Citations

Abstract Introduction:In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells accumulates in tissue, resulting in the dysfunction of vital organs and systems (eg, heart, kidneys, nervous system). Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. Approximately 75% of patients do not achieve organ responses and have persistent organ dysfunction. Amyloid-directed therapies may stabilize and potentially reverse organ damage by specifically targeting existing LC aggregates. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. We have previously reported that monthly infusions of NEOD001 were safe and well tolerated. In addition, NEOD001 was associated with renal and cardiac responses. Here we analyzed the association between organ response and depth and time since last plasma cell-directed (PCD) treatment in the entire cohort of 69 patients enrolled in both the dose-escalation and the expansion phases of the phase 1/2 study. Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed cardiac and renal responses based on consensus criteria and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL). For this analysis, we focused on the relationship between organ response after treatment with NEOD001 to the time since last or best HR and the depth of best and last HR. Results: A total of 69 patients were enrolled, 27 in the dose-escalation and 42 in the expansion cohorts. The entire population included 36 cardiac-evaluable patients, 35 renal-evaluable patients, and 11 patients evaluated for peripheral neuropathy; 39% were women, and the median age was 60 years. Time since diagnosis was 2.8 (0.4-12.8; median, range) years, and 45% of patients had undergone ≥3 previous PCD regimens. Of the patients evaluable for organ response, best response rates indicating organ response were observed in 53% of cardiac-evaluable patients (n = 19/36) and 63% of renal-evaluable patients (n = 22/35). NIS-LL scores indicated that 82% (n = 9/11) of patients met criteria for a peripheral neuropathy response to NEOD001. Cardiac and renal response rates for NEOD001-treated patients could not be attributed to previous PCD treatment regimens. For example, 37% of the NEOD001 cardiac responders and 35% of nonresponders received cyclophosphamide-bortezomib-dexamethasone. Similarly, for NEOD001 renal responders vs nonresponders, 27% vs 25% were treated with autologous stem cell transplantation and 27% vs 31% were treated with bortezomib-dexamethasone. There was no relationship between NEOD001 cardiac, renal, or peripheral nerve organ response and time since last chemotherapy, time since last or best HR, or depth of last or best HR. Finally, an equivalent percentage of evaluable patients experienced renal or cardiac response regardless of whether they had received their most recent PCD treatment ≤6 months or >6 months before NEOD001 initiation. The median time since last PCD treatment to the start of NEOD001 intervention for all patients was 6.5 (range, 0.6-85.8) months and the median time to first cardiac response after NEOD001 treatment for all cardiac responders was 2 months. NEOD001 treatment was safe and well tolerated. Conclusions: Patients treated with monthly NEOD001 infusions had high organ response rates that were independent of time since previous chemotherapy, depth of hematologic response, or predominant type of PCD treatment. Ongoing studies of NEOD001 include VITAL (phase 3 in patients with newly diagnosed AL amyloidosis) and PRONTO (phase 2b in previously treated AL amyloidosis patients with persistent cardiac dysfunction). Disclosures Liedtke: Gilead: Research Funding; Prothena: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Research Funding. Comenzo:Takeda: Consultancy, Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sanchorawala:Prothena: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:Prothena: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Array Biopharma: Consultancy. Walling:Corcept: Consultancy; Stealth: Consultancy; Codexis: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Apex: Consultancy; Aduro: Consultancy; Prothena: Consultancy; Upsher Smith: Consultancy, Patents & Royalties; KaloBios: Consultancy; NuMedii: Consultancy; Pharm-Olam: Consultancy; Crown Bioscience: Consultancy; BioMarin: Equity Ownership; Amgen: Equity Ownership, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Gertz:Annexon Biosciences: Research Funding; Ionis: Research Funding; Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria.

Abstract Background Systemic AL amyloidosis is a life-threatening disease with limited treatment options. Response criteria have been recently updated and retrospectively validated (Palladini et al, J Clin Oncol 2012). Hematologic response (suppression of FLCs) has been shown to predict for both organ response and survival (ibid). Preliminary results from the present phase 1 study (NCT01318902) regarding the safety, tolerability, and maximum tolerated dose (MTD) of ixazomib (the first oral PI to be investigated in the clinic) in RRAL were reported previously (Merlini et al, ASH 2012). At that time, 11 pts had received the MTD/RP3D of ixazomib - 4.0 mg. Here we update the safety data (primary objective) and report hematologic and organ responses, progression-free survival (PFS), and overall survival (OS) (secondary objectives) for the extended population of 22 pts receiving the RP3D. Methods Pts with RRAL after ≥1 prior therapy and with measureable heart/kidney involvement and cardiac biomarker stage I/II disease were eligible. Two expansion cohorts (PI-naïve and PI-exposed) were enrolled at the RP3D. Pts received oral ixazomib on days 1, 8, and 15 for up to 12 x 28-day cycles; continuation until disease progression was allowed. Pts with less than partial response (PR) after 3 cycles received added dexamethasone (Dex) 40 mg, days 1–4 from cycle 4 onwards. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Responses were assessed per standard criteria (Palladini et al, J Clin Oncol 2012). Results At data cut-off (Dec 6, 2013), 27 pts had been enrolled, 22 at the RP3D of ixazomib 4.0 mg; the other 5 pts were enrolled at 5.5 mg and are not included in these analyses. In pts who received ixazomib 4.0 mg, median age was 64.5 yrs (range 54–78); 13 were male. Mayo cardiac biomarker risk stage was I/II/III in 11/10/1 pts, respectively. Median baseline FLC differential (dFLC) and NT-proBNP were 146 mg/L (range 40–734) and 849 pg/mL (range 51–5691). Major organ involvement included heart, kidney, or both in 9, 8, and 5 pts, with a median of 2 (range 1–6) organ systems involved. Pts had received a median of 3 prior therapies, including transplantation in 16 pts; 16 pts had received prior bortezomib (PI exposed) and 6 were PI naïve. Other prior therapies included melphalan (n=21), Dex (n=16), IMiDs (n=11), and cyclophosphamide (n=10). Best hematologic response to prior therapy was complete response (CR) in 3 pts, very good PR (VGPR) in 4, PR in 14, and stable disease (SD) in 1 pt; organ response was achieved by 5 pts, with 12 pts having no response. Exposure and outcome data by prior PI exposure are shown in the table. Pts discontinued due to disease progression (n=6), pt withdrawal, symptomatic deterioration (each n=3), or unsatisfactory response (n=2); 5 pts completed 12 cycles; 3 pts are ongoing. Overall hematologic response rate (ORR) was 52%. After a median follow-up of 16.9 mos, the 9 pts who achieved ≥VGPR, had a median PFS of 17.0 mos compared with 10.7 mos in pts who achieved a lesser response (p=0.03). Cardiac/renal response was observed in 50%/18% of pts (all ≥VGPR). The most common drug-related AEs included diarrhea, nausea (each n=7), fatigue, thrombocytopenia (each n=6), peripheral neuropathy, and pyrexia (each n=4). Drug-related grade 3 AEs (>1 pt) were thrombocytopenia (n=3), diarrhea, and maculo-papular rash (each n=2). Table.PI naïven=6PI exposed n=16TotalN=22Cycles received, median (range)12 (1–22)3.5 (1–16)5.5 (1–22)Dex added, n358Hematologic response-evaluable ptsn=5n=16N=21Response, n (%)ORR5 (100)6 (38)11 (52)CR2 (40)02 (10)VGPR3 (60)4 (25)7 (33)PR02 (13)2 (10)SD09 (56)9 (43)Cardiac response/heart evaluable, n/N (%)3/4 (75)3/8 (38)6/12 (50)Renal response/kidney evaluable, n/N (%)1/3 (33)1/8 (13)2/11 (18)1 yr hematologic PFS rate, %8341602 yr OS rate, %835157 Conclusions This is one of the first studies prospectively assessing hematologic and organ response according to the updated consensus criteria. These data suggest weekly oral ixazomib 4.0 mg is feasible and generally well tolerated in RRAL pts with vital organ dysfunction. High quality hematologic responses (≥VGPR) were observed in 43% of pts; these responses were sustained at 1 yr in 60% of this heavily-pretreated population. Achieving ≥VGPR was associated with cardiac response and extended PFS. These results warrant a phase 3 study of ixazomib plus Dex vs physician's choice of treatment, which is ongoing (NCT01659658). Disclosures Merlini: Pfizer: Honoraria; Millennium: the Takeda Oncology Company: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of the investigational agent ixazomib, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium: the Takeda Oncology Company: Research Funding; Onyx: Research Funding. Jeffrey:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Consultancy, Honoraria. Schoenland:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau. Jaccard:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Millennium: the Takeda Oncology Company: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Janssen: Research Funding. Cohen:Onyx Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other; Celgene: Member, Independent Response Adjudication Committee Other. Berg:Takeda Pharmaceutical International Co.: Employment. Yuan:Takeda Pharmaceutical International Co.: Employment. Hui:Takeda Pharmaceutical International Co.: Employment. Comenzo:Millennium:the Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract Abstract 731 Background: Treatment with bortezomib achieves high hematologic response rates and rapid and durable responses in AL patients (pts), providing the rationale for proteasome inhibition in this population. MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor (PI). In preclinical studies, MLN9708 has shown improved antitumor activity compared to bortezomib in a range of xenograft models. This phase 1 study (NCT01318902) assessed weekly doses of oral MLN9708 in pts with relapsed or refractory AL. Methods: Pts aged ≥18 years with relapsed or refractory AL after ≥1 prior therapy, cardiac biomarker stage I/II disease, and measurable major organ (heart/kidney) involvement, received increasing doses of oral MLN9708 (standard 3+3 dose escalation fixed doses of 4.0 and 5.5 mg), on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Pts with no major hematologic response (<PR) after 3 cycles received dexamethasone (dex; 40 mg, days 1–4). Two expansion cohorts of PI-naïve and PI-exposed pts were enrolled at the MTD. The primary objectives were to determine the safety, tolerability, and MTD. Secondary objectives included analysis of plasma pharmacokinetic (PK) and whole blood pharmacodynamic effects of MLN9708, and assessment of overall hematologic response rate, time to and duration of hematologic and organ response. Adverse events (AEs) were graded using NCI-CTCAE version 4.03. Blood samples were collected at multiple timepoints pre- and post-MLN9708 dosing for PK analysis during cycle 1. Hematologic response and amyloid-related organ assessments were performed according to standardized criteria. Results: At data cut-off (June 29, 2012) 16 pts had been enrolled and received ≥1 MLN9708 dose (safety population). The median age was 66.5 years (range 54–78) and 7 were male. Median number of prior therapies was 3 (range 1–7); 10 received prior transplant, 7 received prior bortezomib. Major organ involvement, defined by standard criteria, included heart, kidney, or both in 7/5/4 pts, respectively, with a median of 2 (range 1–5) involved organ systems, and Mayo cardiac biomarker risk stage was I, II, III in 6, 9, 1 pts. Five pts were treated in the 5.5 mg cohort and 11 pts were treated in the 4.0 mg (n=6 dose escalation; n=5 dose expansion) cohorts. Of the 11 pts treated at 4.0 mg, 4 were PI-naïve, 7 were PI-exposed. Pts received a median of 3 cycles (range 1–12); 5 pts received ≥5 cycles, and 8 pts remain on treatment. Dex was added in 4 pts (2 in each MLN9708 dose level). There were no on-study deaths. Pts discontinued due to disease progression (n=5), AE, withdrawal by pt, or unsatisfactory response (each n=1); 2 pts completed planned 1 year of therapy. One pt in the 4.0 mg cohort experienced a DLT of grade 3 thrombocytopenia. Two pts in the 5.5 mg dose cohort experienced DLTs: grade 3 diarrhea in 1 pt, and renal failure, respiratory failure (both grade 2), and cardiac arrest (grade 4) in another pt. The MTD was determined as 4.0 mg. AEs were reported in 14 pts. The most common drug-related AEs included nausea (n=5), diarrhea and thrombocytopenia (each n=4), abdominal pain and fatigue (each n=3). Grade ≥3 AEs (any cause) reported in >1 pt were thrombocytopenia (n=4), dyspnea (n=3), maculo-papular rash, dehydration, and abdominal pain (each n=2); all were grade 3. Preliminary response data are shown in the table. At data cut-off, one responder had progressed, and the median duration of hematologic response was 7.4 months (range 1.3–11.5+); 2 pts had cardiac organ response. Preliminary PK data showed that MLN9708 was rapidly absorbed, with a median Tmax of 1 hr (range 0.5–6). MLN9708 day 15 plasma Cmax was 73.6 ± 40.2 ng/mL (mean ± SD) and AUC0–168was 1250 ±530 ng*hr/mL (n=8 at 4.0 mg dose cohort). MLN9708 PK parameter values in this study appear similar to other MLN9708 studies in myeloma pts. Conclusions: These data suggest weekly oral administration of MLN9708 is feasible in pts with relapsed or refractory AL. The MLN9708 MTD was determined as 4.0 mg. Assessment is ongoing, with preliminary evidence of hematologic responses noted. A phase 3 study of MLN9708 plus dex versus physician's choice of treatment is planned (NCT01659658). Disclosures: Merlini: Millennium Pharmaceuticals, Inc.: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Onyx: Research Funding. Zonder:Celgene: Research Funding; Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Schonland:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Janssen Research & Development: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Research Funding. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Research has shown that individuals with mild cognitive impairment (MCI) value quality of life (QoL) above and beyond cognitive function or other potential outcomes in MCI. There is evidence supporting the negative impact of poor physical function on QoL ratings. Objective: The study explored whether a modified measure of self-efficacy for managing MCI and education mediated and/or moderated the relationship between physical function and QoL in persons with MCI. Methods: Baseline data from 200 participants with MCI were obtained from a larger study assessing the effectiveness of a behavioral intervention. Physical function was assessed by the Short Physical Performance Battery. QoL was assessed with the Quality of Life in Alzheimer’s Disease scale. Memory-related self-efficacy was assessed using a modified 9-item version of the Chronic Disease Self-Efficacy Scales. Mediation and moderation analyses tested the hypotheses that self-efficacy and education alter the association between physical function and QoL in individuals with MCI. All analyses were adjusted for age, cognitive severity, and sex. Results: Self-efficacy for managing MCI was a significant mediator of the association between physical function and perceived QoL. Individuals with better physical function reported higher self-efficacy which was associated with higher QoL ratings. Conclusions: Greater self-efficacy for managing MCI mediated the negative association between physical function and quality of life in this exploratory study. Interventions aimed at enhancing memory self-efficacy in MCI may improve perceived QoL, even in the presence of poor physical function. Future research is needed to investigate this further.

Abstract This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).