ALBERT

Description: Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).

Description: Background: Although complete remission rates for AML are near 70% with combination induction and consolidation chemotherapy, most patients will relapse and die from the disease or treatment complications. New agents with unique mechanisms are needed. One such class of therapeutics are fusion proteins consisting of protein synthesis inactivating peptide toxins fused to tumor cell selective ligands. DT388-IL3 is one such fusion protein. Rationale: In preclinical studies, DT388-IL3 was cytotoxic to the IL3 receptor expressing leukemia cell lines but not toxic to IL3 receptor negative cell lines. This agent was less toxic to normal progenitors and not toxic to early hematopoietic stem cells. The majority of AML progenitors overexpress IL3 receptors. Animal model work in mice bearing human leukemia cells has demonstrated anti-leukemia efficacy which is dose dependent with this agent. Toxicities in monkeys include vascular leak syndrome and pancytopenia observed only at the highest doses. The MTD in monkeys was estimated at 60mcg/kg/day. We report preliminary data on the use of DT388-IL3 fusion protein in humans from an ongoing phase I trial. Pharmacokinetics; clinical and immune response to this novel fusion protein are also being followed. Patients and Methods: Patients with refractory AML were eligible. The first dose level was qd M-W-F X six doses of DT388-IL3 at 4mcg/kg/day with dose escalation planned for subsequent patients. Patients with progression of disease or unacceptable study drug toxicity were to be removed from the study. Toxicity was graded according to NCI CTCAE version 3.0. Three patients have been treated with DT388-IL3. Serum samples were collected and will be assayed for anti-DT388-IL3 antibodies prior to and after treatment. Blood samples were obtained to measure circulating levels of active DT388-IL3 and its half life. Patient blasts were also collected prior to treatment for later analysis of expression of IL3 receptors. Result: Two patients tolerated the treatment schedule(of six doses) without any significant toxicities. Mild fever, headaches, nausea were noted. Both of these patients had progression of disease-one during treatment and one on day 15 bone marrow biospy. The above mentioned patients died secondary to disease complications at 2 weeks and 18 weeks after their last dose of the study agent respectively. DT388-IL3 levels on these two patients post infusion were below the the reliable detectable limits of the assay. The third patient became febrile and hypotensive after the first dose. The hypotension persisted and she did not receive any further doses. This patient is alive 5 weeks later with supportive care alone. DT388-IL3 levels following this patient’s dose are as follows: 2min post infusion 34.3ng/ml, 30min post infusion 1.9ng/ml, 60min post infusion 0.075ng/ml, 120min post infusion 0.003ng/ml, 240min post infusion undetectable. Conclusion: Preclinical/animal studies suggest that DT388-IL3 has anti-leukemia efficacy. Preliminary data from our ongoing phase I trial reveals minimal study agent related toxicity and no life threatening complications at this first dose level. Dose escalation is planned as per protocol.

Description: Bcl-2 acts as an important regulator of the mitochondrial pathway of apoptosis and promotes resistance of MM cells to chemotherapy. The Bcl-2 antisense oligonucleotide G3139 specifically targets Bcl-2 and may enhance the anti-tumor efficacy of Dex and Thal. In this trial G3139 was administered at 5 mg to the first 3 Pts and then 7 mg/kg/d by IVCI for 7d of 21d cycle. On day 4, Pts started Dex 40 mg daily for 4 d and Thal 100-400 mg as tolerated. After 3 cycles, responding Pts continued G3139 on a 5-week cycle with Dex 20 mg x 4d and Thal at the tolerated daily dose for up to 1 yr with an optional second yr for responding Pts. Thirty-three Pts treated to date had the following characteristics: median age 60 yrs (range: 28- 76), 22 males; 16 Pts had complex karyotypes; 14 Pts had B2M 〉 2.5 g/dl; LDH 〉1.5 normal in 7 Pts; Cr 〉1.5 mg/dl in 6 Pts; platelets

Description: Therapeutic options for chronic lymphocytic leukemia (CLL) at relapse are limited because of myelosuppressive toxicity. Denileukin diftitox (ONTAK®, Ligand Pharmaceuticals) is a genetically engineered fusion protein comprising the enzymatically active domain of diphtheria toxin and the full length sequence of interleukin-2 (IL-2) targeting malignancies expressing the medium and high affinity IL-2 receptors. We designed a phase II study to evaluate the efficacy of ONTAK® in patients with fludarabine-refractory CLL, which is a follow-up to the previously published study (Frankel, et al, Clin. Cancer Res.2003; 9:3555). Denileukin diftitox was administered at a dose of 18μg/kg IV daily for 5 days every 3 weeks, for a maximum of 8 cycles. Thirteen patients have been treated so far, with 10 patients being evaluable for response (completed ≥ 3 cycles). Median age was 59 years (range 44–84), and 62% (8/13) were Rai stage III-IV, with a median of 3 prior therapies (range 1–6). The overall response was 40%, with 1 CR (10%, duration of response 5+ months) and 3 PR (30%, duration of response 3+, 3+ and 4+ months). Two responding patients (both PR) are still on study, while two (1 CR, 1 PR) were removed from study because of toxicities after 7 and 5 cycles, respectively. Four patients (40%) had progressive disease after cycles 3, 4, 4, and 7, respectively. One patient has completed four cycles and restaging studies are pending. Of the 3 patients not evaluable for response, two are still on study (having not completed 3 cycles), while one refused further treatment after 4 doses of cycle one. The grade 3/4 toxicities encountered were: neutropenia 4/13, thrombocytopenia 4/13, vascular leak syndrome 3/13, left ventricular cardiac dysfunction 1/13, hypotension 2/13, tachyarrhythmia 3/13, elevated PT 1/13, fatigue 1/13, rash 1/13, SIADH 1/13, constipation 1/13, vomiting 2/13, petechiae 1/13, transient elevation of GGT 1/13, transient elevation of AST/ALT 7/13, hyperglycemia 4/13, electrolyte imbalance 8/13, infection and/or febrile neutropenia 4/13, insomnia 1/13, visual disturbance 1/13, dyspnea 2/13, hypoxia 2/13. We conclude that denileukin diftitox has activity in CLL, with toxicities that can be managed with adequate premedication and close monitoring.

Description: Introduction Both blinatumomab and lenalidomide have proven, but limited, efficacy in relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). Failure of blinatumomab to mediate durable responses is due to its inability to recruit competent cytotoxic T cells which leads to eventual T cell exhaustion. Lenalidomide has been shown to improve efficacy of rituximab through T and NK cell activation even in patients who have previously failed rituximab containing regimens. Based on this, we hypothesized that lenalidomide, when combined with blinatumomab, will enhance its efficacy. We report safety, efficacy and correlative analysis of blinatumomab and lenalidomide in R/R NHL. Methods We conducted a phase I, open-label trial involving patients 18 years and older with R/R CD19+ NHL who have received at least two prior chemotherapeutic or biologic regimens and were not eligible for standard curative options at time of enrollment. Previous CD19-targeted therapy was allowed. Study consisted of a dose escalation followed by a dose expansion phase once the maximum tolerated dose (MTD)/ recommended phase II dose (RP2D) was established using a Phase I Queue modified 3+3 design. The escalation phase has been completed and consisted of blinatumomab continuous infusion (level 1 and 2: 9 mcg/day to 112 mcg/day) from days 1-56 and lenalidomide (level 1: 10 mg and level 2: 20 mg daily) days 29-49 of a 56-day induction cycle. Patients who responded underwent consolidation with blinatumomab continuous infusion days 1-7 and lenalidomide days 1-21 of a 28-day cycle for a maximum of 6 cycles followed by lenalidomide maintenance for 2 years or until unacceptable toxicity or disease progression. Dose limiting toxicities (DLT) included any grade 3/4 drug related adverse events (AE) observed during and up to 7 days after blinatumomab/lenalidomide simultaneous administration. Additional patients were accrued to replace patients who had grade 3/4 AE or progressed before receiving lenalidomide for dose-finding purposes. Primary endpoints included toxicity and determination of the MTD/RP2D during the first 8 weeks of blinatumomab/ lenalidomide induction. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, progression free survival (PFS) which was censored at time of transplant and immune response biomarkers. Results As of July 17, 2019, 18 patients initiated therapy; 7 with diffuse large B cell lymphoma, 3 with mantle cell lymphoma, 3 with follicular lymphoma, 2 with nonspecified B cell lymphoma and 1 each with marginal zone lymphoma, Burkitt's lymphoma and small lymphocytic lymphoma. Median age was 58 (range 30-84) years and the median number of prior regimens was 2.5 (range 2-5); 5 patients had previous stem cell transplant (SCT). 6 patients had disease progression prior to starting lenalidomide. 3 patients received blinatumomab/lenalidomide at dose level 1 with no DLT noted. 9 patients received blinatumomab/lenalidomide at dose level 2 with 4 requiring blinatumomab dose reduction prior to starting lenalidomide. Due to favorable safety profiles with the combination using the MTD/RP2D of lenalidomide 20 daily, upfront doublet therapy was initiated as part of the planned expansion phase. Most common grade 3/4 adverse events were lymphopenia (39%), hypophosphatemia (22%) and hyponatremia (11%). 1 patient (5.5%) experienced grade 3 neurotoxicity. No grade 3/4 cytokine release syndrome or treatment related deaths were seen. At time of data cutoff, three patients remain on active treatment. At a median follow-up time of 14.3 months, ORR was 56% for all patients and 83% (50% CR) for those who received blinatumomab/lenalidomide combination therapy. Median PFS was 3.8 months (95% CI, 1.1 to NR) for all patients and 8.3 months (95% CI, 2.2 to NR) for those who received blinatumomab/lenalidomide combination therapy. 3 patients who achieved response underwent allogeneic SCT and remained in remission for 14.2 to 22.3 months thereafter. Correlative studies are pending and will be reported at time of presentation. Conclusions The combination of blinatumomab and lenalidomide, given at the RP2D dose of 20 mg daily, is safe and well tolerated. This regimen demonstrates encouraging efficacy in this heavily pretreated patient population and is a promising alternative treatment option for R/R NHL patients who are not candidates for aggressive cytotoxic chemotherapy or as a bridge to allogeneic SCT. Disclosures Abedi: Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Zain:Seattle Genetics: Consultancy; Spectrum: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. William:Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy. Foss:Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; miRagen: Consultancy; Eisai: Consultancy; Mallinckrodt: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services . Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Rosenberg:Amgen: Consultancy, Research Funding. Tuscano:Seattle Genetics: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Spectrum: Research Funding; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. OffLabel Disclosure: The use of blinatumomab and lenalidomide in patients with aggressive lymphoma

Description: Background MLN8237 is an oral inhibitor of aurora kinase A (AURKA) that causes mitotic spindle defects, mitotic delay, and apoptosis in lymphoma cell lines and mouse models. Human studies have shown promising responses in hematologic malignancies. Vorinostat is an oral HDAC inhibitor that is FDA-approved for cutaneous T-cell lymphoma, and is under study in other lymphomas. AURKA inhibitors in combination with vorinostat show synergistic pro-apoptotic effects in vitro in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cell lines (Kretzner 2011, Cancer Res 71:3912). Our phase I multicenter study assessed the safety and tolerability of MLN8237 combined with vorinostat in patients with lymphoid malignancies [NCT01567709] and determined the maximum tolerated dose (MTD) to be 20 mg twice daily (BID) of MLN8237 and 200 mg BID of vorinostat orally in an interrupted dosing schedule (Schedule II). We have recently completed accrual to an expanded cohort at MTD and report preliminary data on our secondary endpoints among patients treated on Schedule II of this study. Methods Eligible patients were ≥18 years old with relapsed or refractory (r/r) lymphoid malignancies (HL, B-NHL, T-NHL), measureable disease, ECOG performance status 0-2, neutrophils ≥1500/µL, platelets ≥100,000/µL, and adequate kidney and liver function. Secondary endpoints were toxicities, clinical response, pharmacokinetic (PK) analysis, and correlative studies. A 3+2 modified rolling-6 design was employed to determine the MTD. Enrollment was initiated on a continuous dosing schedule (Schedule I) that was poorly tolerated, with adverse events (AEs) on dose levels 1 and 2 leading to many dose delays primarily due to gastrointestinal intolerance and myelosuppression. The protocol was amended to the interrupted dosing Schedule II: MLN8237 escalated from 20 to 50 mg BID on days 1-3 and 8-10, and vorinostat given at 200 mg BID on days 1-5 and 8-12 of a 21-day cycle. Results We treated 25 patients (11 DLBCL, 7 HL, 3 FL, 2 MCL, 1 PTCL, 1 NK/T cell) on the interrupted dosing Schedule II. Median age was 59 years (range 26-78). Mediannumber of prior therapies was 4 (range 1-10); 9 patients (36%) underwent prior stem cell transplantation. See Table for treatment summary. MTD of the combination is 20 mg BID for MLN8237 and 200 mg BID for vorinostat on the interrupted schedule. The commonest (〉5%) ≥ grade 3 drug-related AEs were neutropenia (52%), thrombocytopenia (44%), leukopenia (44%), anemia (28%), lymphopenia (24%), febrile neutropenia (12%), oral mucositis (8%), diarrhea (8%), and lung infection (8%). There were no study-related deaths. 4 patients stopped treatment due to AEs and 13 due to progressive disease (PD). 2 patients achieved complete remission (CR); both had DLBCL, and both halted therapy after completing 2 further cycles of treatment post-CR. They both remain in CR (18 months and 1 month at data lock). 1 patient had a partial response (PR), and 8 patients maintained stable disease (SD). PKs demonstrated a clearance of 230 L/h (sd=495) and 2.94 L/h (sd=1.57) for vorinostat and MLN8237, respectively. Archived baseline biopsies are being analyzed to determine AURKA expression. Six fresh paired tumor biopsies were obtained before and on-treatment in the expanded cohort at MTD for correlative studies. Conclusions MLN8237 when given in combination with vorinostat is safe and tolerable in an interrupted dosing schedule among heavily pre-treated patients with r/r lymphoid malignancies. The MTD for MLN8237 is 20 mg BID on days 1-3 and 8-10, combined with vorinostat at 200 mg BID on days 1-5 and 8-12, of 21 day cycles. The commonest AEs were hematologic and gastrointestinal. Promising responses were seen in several patients, especially those with DLBCL, which support phase 2 exploration of this therapy in patients with intermediate-high grade NHL. PK analysis suggests that combination therapy exposures are similar to single agent exposure. Correlative studies done in a 12-patient expanded cohort will be presented. [Trial supported in part by UM1CA186717] Table 1. Schedule II:MLN8237 (mg)/ Vorinostat (mg) # of patients treated # of cycles completed Median (range) # of dose limiting toxicities (DLT) DLT Description Best response Dose level 1 (30/200) 7 3 (0-18) 2 1 pt had grade 3 febrile neutropenia; 1 pt had grade 3 thrombocytopenia requiring transfusion 1 CR, 3 SD, 2 PD, 1 N/A Dose level -1 (20/200) 18 2 (0-14) 0 1 CR, 1 PR, 5 SD, 8 PD, 3 too early to assess Disclosures Siddiqi: Kite pharma: Other: attended advisory board meeting; Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau. Off Label Use: Vorinostat is only FDA-approved for CTCL but in this study it is being used in conjunction with MLN8237 (not FDA-approved) for all lymphomas.. Beumer:Millenium: Other: Research support. Forman:Mustang Therapeutics: Research Funding.

Description: Background: There is an unmet need fortreatments (Tx) for myeloid malignancies, particularly relapsed/refractory (RR) AML, that provide durable remissions without worsening existing cytopenias that place patients (pts) at risk for serious infections or bleeding. Oral AG-221 is a selective, potent inhibitor of the mutant isocitrate dehydrogenase 2 (mIDH2) enzyme associated with hematologic malignancies. A phase 1/2 dose-escalation and expansion study of AG-221 [NCT01915498] is ongoing in pts with advanced hematologic malignancies. Reported here are AG-221 safety and efficacy results with a focus on pts with RR-AML, and the first AG-221 data to show changes in absolute neutrophil count (ANC) in early Tx and associated adverse events (AEs), response by mIDH2 type (R140Q or R172K), and mIDH2 variant allele frequency (VAF) on Tx over time. Objectives: Assess AG-221 safety and efficacy in pts with advanced myeloid malignancies; and in responding RR-AML pts, evaluate response by mIDH2 mutation type, associations between ANC improvement and AEs, and mIDH2 VAF over time. Methods: Pts ≥18 years with mIDH2-positive myeloid malignancies are eligible. AG-221 is administered QD or BID in continuous 28-day cycles. Dosing began at 50 mg QD or 30 mg BID and increased in subsequent cohorts. Response is measured from peripheral blood (PB) and bone marrow (BM) samples on days 15, 29, 57, and every 56 days thereafter, and by objective investigator report. Evaluable pts had a response assessment at Cycle 2 Day 1 or later, or discontinued before assessment. Stable disease (SD) is failure to achieve at least partial remission (PR) but no progressive disease (PD). ANC improvement in this analysis is defined as ≥1.0x109/L increase from baseline (BL). Next-generation sequencing was used to assess mIDH2 VAF longitudinally in a subset of responders, using the FoundationOne Heme test on purified mononuclear cells from BM or PB. Results: At data cut-off (1 July 2015), 198 pts had received AG-221 and 83 (42%) remained on Tx. Median age was 69 yrs (19-100). 70% of pts had an R140Q and 25% had an R172K mutation (5% unknown). Most pts had RR-AML (n=138, 70% [untreated AML 17%, MDS 7%, other 6%]). Among RR-AML pts, 88 (64%) had received ≥2 prior Tx regimens (2 n=46, 3 n=24, ≥4 n=18), including intensive therapy, HMAs, or BM transplant. Median Tx durations overall and for RR-AML pts were 4.5 (95%CI 3.6-5.9) and 5.2 (3.6-6.1) months (mos), respectively. The highest daily AG-221 dose was 450 mg; maximum tolerated dose has not been reached. The most common Tx-related AEs were indirect hyperbilirubinemia (19%) and nausea (18%). Serious AEs (SAEs) were mainly disease-related; 35 pts (18%) had Tx-related SAEs, notably, leukocytosis (n=7). In all, 181 pts (91%), including 128 RR-AML pts, were efficacy evaluable. Objective responses were seen in 74 pts (41%), including 52 RR-AML pts (41%) (Table). Median response durations overall and in RR-AML pts were 6.9 (95%CI 3.7-9.2) and 6.0 (3.7-9.2) mos, respectively. Response rates were consistent in RR-AML pts, regardless of number of prior Tx regimens or mIDH2 type (R140Q 36%, R172K 39%). Eight pts went to transplant, including 5 RR-AML pts (Fig 1). Improvement from BL ANC (median 0.4 x109/L [0-15.5]) occurred in 72 RR-AML pts (56%), including 43 responders, and 23pts (40%) with SD. Among RR-AML responders, ANC increases occurred in cycle 1 (median 0.6 mos; 0.1-9.3), were durable through cycle 6 (Fig 2), and were associated with lower rates of infections and febrile neutropenia at cycles 1, 3, and 6 vs pts without ANC improvement. mIDH2 VAF did not decrease on-Tx in RR-AML pts who achieved a CR, CRp, or PR (Fig 3). Conclusions: AG-221 was well-tolerated and induced responses in pts with advanced myeloid malignancies, including heavily pretreated RR-AML. Response rates in RR-AML were consistent regardless of number of prior Tx regimens or mIDH2 type. mIDH2 VAF did not change from BL in responding pts; however, rapid ANC improvements suggest that despite the persisting mutant clone, differentiation into mature myeloid cells (eg, neutrophils) occurred. These data give insight into the putative mechanism of AG-221 as a differentiation agent associated with early ANC improvement and clinical benefits. Table. All(N=181) RR-AML(N=128) n (%) Overall Response (CR, PR, CRp, CRi, mCR) 74 (41) 52 (41) CR 30 (17) 23 (18) CRp 3 (2) 1 (1) CRi 1 (1) 1 (1) mCR 15 (8) 8 (6) PR 25 (14) 19 (15) SD 81 (45) 57 (45) PD 9 (5) 7 (6) Not evaluable 17 (9) 12 (9) Disclosures Stein: Seattle Genetics: Consultancy; Agios Pharmaceuticals: Consultancy. DiNardo:Novartis: Research Funding. Altman:BMS: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Seattle Genetics: Consultancy; Ariad: Consultancy; Novartis: Consultancy. DeAngelo:Incyte: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Celgene: Consultancy. Kantarjian:ARAID: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation. Flinn:Celgene Corporation: Research Funding. Frankel:Stemline: Consultancy, Patents & Royalties, Research Funding. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Medeiros:Agios Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding. Pollyea:Ariad: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Other: Member of data safety monitoring board. Stone:Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Celator: Consultancy; Celgene: Consultancy; Juno: Consultancy; AROG: Consultancy; Merck: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Karyopharm: Consultancy. Yen:Agios Pharmaceuticals: Employment, Equity Ownership. Attar:Agios Pharmaceuticals: Employment, Equity Ownership. Xu:Celgene Corporation: Employment, Equity Ownership. Tosolini:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership. De Botton:Agios Pharmaceuticals: Research Funding.

Description: To develop a cytotoxic drug which targets the IL-3 receptor (IL-3R) on human AML cells we previously developed a fusion protein containing a truncated form of diphtheria toxin which lacks the native binding site (DT388) fused to human IL-3. This molecule kills leukemic progenitors from many AML patients while showing little toxicity to normal hematopoietic progenitors. However, some AML samples showed little or no cell kill after exposure to this molecule. To attempt to improve the cytotoxicity of DT388IL-3 two variants of the toxin were constructed which contain alterations in the IL-3 residues that are designed to enhance binding affinity to the IL-3R. The two variants, DT388IL3[K116W] and DT388IL3[D125-133], have substitution of a hydrophobic tryptophan group at the 116 position and an eight amino acid deletion from the C-terminus of the IL-3 molecule, respectively, while the catalytic and translocation domains of DT388 remain unchanged. These variant DT388IL3 molecules and the unmodified ‘native’ fusion toxin were compared for their ability to kill AML colony forming cells (AML-CFC) from the peripheral blood of 13 newly-diagnosed AML patients and myeloid CFC from 3 normal bone marrows (NBM). AML and NBM cells were cultured for 24h with or without fusion toxin at concentrations varying between 1 and 250 ng/ml prior to plating in CFC assays. Little or no AML-CFC kill was observed for 3/13 samples. The mean % AML-CFC kill for the remaining 10 AML samples ranged from 21 – 61% for the lowest and highest concentration of native DT388IL3 tested and was significantly higher (P90% kill achieved for 6 of these at concentrations as low as 1 ng/ml. The concentration of DT388IL3[Kll6W] required to achieve ≥50% kill of AML-CFC was on average ≥5-fold lower than the concentration of native toxin required to achieve the same effect. Thus, the variant DT388IL3 molecules tested show enhanced cytotoxic activity against AML progenitors with little change in the toxicity profile against normal hematopoietic precursors. In particular, the DT388IL3[K116W] variant warrants further testing against more primitive normal and leukemic progenitors as a potentially promising new therapeutic agent for AML. Such studies are underway.

Description: Patients with relapsed AML over the age of 60 have a poor prognosis. Gemtuzumab ozogamicin (GO) has been approved for older pts in first relapse, although many pts who attain complete remission (CR) do not fully recover normal platelet count (so-called CRp). In vitro studies have shown that oblimersen down-regulates Bcl-2 in AML cells and enhances apoptotic cell death induced by GO. We conducted a Phase 2 study to evaluate the safety and efficacy of GO combined with oblimersen for older pts with AML. Eligibility requirements included: age ≥ 60 yrs; AML in 1st relapse; ≥ 3 mos 1st CR duration; ≥ 25% CD33-positive AML cells. Pts received oblimersen at a dose of 7 mg/kg/d for 7 days by CIV beginning on days 1 and 15; GO was given at a dose of 9 mg/m2 IV over 2 hrs on days 4 and 18. A total of 48 pts were enrolled (ITT population), all of whom received at least 1 dose of oblimersen; 9 pts failed to receive the required 2 doses of GO (per-protocol population, n=39). The median age was 67 (range, 59 to 88 yrs). Duration of 1st CR: 〈 6 mos: 7 pts; (15%); 6 to 12 mos: 29 pts (60%); 〉 12 mos: 12 pts (25%). No. of prior regimens: 1 (17 pts, 35%); 2 or 3 (26 pts, 54%); ≥ 4 (5 pts, 10%). Among treated pts, 79% completed 21 days of protocol therapy. Overall, 12 pts achieved a major response, either CR (n=5) or CRp (n=7), for an ITT response rate of 25% and a per-protocol response rate of 31%. The median time to remission was 52 days. Ten of the 12 responders survived 〉 6 mos, whereas only 6 non-responders survived ≥ 6 mos. Serious adverse events for the oblimersen/GO combination were qualitatively similar to those reported for GO alone and included among other reactions: Grade 3-4 febrile neutropenia (42%) or thrombocytopenia 33%; nausea; fever; rigors, and dyspnea. Treatment-emergent adverse reactions led to discontinuation of protocol therapy in 10 pts (21%). The most common serious adverse event was febrile neutropenia (25%). One pt (2.1%) died during treatment (sepsis) and 16 pts (33%) died within 30 days of last study medication (infection, bleeding, respiratory failure, progressive AML, and other disease-related complications). No episodes of VOD were observed. Oblimersen can be safely combined with GO; however, pts enrolled in this study appear to have had more unfavorable characteristics at entry compared with prior studies using GO alone in pts with relapsed AML. Therefore, assessment of an incremental benefit from the addition of oblimersen will require a randomized trial.

Description: Over-expression of Bcl-2 has been linked to acquired dex resistance in MM cells. Conversely, reduction of Bcl-2 using oblimersen has been shown to enhance dex-induced apoptosis in MM cell lines and in fresh MM cells in culture (Liu et al., Blood101:4105, 2003). Preliminary non-randomized clinical studies have suggested that oblimersen may potentiate the activity of VAD and dex/thalidomide in patients (pts) with resistant MM. We have conducted a randomized, multinational, Phase 3 trial of pts with advanced MM using dex given with or without oblimersen. Eligibility requirements included: relapsed or refractory MM; measurable M-protein in serum or urine; ≤ 6 prior regimens; ECOG PS ≤ 3; serum Cr ≤ 1.5 mg/dL; ANC 〉 1,000/ml; plts ≥ 50,000/ml. Exclusions: previous allogeneic transplant; other significant medical disease. Pts were stratified according to number of prior treatments (1 or 2 vs. ≥ 3 regimens), prior autologous stem cell transplant (yes/no), and primary resistance to vs. relapse from primary treatment. All pts received dex 40 mg p.o. x 4 days during weeks 1, 2 and 3. Pts randomized to oblimersen received 7 mg/kg/d x 7 days by IV infusion, beginning 3 days before dex treatment during the 1st and 3rd weeks, and during all subsequent dex cycles. Beginning on week 5, additional 4-day dex cycles were repeated in stable or responding pts every 3 weeks, for a maximum of 12 months. All pts received prophylactic H-2 antagonists, TMP/SMZ, and a bisphosphonate. Response assessments were conducted prior to each treatment cycle. The primary endpoint of the study was to compare time-to-disease progression between the 2 treatment groups. Secondary endpoint comparisons included overall survival, event-free survival at 6 months, overall response rates, response duration, clinical benefit, and safety. A total of 224 pts were randomized into the study. All pts have completed 〉 12 mos follow-up, and final results of this trial will be presented.