ALBERT

Description: Background MLN9708 (ixazomib citrate) is an oral proteasome inhibitor that is being investigated in phase 3 trials. MLN9708 rapidly hydrolyzes to the biologically active form, MLN2238 (ixazomib). Preliminary findings from studies using weekly and twice-weekly schedules in relapsed/refractory MM have suggested evidence of single-agent activity (Kumar et al, ASCO 2013; Lonial et al, ASCO 2012), and a phase 1/2 study has suggested the feasibility and activity of weekly oral MLN9708 plus len-dex in newly diagnosed MM (Kumar et al, ASH 2012). Here we report the results of a phase 1/2 study, conducted in collaboration with the Multiple Myeloma Research Consortium, of twice-weekly oral MLN9708 plus len-dex (NCT01383928). Methods Phase 1 primary objectives were to determine safety, tolerability, the MTD, and the recommended phase 2 dose (RP2D); secondary objectives included characterizing MLN2238 pharmacokinetics (PK). Phase 2 primary objectives were to determine the combined CR+VGPR rate and further evaluate safety and tolerability; secondary objectives included overall response rate (≥PR), time to response, and duration of response (DOR). Pts aged ≥18 yrs who had no grade ≥2 peripheral neuropathy (PN) and no prior/concurrent DVT/pulmonary embolism received MLN9708 3.0 or 3.7 mg (d 1, 4, 8, 11), len 25 mg (d 1–14), and dex 20/10 mg (cycles 1–8/9–16; d 1, 2, 4, 5, 8, 9, 11, 12) for up to 16 21-day cycles, followed by MLN9708 maintenance (same schedule) until progression or unacceptable toxicity. Transplant-eligible pts could undergo stem cell collection after ≥4 cycles and discontinue for ASCT after ≥8 cycles. Responses were assessed per IMWG uniform response criteria. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points during cycles 1 and 2. Results 64 pts were enrolled; median age was 64 yrs (range 34–82), 63% were male, and 31%/16% had ISS stage II/III MM. In phase 1, 14 pts received MLN9708 3.0 mg (n=7) and 3.7 mg (n=7). No DLTs were seen in cycle 1; based on overall tolerability and incidence of rash at 3.7 mg, the RP2D was chosen as 3.0 mg. 50 pts were enrolled at this dose in phase 2. At data cut-off (July 1, 2013), the median follow-up was 6.9 months and median number of cycles received was 8 (range 1–26); 73% had received ≥8 cycles and 9% had received ≥16 cycles. At data cut-off, 22% of pts had discontinued to undergo ASCT (median CD34+ stem cell yield 14.9 x 106/kg [range 7–52 x 106]), a further 14%, 5%, and 19% had discontinued due to AEs, progressive disease, and other reasons, respectively, and the other 41% remained on treatment. In 58 response-evaluable pts, ≥PR rate to date was 93%, including 67% ≥VGPR (24% CR, including 14% sCR). 54% of pts had 100% decreases in M-protein or serum free light chain from baseline. Analysis of minimal residual disease is ongoing; data will be presented. Depth of response increased over the course of treatment; median time to first response (≥PR) was 0.69 mos and to best response to date was 2.07 mos. Median DOR to date was 5.9+ mos, ranging up to 18+ mos. Most common AEs were rash (61%; pooled high-level terms), fatigue, peripheral edema (each 50%), diarrhea (41%), and neuropathy peripheral (36%). Drug-related (to any drug in the regimen) grade 3 AEs were seen in 56% of pts, including rash (16%), hyperglycemia (8%), pneumonia (6%), and PN (5%; high-level term). No drug-related grade 4 AEs were seen; 58% of pts required dose reductions of at least one drug due to AEs including rash (16%), anxiety (11%), and PN (8%). AEs resulting in discontinuation were seen in 11%, with the majority reported as not related to therapy. There was 1 on-study death due to cardio-respiratory arrest, likely a pulmonary embolism, considered by the investigator to be unrelated to MLN9708 or dex, but probably len. Based on phase 1 preliminary PK data, MLN2238 was absorbed quickly with a Tmaxof 0.5–4 hours. Terminal half-life was 2–8 days. PK data were similar to single-agent twice-weekly dosing studies, suggesting no MLN2238 PK interaction with len or dex. Conclusions These data suggest that twice-weekly oral MLN9708 plus len-dex is feasible and active in pts with newly diagnosed MM. However, rates of rash, PN, and dose reductions appear higher than in the parallel study using weekly MLN9708, with similar response rates and better convenience, supporting use of weekly dosing in ongoing phase 3 trials. Disclosures: Richardson: Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the first-line treatment of patients with multiple myeloma. Hofmeister:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Rosenbaum:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau. Vesole:Millennium: The Takeda Oncology Company: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Liedtke:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chari:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Berg:Millennium: The Takeda Oncology Company: Employment. Liao:Millennium: The Takeda Oncology Company: Employment. Gupta:Millennium: The Takeda Oncology Company: Employment. Di Bacco:Millennium: The Takeda Oncology Company: Employment. Estevam:Millennium: The Takeda Oncology Company: Employment. Hui:Millennium: The Takeda Oncology Company: Employment. Baz:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding.

Description: Background: Inotuzumab ozogamicin (InO), a humanized anti-CD22 antibody-calicheamicin conjugate, produced a superior response compared with standard of care (SOC) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in an intent-to-treat (ITT) analysis of the first 218 of 326 patients (pts) randomized (ITT218) in the INO-VATE trial (complete remission [CR], including CR with incomplete hematologic recovery [CRi], 80.7% [95% CI, 72-88] vs 29.4% [21-39]; 1-sided P

Description: Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.

Description: Abstract 4742 Introduction While the distance patients travel to a treatment center (DTC) adversely impacts survival of patients with trauma, cardiac, or neurological disorders, as well as certain solid tumors, less is known of its influence in acute myeloid leukemia (AML). Care for patients with AML involves frequent emergent and urgent management, often complicating primary therapy provided in distant tertiary referral centers. We therefore hypothesized that increased DTC has a negative impact on outcome. We tested this hypothesis by assessing the effect of DTC on survival of patients with AML receiving care at a single institution. Patients and Methods Within the Stanford Leukemia Database, we identified 884 consecutive adult patients between 1993 and 2009 meeting the following criteria: age 〉=18, newly diagnosed AML (excluding APL), clinical management at Stanford University Medical Center (SUMC), and verified residence location available for DTC determination. Of these, 571 were deemed fit by the admitting physician to receive myelosuppressive induction chemotherapy. DTC was calculated by straight-line journey distance between home address at the time of diagnosis and treatment center. Results The median age for the entire cohort is 55 years and 322 patients (36%) are older than 60 years of age. Median survival for the entire cohort was 14.0 months. DTC was not univariately associated with outcome as a continuous variable. When testing for a critical DTC threshold impacting outcomes across the entire cohort, we found a significant correlation between longer DTC and adverse outcomes, shorter DTC was associated with lower OS. Patients living within 20 miles of SUMC had a worse median overall survival (10.4 months versus 15.0 months, HR 1.23, corrected p-value 0.02). However, when adjusted for administration of induction chemotherapy (p

Description: Abstract 4044 Background: Conventionally, multiple myeloma is believed to coexist in approximately 10% of AL amyloidosis patients. However, it is unclear whether this figure is too low based on current World Health Organization criteria. These criteria, mainly created to differentiate myeloma from monoclonal gammopathy of undetermined significance, include the presence of ≥ 10% plasma cells on a bone marrow biopsy or aspirate as being diagnostic of myeloma. Aims: To define the frequency and relevance of a concomitant diagnosis of myeloma in patients with AL amyloidosis. Methods: Records from consecutive patients with biopsy-proven AL amyloidosis treated at the Stanford University Amyloid Center were reviewed. Plasma cell percentages were determined by manual counts from bone marrow aspirate smears and by CD138 immunohistochemistry (IHC) performed on bone marrow core biopsies. Results: A total of 41 patients (median age 61 years, 32% female) were evaluated. The median number of organs involved with amyloidosis was 2 (range 1–4), with 28 patients (68%) having cardiac involvement, 22 patients (54%) having renal involvement, 15 patients (37%) having gastrointestinal involvement, 12 patients (29%) having soft tissue involvement, and 10 patients (24%) having nervous system involvement. All patients had bone marrow biopsies and aspirates performed at the time of amyloid diagnosis, with most undergoing both manual counts of plasma cells from aspirates and IHC from core biopsies. Based on conventional criteria, manual aspirate counts defined 15/28 (54%) patients as having myeloma, and IHC defined 26/31 (84%) patients as having myeloma (p=0.01). Only nine patients had a detectable serum paraprotein on immunofixation (median 1.1 g/dl, range 0.4–2.6). 81% of patients had an elevated serum free light chain (85% lambda), with a median level of 37.3 mg/dl (range 8.6–256 mg/dl). Compared to the frequency of elevated plasma cells, the prevalence of anemia (29%), hypercalcemia (14%), impaired kidney function (21%), and lytic lesions (7%) was low. After a median follow-up of 13 months (range 1–127 months), the one-year overall survival (74% vs. 58%) and three-year overall survival (50% vs. 50%) was not significantly different between patients with ≥10% plasma cells and patients with

Description: Abstract 1946 Background AL amyloidosis is a clonal disorder of light-chain secreting plasma cells. The light chains deposit as beta-pleated sheets, resulting in significant hematologic and organ toxicity. A recent randomized trial failed to demonstrate superiority of myeloablative melphalan followed by autologous stem cell infusion over the less toxic oral melphalan and high-dose dexamethasone regimen (Jaccard, New Engl J Med 2007). Furthermore, chemotherapeutic options now often include lenalidomide; however, this agent has had limited evaluation in combination with melphalan and dexamethasone and has been hampered by high rates of toxicity at doses of 25mg/day. To assess whether combination therapy at reduced doses would be tolerable and effective, we conducted a single center prospective clinical trial of an oral three drug regimen consisting of melphalan, lenalidomide and dexamethasone (MLD) in AL amyloidosis. Methods The primary endpoint is evaluation of the safety and tolerability of MLD in patients with AL amyloidosis. The secondary endpoint is evaluation of the hematologic response rate, the relevant organ responses and the time to progression. Enrolled patients had a biopsy-proven diagnosis of AL amyloidosis with the presence of measurable disease. Exclusion criteria included absolute neutrophil count 〈 1000 cells/mm3, platelets 〈 75,000/mm3, creatinine clearance 〈 15 ml/min, an ECOG performance status 〉 3, and potential future candidacy for autologous stem cell transplant. There were no exclusions based on patients’ cardiac function. Treatment consisted of a 28 day cycle of lenalidomide 10 mg days 1–21, melphalan 0.18 mg/kg days 1–4, and dexamethasone 40 mg weekly. Stepwise dose reductions were allowed for toxicity. Evaluation of hematologic response rate was via serum free kappa and lambda light chains and/or serum or urine immunofixation. Relevant organ responses were measured with 24-hour urine protein/serum creatinine for patients with renal amyloidosis, transthoracic echocardiogram, troponin-I and NT-BNP for patients with cardiac amyloidosis, and alkaline phosphatase for patients with hepatic amyloidosis. The trial has been expanded from the originally planned 15 patients to 25 patients given rapid enrollment; this report reflects an interim analysis of the first 12 patients. Results Twelve patients have been enrolled. One patient died prior to initiation of therapy, and thus was excluded from further evaluation. The median age of the remaining 11 patients was 65 years (range of 62–84). The median number of organs involved was 2 (range of 1–4). Ten patients had cardiac involvement, 3 patients had renal involvement, and 2 patients had hepatic involvement. Nine of the 11 patients (82%) were newly diagnosed. The mean number of cycles was 3 (range of 1–9 with a total of 36 cycles). A complete hematologic response (CHR) was seen in 3 patients, a partial hematologic response (PHR) was seen in 4 patients, and 3 patients exhibited stable disease, according to consensus criteria (Gertz, Am J of Hem 2005). One patient died during the first cycle and thus response to treatment was not evaluable. Toxicities included: grade 4 neutropenia in 1 patient and grade 3 anemia, thrombocytopenia, and infection in 3 patients. Seven of the 11 patients have died, all of whom had cardiac amyloidosis, of progressive heart failure or arrhythmias. Of these 7 patients, 2 exhibited a CHR and 3 had a PHR. Of the 9 evaluable patients with cardiac amyloidosis, 2 patients exhibited stable cardiac disease, while the other 7 patients had disease progression, primarily via a rising NT-BNP and Troponin-I. Of the 3 patients with renal involvement, 2 had organ disease progression and 1 patient had stable disease, and of the 2 patients with hepatic involvement, 1 had organ disease progression and 1 had stable disease, according to consensus criteria (Gertz, Am J of Hem 2005). Conclusion In a patient cohort consisting primarily of newly diagnosed patients with advanced AL amyloidosis, MLD has promising complete and partial hematologic response rates. Hematologic and infectious toxicities remain significant even at reduced doses. Despite promising hematologic response rates, organ responses occur less frequently. Patients with cardiac amyloidosis, particularly those presenting with heart failure, continue to have poor overall prognosis. A larger trial is warranted to further assess drug toxicity and organ response rates. Disclosures: Witteles: Celgene: Research Funding. Witteles:Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding. Off Label Use: Melphalan and Lenalidomide as therapy for AL amyloidosis.

Description: The prognosis of patients (pts) with relapsed/ refractory acute lymphoblastic leukemia (ALL) remains poor and novel therapies are needed. The anti-CD22 immunoconjugate inotuzumab ozogamicin (INO) has demonstrated promising results in both phase 2 and 3 trials (Kantarjian et al. Lancet Oncology 2012; 13(4): 403-11). Pre-clinical studies have demonstrated superior anti-tumor activity when INO is co-administered with cyclophosphamide (C), vincristine (V), and prednisone (P). In this study, SWOG 1312, we assess the safety of INO in combination with CVP and determine the maximum tolerated dose (MTD) of INO in this regimen for patients with relapsed or refractory (R/R) CD22+ acute leukemia (B-ALL, mixed phenotype, and Burkitts). Here, we present our toxicity results. Methods: Pts were treated at limited SWOG institutions from Apr 2014 to present. INO was supplied by Pfizer and an IND was approved by the FDA. The protocol was reviewed and approved by each institutional review board. Eligibility criteria included: age 〉 18 years (yrs), 〉 20% blasts expressing CD22, R/R CD22+ acute leukemia (B-ALL, mixed phenotype, or Burkitts), and adequate organ function. All pts received treatment with C (750 mg/m2) intravenous (IV) Day 1, V (1.4 mg/m2) (max 2 mg) IV Day 1, P (100 mg) orally Days 1-5 and IO (dose escalated as in Table 1) IV Days 1, 8, and 15. Each cycle was 28 days, and a maximum of 6 cycles could be administered. Dose escalation was performed using a standard 3x3 design; with the plan to treat 12 pts once the MTD was defined. Dose limiting toxicities (DLTs) were considered: (1) 〉 Grade 4 non-hematologic toxicities with the exception of nausea, vomiting and toxicities secondary to neutropenia and sepsis; (2) prolonged myelosuppression [absolute neutrophil count (ANC) 〈 500/ uL or platelet count 〈 25,000/uL] in a bone marrow with 〈 5% blasts and no evidence of leukemia that lasts 〉 35 days beyond the most recent dose of IO; (3) any grade 3 non-hematologic toxicity (excluding peripheral neuropathy, hyperglycemia, and toxicities secondary to neutropenia, thrombocytopenia, and sepsis) that does not resolve to Grade 2 or better by 7 days beyond the most recent dose of IO; (4) any 〉 Grade 3 elevation in SGOT/ SGPT or bilirubin lasting ≥ 7 days; (5) any IO-related toxicity resulting in permanent discontinuation of IO. Results: As of 7/14/2016, 24 pts have been enrolled: 2 pts were ineligible and 3 pts are currently receiving treatment and are not evaluable for toxicity. Of the 19 evaluable pts, the median age was 49 yrs (range 21-75), 10 (53%) were male, and the median WBC at registration was 9.4 K/uL (range 0.9-59.6). All pts had B-ALL. The median time from initial diagnosis to registration was 774 days. Five pts were in 1st relapse, 8 in 2nd relapse, 3 in 3rd relapse, 1 in 4th relapse, and 2 pts were primary refractory. Five pts had received prior allogeneic hematopoietic stem cell transplant (AHSCT); 7 pts had poor risk cytogenetics (Ph+, -7, +8, complex, or hypodiploid). One death occurred during treatment and was attributed to pneumonia. Grade 3-4 hematologic toxicity related to treatment was common: neutropenia (11 pts), thrombocytopenia (7 pts), and anemia (6 pts). Grade 3-4 non-hematologic toxicities were almost exclusively febrile neutropenia. One DLT occurred at Dose Level 3: prolonged myelosuppression. No cases of hepatic veno-occlusive disease (VOD) occurred during treatment, and 1 pt experienced Grade 3 alkaline phosphatase at Dose Level 1. Three pts proceeded to AHSCT after study treatment; 1 pt developed VOD post AHSCT however, this fully resolved. Currently, 3 pts have been enrolled to Dose Level 4. Conclusion: The combination of CVP/IO is well tolerated and only 1 significant hepatic event (which subsequently resolved) was observed despite a heavily pre-treated group of patients. Further toxicity results and dose escalation will be presented at the meeting. Response data will also be presented if enrollment is complete. Disclosures Advani: Pfizer: Consultancy, Research Funding. Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Erba:Pfizer: Consultancy; Juno: Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Agios: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy; Celator: Research Funding; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Jannsen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Ariad: Consultancy; Astellas: Research Funding; Astellas: Research Funding; Celator: Research Funding; Agios: Research Funding; Agios: Research Funding; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy.