15(13):1503-12.
Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG.
In this preliminary study involving 65 patients, very good partial response or better was observed in 58% of cases.

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.
Blood Cancer J. 2015 Aug 14;5:e338.
Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A.
In this trial, 33 patients with relapsed myeloma, treated with a median of 2 prior therapies (range, 1-7), received ixazomib, 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added in 67% of patients. Response rate was 34%, and the median event-free survival was 11.5 months.

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.
N Engl J Med. 2016 Apr 28;374(17):1621-34.
Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group.
This is a double-blind study of 722 patients with relapsed/refractory myeloma, randomized to receive lenalidomide 25 mg on days 1-21) + dexamethasone (40 mg on days 1, 8, 15, 22) + ixazomib (4 mg on days 1, 8, 15) vs lenalidomide + dexamethasone + placebo. After a median follow-up of about 15 months, the results were better in the ixazomib group:
  - Response rate was 78% in the ixazomib group, and 72% in the placebo group
  - CR + VGPR were 48% in the ixazomib group, and 39% in the placebo group
  - Median progression-free survival was 20.6 months in the ixazomib group, and 14.7 months in the placebo group
  - Median overall survival was not reached in either group
  - Adverse events: toxicities of at least grade 3 were observed in 74% of patients in the ixazomib group, and 69% of those in the placebo group; rash 36% vs 23%; peripheral neuropathy 27% vs 22%
Based on the results of this study, the FDA approved the use of ixazomib (in combination with lenalidomide and dexamethasone) for the treatment of patients with multiple myeloma who previously received at least one line of therapy.

Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib.
Blood. 2016 Nov 17;128(20):2415-2422.
Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, Gertz MA, Bergsagel PL, Dispenzieri A, Thompson MA, Crawley J, Kapoor P, Mikhael J, Stewart K, Hayman SR, Hwa YL, Gonsalves W, Witzig TE, Ailawadhi S, Dingli D, Go RS, Lin Y, Rivera CE, Rajkumar SV, Lacy MQ.
In this study, 70 patients with relapsed myeloma were given ixazomib 4 (35 patients) or 5.5 mg (35 patients) on days 1, 8, 15 every 28 days, along with dexamethasone 40 mg once a week. Results:
  - Response rate: 43% (95% CI: 31-55%)
  - Median event-free survival: 8.4 months
  - Event-free survival: 5.7 months in patients with prior bortezomib treatment, and 11 months in patients without prior bortezomib treatment
  - Patients treated with 5.5 mg had a higher response rate, but more toxicity

 

 


 

OTHER PROTEASOME INHIBITORS

 

Their use is in the experimental phase.

 

Delanzomib (CEP-18770)
Oral.
Peptide boronic acid PI.
Reversible inhibitor. It inhibits the chymotrypsin-like activity of the proteasome.
Produced by Cephalon.
A phase II study in patients with relapsed/refractory disease was stopped, due to lack of efficacy.

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.
Leuk Lymphoma. 2017 Aug;58(8):1872-1879.
Vogl DT, Martin TG, Vij R, Hari P, Mikhael JR, Siegel D, Wu KL, Delforge M, Gasparetto C.
Among 61 patients enrolled in this clinical trial, the median time to progression was only 2.5 months. The development of delanzomib was discontinued.

 

Marizomib (NPI-0052)
Oral/IV.
Irreversible, nonpeptide beta-lactone PI.
Marizomib is salinosporamide A, a metabolite extracted from Salinispora tropica. This is an actinomyces present in ocean sediments, and first isolated from a marine sediment sample collected in the Bahamas.
Marizomib can cross the blood-brain barrier.

 

Oprozomib (ONX-0912)
Oral analogue of carfilzomib (a truncated derivative).
Irreversible inhibitor, tripeptide epoxyketone PI.
It inhibits the chymotrypsin-like activity of the proteasome.
Produced by Onyx.

 

 


Giampaolo Talamo, M.D.