ALBERT

Description: Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Description: To evaluate the potential antitumor activity of zoledronate-activated gd T cells in vivo, we initiated a pilot study involving administration of zoledronate-activated gd T LAK cells to patients with multiple myeloma. Subjects (n=4) received four intravenous infusions, at two week intervals, of zoledronate-activated gd T LAK cells generated from culture of peripheral blood mononuclear cells in the presence of zoledronate and IL-2. The patient receiving the highest numbers of gd T LAK cells (patient 02) received a median of 3.86 × 108 zoledronate-activated gd T LAK cells. The other patients received a median of 4.0 × 107 zoledronate-activated gdT LAK cells. Immunological monitoring included immunophenotyping of PB by flow cytometry to determine relative numbers and with the use of full blood cell counts, absolute numbers of Vg9gd T cells, Vg9gd T cell subsets and T cell subsets (CD3+CD4+, CD3+CD8+ or CD3+CD56+). Bone marrow gd T cell numbers, including subsets, were assessed before and 4 weeks after the final treatment. In all patients the absolute and relative numbers of PB T cells and T cell subsets changed minimally during and up to 4 weeks after the treatment period. The percentage of Vg9gd T cells in PBMCs and absolute numbers of Vg9gd T cells in PB increased in one out of 4 patients, patient 02 in whom the largest number of gd T cells were administered. Of potential interest, this was associated with a 30% decrease in M protein levels (IgA) and decreased serum β2-MG following therapy. The other three patients, administered lower numbers of gd T cells, had no change in PB levels of gd T cells and no change in M protein levels, although serumβ2-MG levels fell in 2 out of the 3 cases. To further evaluate the potential for large number of gd T cells to induce immunological changes in the recipients, we focused on the immunological outcomes in the recipient of the highest gd T cell dose (patient 02). The percentage of TEM gd T cells in total Vg9gd T cells and absolute numbers of TEM gd T cells in PB increased during the treatment and remained high in comparison to baseline levels for 4 week after treatment. In parallel, numbers of T naive gd T cells decreased during the treatment and remained below base line levels at 4 weeks after treatment. Interestingly, the increased percentage of TEM gd T cells on day 1 after the final treatment (82.8%) persisted for a further 4 weeks (82.5%), but returned almost to base line levels by 10 weeks after the final treatment (11.3%). In vitro re-stimulation of PBMC with zoledoronate in this case produced higher production of IFNg by the PBMCs than the other 3 cases evaluated. The percentages of Vg9gd T cells and TEM gd T cells in bone marrow increased in 2 out of 4 patients 4 weeks after the final treatment. In parallel, the percentages of T naive gd T cells decreased. Minor systemic side effects, including fever, malaise and lethargy were noted but there were no serious treatment related adverse events. In summary, administration of gd T LAK cells is well tolerated and may modulate PB and BM Vg9gd T cells when sufficient cells are administered. The increased percentage of TEM Vg9gd T cells in PB and BM may induce antitumor activity in patients with multiple myeloma.

Description: Abstract 1684 Imatinib masylate (IM) induces sustained molecular remissions in patients with chronic myeloid leukemia (CML) but a life-long therapy is required for most of these patients. In STIM study, Mahon et al. reported that among patients with a complete molecular response (CMR) lasting at least two years, the CMR was sustained in 41% after discontinuation of IM. German study group showed that treatment with Interferon-alpha (IFN) enables IM discontinuation in most patients after prior IM/IFN combination therapy. We previously reported that CD8+ memory T cells showed significant predominance over naive T cells in the patients with sustained therapy-free major molecular response (MMR), all of that had previously received IFN [1]. We have been performing a phase 2 study of treatment discontinuation after the drug change from IM to IFN (Japanese Imatinib Stop And Interferon Study; JISAS). Since the aim of this study is to confirm the finding that IFN is able to maintain MMR induced by IM after its discontinuation, we present here the result of the interim analysis. Patients Patients with a confirmed diagnosis of CML in 1st chronic phase (CP1) as well as in CMR (undetectable BCR-ABL transcript) following over 2 years of MMR on IM were enrolled in this pilot study after obtaining the written informed consent. All the eligible patients were recruited from September 2009 to December 2011 whether or not any therapeutic drug had been given before IM. Evaluation and response criteria Since a conversion factor for International scale was not available in Japan until recently, for entry to the study, BCR-ABL transcripts at a level equal to or below 100 copy/mg RNA in a real-time quantitative-polymerase chain reaction (RQ-PCR) assay or equal to or below 50 copy/assay in a highly sensitive transcription-mediated amplification (TMA) method were defined as MMR. CMR was defined as detection of no BCR-ABL transcript in RQ-PCR assay, nested reverse transcriptase-polymerase chain reaction (RT-PCR) assay, or TMA. During the study, molecular response was assessed at the baseline and every month thereafter, by determining the BCR-ABL to ABL mRNA transcript ratio isolated from the peripheral blood using RQ-PCR and RT-PCR. The BCR-ABL to ABL transcript ratio at a level below 0.001 was defined as MMR and no detectable BCR-ABL transcript in RT-PCR was defined as CMR. Molecular relapse defined as a loss of MMR was taken into account if confirmed in 2 successive assessments. Study design and treatment Administration of IFN is started at a dose of 3 million units 2–5 times per week within 4 weeks after IM discontinuation. In case of molecular relapse, IM was resumed at 400 mg daily. Statistical analysis Non-parametric values or numbers were compared between the two groups using the Mann-Whitney test. Relapse-free survival was estimated using the Kaplan-Meier method. Results Fifteen patients were enrolled from September 2009 to December 2011. Median age was 50 years (range, 28–67 years) and male to female ratio was 1.5. Sokal score at the diagnosis was low in 13 patients and high in 2 patients. Four patients had been treated before IM. Previous therapies comprised IFN in all these patients, including 1 patient who relapsed after allogeneic stem cell transplantation (SCT). The clinical stage of this patient was amended to be accelerated phase at the time of diagnosis. Two other patients withdrew the consent. Excluding these 3 patients, the remaining 12 patients with low risk of Sokal score were analyzed. The median follow-up period is 23 months (range: 6–27 months). Three patients lost MMR (1, 3, and 6 months, respectively) and other 9 maintained CMR. Molecular relapse-free survival is 74%. The sustained CMR patients had the significantly longer CMR period on IM (median 31 months, range 26–79 months) compared with relapsed patients (0, 9, and 14 months, respectively; p=0.0142). There was no difference between the relapsed and the sustained CMR patients in the duration of IM treatment. All the relapsed patients achieved MMR after 2, 4, and 5 months of IM resumption, respectively. In conclusion, IFN monotherapy is a promising option for sustained molecular response after IM discontinuation in CML patients with CMR. Disclosures: No relevant conflicts of interest to declare.