ALBERT

Description: Cutaneous T cell lymphoma—CTCL is a malignancy of skin-tropic T cells. CTCL cells have ubiquitous overexpression of CD3. Although uncommon, CTCL has been estimated to affect 1,500 patients per year in the United States. There are multiple approved systemic therapies for CTCL, but responses are brief lasting months. Allogeneic stem cell transplantation may provide long-term remissions, but is suitable for only rare CTCL patients. Overall, CTCL has a long clinical course with relentless progression over months to years with estimated median survival of 3-5 years for stage IB-IIB patients. The CD3 targeted agent, Resimmune, was synthesized and prepared for clinical use. It consists of the catalytic and translocation domains of diphtheria toxin fused to two anti-human CD3 Fv fragments. DNA encoding Resimmune protein was integrated into the Pichia pastoris genome, and recombinant protein was produced in Pichia pastoris via the secretory route (Woo, Protein Expr Purif 25, 270, 2002). Protein was purified by anion exchange and size exclusion chromatography. The CD3+ Jurkat cell line incubated with Resimmune yielded an IC50 for protein synthesis inhibition of 0.017pM. The CD3- Vero cell line incubated with Resimmune showed an IC50 〉10pM. Mice, rats, and monkeys given total doses of 〉200mg/kg over four days showed only transient transaminasemia without histopathologic tissue injury or clinical signs or symptoms (Woo, Cancer Immunol Immunother 57, 1225, 2008). In a mouse model with human CD3e transfected lymphocytes, four logs of antigen positive cells were reproducibly depleted from nodes and spleen with 100mg/kg total dose of Resimmune (Thompson, Protein Eng 14, 1035, 2001). Based on these findings, a phase 1 study was initiated and this report serves to update the results of a single cycle of Resimmune given at 2.5-11.25mg/kg 15 min IV infusion twice daily for 8 doses to 18 CTCL patients. There were 10 females and 8 males with ages 20-81 years. Two patients were naïve to systemic therapies, and all others had failed 1-4 prior treatments including interferon, bexarotene, gemcitabine, vorinostat, chlorambucil, etoposide, pralatrexate, doxil, romidepsin, methotrexate, CHOP, and brentuximab vedotin. None of the Resimmune treated CTCL patients had dose-limiting toxicities. Side effects were mild-moderate and transient with fevers, chills, nausea, transaminasemia, hypoalbuminemia, lymphopenia, reactivation of EBV and CMV, and hypophosphatemia. Toxicities responded to antipyretics, anti-emetics, albumin infusions, rituximab treatment and valgancyclovir. Among measured patients, there was a 3 log decline in normal, circulating T cells by day 5 that recovered by day 14. Because of vascular leak syndrome toxicities in non-CTCL patients, the MTD was defined as 7.5mg/kg x 8 doses. Cmax ranged from 1.9-40.7ng/mL and half-life from 5-66min. Pretreatment anti-DT titers were 0.9-251mg/mL and day 30 post-therapy increased to 5-4059 mg/mL. 17 CTCL patients were evaluable for response. There were six responses for a response rate of 35%. There were four CRs (24% CR rate). Three of the CRs are over 4-years duration. Patients with IB or IIB disease and mSWAT

Description: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematologic malignancy derived from plasmacytoid dendritic cells. The clinical presentation of BPDCN typically involves the skin at outset and invariably progresses to a leukemic phase with or without lymph node and splenic involvement. BPDCN blasts have a distinctive phenotypic appearance with ubiquitous overexpression of CD4, CD56, and CD123 (interleukin-3 receptor [IL-3R]). Although rare, BPDCN has been estimated to affect at least two thousand patients in the United States and Europe annually. There is no standard therapy for BPDCN, but treatment usually incorporates intensive combination chemotherapy, occasionally with allogeneic stem cell transplant. Treatment-naïve patients generally respond to these measures, but disease-free survival is brief, and most patients relapse with chemo-resistant disease. Despite aggressive upfront therapies, BPDCN has a dismal prognosis with estimated median survival of 9-14 months. SL-401, a novel biologic targeted therapy directed to IL-3R, is being developed to treat BPDCN, acute myeloid leukemia (AML), and several other IL-3R-expressing hematologic malignancies. SL-401, which is comprised of IL-3 conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis, has demonstrated ultra-high anti-tumor potency against BPDCN cell lines and primary BPDCN tumor cells, with IC50 values in the femtomolar (10-15 M) range and robust activity after treatment of an in vivo model of human primary BPDCN cell engraftment (Angelot-Delettre et al; ASH 2013). This report serves to update the results of SL-401 treatment in BPDCN patients who are participating in a Phase 1/2 study of SL-401 administered as a single cycle (15 minute infusion daily for 5 days). To date, 6 subjects with BPDCN (5 male/1 female; ages 35-72 years) received a single cycle of SL-401. The BPDCN blasts of all 6 patients expressed CD123 (IL-3R) as well as CD4 and CD56. Five patients had failed previous chemotherapy regimens, with 3 of these subjects also having received allogeneic stem cell transplantation, whereas one patient was treatment naïve. There have been no serious adverse events. Two patients had SL-401-related Grade 3 liver function test (LFT) elevations that recovered to Grade ≤2 within 24 hours and one patient had a brief episode of SL-401-related Grade 3 neutropenia and thrombocytopenia; all other SL-401-related adverse events (AEs) were Grade ≤2. One patient was not evaluable for response. To date, 5 (100%) of the 5 evaluable patients have had major responses. All five responding patients were treated with SL-401 at 12.5 µg/kg/day for 5 days, and experienced either a complete response (CR; 4 patients) or a partial response (1 patient). The CRs included disappearance of BPDCN in the skin, bone marrow, peripheral blood, spleen, and lymph nodes. As of August 2013, CR durations following a single cycle of SL-401 treatment are 11+ (ongoing), 5, 3, and 1 months; the PR duration is 1 month. Given these promising clinical responses to this targeted therapy, additional BPDCN patients are being accrued to this study and a pivotal program will begin in 2014. Disclosures: Frankel: Stemline Therapeutics: Research Funding. Woo:Angimmune: Patents & Royalties, Research Funding. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Description: H65-RTA is an immunoconjugate that consists of the A chain of ricin (RTA), a ribosomal-inhibiting protein, coupled to a murine monoclonal antibody (H65) directed against the pan-T-cell antigen CD5. The CD5 antigen is heterogeneously expressed on cutaneous T-cell lymphoma tumor cells, but is not expressed on normal cells except lymphocytes. A phase I trial was therefore conducted in which 14 patients with cutaneous T- cell lymphoma progressive on other therapies were treated with up to three cycles of H65-RTA. The maximal tolerated dose (MTD) of H65-RTA was 0.33 mg/kg/d administered intravenously for 10 days as defined by dyspnea at rest at higher doses. Other reversible side effects included myalgia, mild hypoalbuminemia with weight gain, pedal edema, fatigue, fevers, and chills. Six patients received more than one cycle of H65- RTA without increased side effects compared with the first cycle. Pharmacokinetic analysis showed that peak serum drug levels were dose- dependent, and ranged from 1.13 to 5.56 micrograms/mL, with a terminal half-life ranging from 1.0 to 2.9 hours. The development of antibodies against the immunoconjugate was associated with a lower peak drug level, but not with enhanced side effects. Partial responses lasting from 3 to 8 months were documented in four patients. Three of the responding patients received more than one cycle of H65-RTA in the presence of anti-immunoconjugate antibodies. The results from this phase I trial suggest that H65-RTA is an active drug in the treatment of cutaneous T-cell lymphoma. The immunoconjugate may be safely administered repeatedly, even in the presence of anti-immunoconjugate antibodies, with responses noted. Additional studies at the MTD are needed to define the response rate in this disease.

Description: Abstract 3625 Background: SL-401 is a novel biologic targeted therapy, comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis, directed at the interleukin-3 receptor (IL-3R). IL-3R is overexpressed on leukemia blasts and cancer stem cells (CSCs) relative to normal hematopoietic cells. Since SL-401 uniquely targets both the leukemia blasts (tumor bulk) and CSCs, it would be expected to induce tumor regression (anti-tumor bulk effect), as well as inhibit tumor repopulation (anti-CSC effect), thereby improving survival. SL-401 has been evaluated in a Phase 1/2 clinical trial in patients with advanced hematologic cancers. In this study, SL-401 has demonstrated objective clinical responses, including durable complete responses (CRs) and protracted overall survival (OS) in patients with heavily pretreated AML. The current report is a final analysis of the patients with AML or MDS. Study Design: Seventy-eight patients with advanced hematologic cancers, including relapsed or refractory AML (n = 59), de novo AML unfit for chemotherapy (n = 11), high-risk MDS (n = 7), and other (n = 1), were enrolled in a multicenter study. Among the patients with relapsed or refractory AML, the numbers of patients receiving SL-401 as 2nd, 3rd, or 〉3rd line therapy were 24, 16, and 19, respectively. The median (range) age for AML patients was 65 (7, 84) years. Patients received SL-401 as a 15-minute intravenous infusion in one of two dosing regimens for a single cycle to determine the maximum tolerated dose (MTD) and assess antitumor activity. In Regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. In Regimen B, 33 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses. Results: A single cycle of SL-401 demonstrated single agent activity in patients with relapsed or refractory AML, including 2 durable CRs of 8 and 〉25 months duration and 5 partial responses (PRs). OS was also notable among patients who received one cycle of SL-401 as ≥3rd line therapy for AML; the median OS was 3.6 (2.3, 6.1) months. Moreover, at therapeutically relevant doses, defined as the MTD or one or two dose levels below the MTD (9.4, 12.5, or 16.6 μg/kg/day), the median OS among AML patients who received SL-401 as ≥3rdline therapy (n = 16) was 5.6 (2.5, 10.8) months. These OS values compared favorably to historical results of 1.5 months for patients treated with standard chemotherapy. SL-401 was well tolerated. The MTD was not achieved with Regimen A, whereas the MTD for Regimen B was 16.6 μg/kg/day, with manifestations of capillary leak syndrome, including hypoalbuminemia and edema, as the dose-limiting toxicity (DLT) at the 22.1 μg/kg/day dose level. Transient (i.e., lasting ≤2 weeks) transaminase elevations were among the most common ≥Grade 3 AEs. Notably, there was no evidence of treatment-related bone marrow suppression. Conclusion: SL-401 demonstrated single agent anti-tumor activity and was well tolerated in patients with advanced AML. Improved survival was observed among patients who received a single cycle of SL-401 as ≥3rd line treatment, a disease setting in which there is no standard therapy. SL-401 may be an attractive treatment option for these patients given their tendency to be myelosuppressed and therefore are often poor candidates for myelosupressive therapies that have limited benefit on clinical response and survival in this setting. Based on these positive findings, SL-401 will be advanced into a randomized Phase 2b trial to treat patients with AML in the 3rd line setting. Patients will be randomized to treatment with either multiple cycles of SL-401 or physician's choice, which will consist of available standard therapeutic agents. In addition, the efficacy and safety of SL-401-based combination therapy will also be studied in earlier lines of AML given the lack of overlapping toxicities with existing hematologic cancer therapies. Disclosures: Konopleva: Stemline Therapeutics: Research Funding. Cirrito:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Hoberman:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Consultancy, Equity Ownership. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Frankel:Stemline Therapeutics: Research Funding.

Description: Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.