Hoke, Eva

Abstract BACKGROUND: Pomalidomide-dexamethasone (Pom-Dex) represents an important therapeutic advance for the treatment of patients with relapsed/refractory multiple myeloma (MM). Nonetheless, patients with lenalidomide (Len) and bortezomib (double) refractory disease have a median progression-free survival of only 3.7 months with the combination, thus highlighting the need for further progress. Ixazomib, a novel, oral proteasome inhibitor, has pharmacodynamic properties that may allow for improved proteasome inhibition at the tumoral level and has synergistic activity in combination with IMiDs in preclinical MM models. Clinical studies have demonstrated activity as a single agent in relapsed/refractory MM and in combination with Len-Dex in newly diagnosed patients. We therefore evaluated the safety and preliminary efficacy of the combination of Pom, ixazomib and Dex in patients with Len and proteasome inhibitor (PI) refractory MM in the phase I portion of Alliance study A061202. METHODS: Key eligibility criteria included: relapsed or relapsed/refractory disease; ≥2 prior lines of therapy; double refractory disease (progression on or ≤60 days from the last dose of a Len- and PI-based therapy); ECOG performance status (PS) ≤2; absolute neutrophil count ≥1.0 x 109/L, platelets ≥50 x 109/L, creatinine clearance ≥50 mL/min; and ≤grade 2 peripheral neuropathy. Patients were treated with escalating doses of Pom and ixazomib utilizing a standard 3 + 3 dose escalation design in combination with standard dose Dex (Table 1). Patients received 2 - 4 mg of Pom on days 1 - 21; ixazomib 3 - 4 mg on days 1, 8 and 15; and Dex 40 mg (20 mg for those >75 years of age) on days 1, 8, 15 and 22 of a 28-day cycle. Patients were treated until disease progression or the development of unacceptable toxicity. RESULTS: Out of 17 evaluable patients, the median age was 64 (range 47 - 77) and the median time from diagnosis 5.5 years (range 3.3 - 8.3). Sixty-five percent, 24% and 12% had ISS stage 1, 2 and 3 disease at the start of treatment, respectively, and 65% had high-risk cytogenetics (gain of 1q, del[17p] and/or high-risk IgH translocation). All patients had an ECOG PS of 0 or 1 (59% and 41%, respectively). Of 14 patients with complete prior treatment data available, 100% had received prior Len, bortezomib and Dex, 71% alkylating agents (cyclophosphamide or low dose melphalan), 71% autologous stem cell transplant and 29% carfilzomib. Eighty-two percent were refractory to sequential Len- and bortezomib regimens, whereas 6% were refractory to a prior Len/proteasome inhibitor combination (12% not reported). Two dose limiting toxicities have occurred to date, 1 each at dose levels 3 and 4 (Table 1). Grade 3 and 4 neutropenia, thrombocytopenia and lymphopenia attributable to protocol therapy have been seen in 29%/6%, 12%/6% and 29%/0% of patients, respectively. Twelve percent of patients have experienced grade 3 infection, regardless of attribution, but none have experienced ≥grade 4 infection. The incidence of therapy-related peripheral neuropathy was 24%, none of which was ≥grade 3 in severity. Other common, therapy-related adverse events have included fatigue (53%), nausea (24%), constipation (18%), diarrhea (29%), rash (18%), tremor (24%), anxiety (18%), insomnia (29%) and edema (24%), all of which were ≤grade 2 in severity. Fifty-three percent of patients had at least 1 of the 3 medications dose reduced, and 35% experienced dose delays. To date, 1 patient has discontinued therapy due to adverse events and 1 due to refusal of further therapy. Of 13 patients receiving >1 cycle of therapy, the best overall response rate was 62% (7 partial responses, 1 very good partial response). CONCLUSIONS: The Pom, ixazomib and Dex combination has demonstrated an acceptable toxicity profile thus far with encouraging preliminary efficacy. Updated results of the phase I portion of the study will be presented at the meeting, including the maximum tolerated dose that will be used in the randomized, phase II portion of the study, in which the 3-drug combination will be compared with Pom-Dex in double refractory MM patients. ClinicalTrials.gov Identifier: NCT02004275. Supported by U10CA180821, U10CA180882. Table 1. Dose Level Pomalidomide Dose (mg) Ixazomib Dose (mg) DLT Evaluable DLTs 1 2 3 3 None 2 3 3 3 None 3 4 3 6 1 febrile neutropenia 4‡ 4 4 4 1 grade 4 thrombocytopenia lasting 8 days ‡enrollment into dose level 4 is complete. Disclosures Voorhees: Janssen, Celgene, GlaxoSmithKline, Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: We will discuss the use of Ixazomib, an agent that is not FDA approved, in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

Key PointsBrief lenalidomide consolidation after chemoimmunotherapy is acceptably tolerated and extends PFS and OS in CLL. FCR has superior efficacy compared with FR chemoimmunotherapy for CLL.

BACKGROUND Recombinant interleukin‐2 (rIL‐2) induces cellular cytotoxicity against leukemia blasts. Patients with acute myeloid leukemia (AML) in first complete remission (CR) may harbor minimal residual disease that is susceptible to rIL‐2–activated effector cells. METHODS In the Cancer and Leukemia Group B (CALGB) 19808 study, patients with AML in first CR were randomly assigned after all planned chemotherapy to receive a 90‐day course of subcutaneously administered rIL‐2 or no further therapy. The primary objective was to compare disease‐free survival (DFS) between the 2 treatment arms. A total of 534 patients achieved a CR, 214 of whom were randomized. Six courses of low‐dose daily rIL‐2 were given for the expansion of cytotoxic effector cells, each followed by 3‐day high‐dose boluses given to trigger cytotoxicity against minimal residual disease. RESULTS On the protocol‐specified intention‐to‐treat analysis, the hazards ratio for DFS was 0.75 (95% confidence interval, 0.52‐1.09; P = .13); the 5‐year DFS rate was 42% in the observation arm and 53% in the rIL‐2 treatment arm. The hazards ratio for overall survival (OS) was 0.88 (95% confidence interval, 0.54‐1.23; P = .34); the 5‐year OS rate was 58% for the observation arm and 63% for the rIL‐2 treatment arm. Twenty‐five of the 107 patients randomized to treatment with rIL‐2 either refused or were unable to initiate therapy and 30 patients did not complete their assigned therapy. However, significant toxicities were not commonly observed. The trial design did not anticipate the difficulties patients would encounter with protocol compliance. CONCLUSIONS The efficacy of immunotherapy with rIL‐2 administered after intensive postremission treatment was not assessed as planned because of unexpected refusals by patients and/or their physicians to comply with protocol‐directed therapy. Neither DFS nor OS was found to be significantly improved. Cancer 2014;120:1010–1017 . © 2013 American Cancer Society .