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This phase 1 study evaluated safety, tolerability, and preliminary efficacy of obinutuzumab in combination with venetoclax in patients with previously untreated grade 1-3a follicular lymphoma in need of systemic therapy. Two DLs of venetoclax were evaluated with an expansion cohort at the recommended phase 2 dose. Twenty-five patients were enrolled. The recommended phase 2 dose was venetoclax 800 mg OD continuously for 6 cycles starting on day 2 of cycle 1, with obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6, followed by obinutuzumab maintenance every 2 months for 2 years. Only 1 patient had a DLT consisting of grade 4 thrombocytopenia after the first obinutuzumab infusion. Neutropenia was the most common adverse event of grade ≥3 at least possibly attributed to study treatment. Twenty-four patients were evaluable for response after cycle 6 by computed tomography (CT) and 19 by positron emission tomography/CT (PET/CT): overall and complete response rates were 87.5% (95% CI, 67.6% to 97.3%) and 25% (95% CI, 9.8% to 46.7%) in the CT-evaluated patients and 84.2% (95% CI, 60.4% to 96.6%) and 68.4% (95% CI, 43.4% to 87.4%), respectively, in the PET/CT-evaluated patients. One-year progression-free survival was 77.8% (95% CI, 54.6% to 90.1%) and 79% (95% CI, 47.9% to 92.7%) for CT and PET/CT-evaluable patients, respectively, whereas progression-free survival at 30 months was 73.2% (95% CI, 49.8%, 87.0%) as assessed by CT and 79.0% (95% CI, 47.9%, 92.7%) by PET/CT. Despite the activity observed, our results do not support further development of the combination in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02877550.

Rationale: Overcoming proteasome inhibitor (PI) resistance is a challenge in multiple myeloma (MM) therapy since most MM patients ultimately develop PI resistance. Induction of excessive activation of the unfolded protein response (UPR) is the major mechanism of PI-induced cytotoxicity in MM. The UPR is a complex transcriptional response that balances biosynthesis, folding and proteasomal destruction of cellular protein. UPR inactivation results in PI resistance in vitro, and MM cells with low UPR activation accumulate and drive the relapse in PI-resistant MM patients. Pharmacologic activation of the UPR overcomes PI-resistance in preclinical models of MM and provides an option for clinical testing. The HIV protease inhibitor nelfinavir (NFV) has UPR-inducing activity via an unknown mechanism that may involve interference with regulatory proteases in the UPR and/or proteasome activity. NFV has single agent activity in MM and sensitizes MM and AML cells for PI treatment in vitro and in vivo. Methods: We performed a multicenter phase I dose escalation study to assess safety and recommended dose for phase II of NFV in combination with bortezomib (BTZ) in patients with advanced hematologic malignancies, and to detect signals for activity. NFV was given d 1-14 twice daily p.o. at the dose levels 1250 mg (DL0), 1875 mg (DL1) and 2500 mg (DL2), BTZ was dosed 1.3 mg/m2 d 1, 4, 8, 11 i.v. in 21 day cycles. The first treatment cycle was preceded by one week of NFV monotherapy for assessment of pharmacokinetic/pharmacodynamic parameters (NFV plasma concentrations, proteasome activity and expression of UPR-related proteins in peripheral blood mononuclear cells (PBMC)). Patients were treated for 3 cycles per protocol with the option to receive up to a total of 7 cycles. Results: 12 patients were treated in the dose escalation cohort (median age 58 years; 8 patients with MM, 1 each with ALL, AML, DLBCL, MCL) for an average of 2.6 cycles. All MM patients had received prior BTZ. DLT was determined in cycle 1 in which 93 % of planned dose was delivered. One DLT was observed (G4 ALT elevation at DL2 that spontaneously resolved). Toxicity was mostly mild, could be handled symptomatically, and did not lead to study drug discontinuation except for one case of thrombocytopenia. Diarrhoea G1-2 was the most frequent toxicity observed. Ten patients were evaluable for best response while on trial therapy after having received at least one full cycle. Of these, three patients achieved a PR (1 MCL, 2 MM), 4 remained in SD for at least 2 cycles (2 MM, 1 AML, 1 ALL), while 3 progressed (2 MM, 1 DLBCL). Peak NFV plasma concentrations during monotherapy were in the dose range putatively required for UPR activation, tended to be higher in patients treated at DL1, compared to DL2 (means 13.3 vs. 8.9 mM, p=0.08) and were significantly higher during NFV monotherapy than during combination therapy with BTZ (means 9.24 vs. 6.60 mM, p=0.04), suggesting induction of NFV clearance either by autoinduction, concomitant BTZ application, or both. Pharmacodynamic analysis revealed upregulation of proteins related to UPR-induced apoptosis by NFV monotherapy in PBMC (CHOP +56%, p=0.008; PARP +57%, p=0.04, n=10). Activity of the BTZ-insensitive proteasome b2 subunit in PBMC decreased (-16%, p=0.01) during NFV monotherapy, compared to baseline, as did the BTZ-sensitive b1/b5 subunit (-17%, p=0.001). To detect additional signals for activity, an extension cohort of 6 heavily pretreated MM patients that had shown BTZ-resistance during the past 12 months and were in addition lenalidomide-resistant was treated at the recommended dose (DL2). Three of these patients achieved a PR and 2 a MR, while 1 showed PD with a mean of 4.3 cycles administered. Overall, 12 MM patients could be evaluated for best response while on therapy with BTZ + NFV in this study, of which 5 achieved a paraprotein reduction of > 50% compared to baseline (figure 1). Conclusion: Nelfinavir 2500 mg p.o. twice daily induces UPR activation and proteasome inhibition. It can safely be combined with bortezomib (1.3 mg/m2 d 1, 4, 8, 11) to potentially increase bortezomib sensitivity of hematologic malignancies. The combination yields promising clinical activity signals in patients with bortezomib-resistant myeloma. Figure 1: Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Figure 1:. Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Disclosures Off Label Use: the presentation will include off label use of nelfinavir as investigational medicinal product (IMP). Hitz:Celgene: Research Funding.

Abstract 2956 Introduction: The HIV protease inhibitor nelfinavir has anti-myeloma activity in mice; it is approved at the 1250 mg bid dose for oral treatment of HIV. We performed a phase I dose escalation trial of nelfinavir in combination with bortezomib in patients with advanced hematologic malignancies. Methods: During cycle 1 (28 days), trial treatment consisted of 1 week nelfinavir monotherapy, followed by nelfinavir in combination with standard dose bortezomib (1.3 mg/m2i.v. day 8, 11, 15, 18), while cycles 2 and 3 (21 days each) consisted of 2 weeks nelfinavir in combination with bortezomib (day 1, 4, 8, 11). Non-progressing patients could continue therapy for up to 4 additional cycles with the same regimen as cycles 2 and 3. Nelfinavir dose was escalated in a 3+3 design over 3 dose levels (1250, 1875, 2500 mg bid). Dose limiting toxicity (DLT), the primary endpoint, was grade 3–4 non-hematological toxicity (excluding grade 3 bilirubin/alanine aminotransferase (ALT) or hyperlipidemia reversible within 2 weeks) or severe hematologic toxicity unrelated to the underlying disease during cycle 1. Secondary endpoints included pharmacodynamic and pharmacokinetic assessments during cycle 1 at baseline, nelfinavir monotherapy and after application of nelfinavir and bortezomib in combination, as well as signals for activity. Results: Twelve evaluable patients were registered (median age 58 years; 8 male; performance status 0–1 in 10/12 patients); 8 had multiple myeloma, 2 leukemia (1 acute myeloid, 1 acute lymphoblastic) and 2 lymphoma (1 diffuse large B-cell lymphoma, 1 mantle-cell (MCL)). All myeloma patients failed both prior bortezomib and lenalidomide-containing therapy; 7/8 had progressed under prior bortezomib. One patient (2500 mg bid dose) experienced a transient grade 4 elevated ALT, categorized as DLT, which resolved within 2 weeks. The patient continued the same regimen off study without recurrent hepatic toxicity. No further DLTs occurred, thus nelfinavir 2500 mg bid was established to be safe in combination with standard dose bortezomib. One patient with highly aggressive lymphoma died from cerebral vein thrombosis; a myeloma patient experienced a non-fatal pulmonary embolism. Elevated ALT (2 patients) was the only additional non-hematological toxicity grade 3/4 observed in >1 patient. Grade 3 febrile neutropenia and grade 4 thrombocytopenia were seen in 1 and 4 patients, respectively. Best treatment response was evaluated for 11 patients (1 not evaluable). Partial response was achieved in 3 patients (2 myeloma, 1 MCL) and stable disease for at least 2 cycles of therapy in 5 patients. Overall, 4/12 patients completed >=3 cycles of treatment. Assessment of proteasome activity in peripheral blood mononuclear cells (PBMC) from treated patients after 1 week nelfinavir monotherapy revealed inhibition of total proteasome activity in vivo by nelfinavir compared to baseline (mean inhibition, as determined by specific, quantitative intracellular affinity labeling of active proteasome subunits: 14.9 %, 95% confidence interval (CI): 8.8–23.5%, p= Conclusion: This is the first trial to report on the use of nelfinavir as an anti-neoplastic agent in patients with hematologic malignancies. It identifies nelfinavir as FDA approved, orally available drug with pan-proteasome inhibiting activity in vivo. Nelfinavir treament up to 2500 mg bid is safe as monotherapy and in combination with standard dose bortezomib. Bortezomib in combination with nelfinavir shows signals for clinical activity in individual myeloma patients that have failed bortezomib and lenalidomide-containing therapies. Nelfinavir warrants further clinical investigation in multiple myeloma, in particular in combination with proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.

Abstract 5007 Panobinostat, an orally active hydroxamic acid derivative, is a potent class I/II/IV pan-deacetylase inhibitor that has shown promising clinical activity in hematologic and nonhematologic malignancies. Patients with cancer frequently have impaired renal or hepatic function. The major clearance pathway of panobinostat is metabolism mediated by cytochrome P450 3A4 (CYP3A4) and non-CYP pathways. Panobinostat and its metabolites are excreted in similar amounts in liver (54.3) and kidneys (40.6); however, the effects of impaired renal and hepatic function on panobinostat pharmacokinetics (PK) have not yet been elucidated. This study was designed to assess whether hepatic dysfunction has an impact on the PK of panobinostat and its safety when compared with that of patients with normal hepatic function. Patients with advanced cancer, Eastern Cooperative Oncology Group performance status (PS) 0 to 2, normal bone marrow function, and serum creatinine 1.5 upper limit of normal were enrolled. Hepatic function was categorized as normal (control), mild, moderate, or severe according to the baseline aspartate aminotransferase and total bilirubin levels per National Cancer InstituteCancer Treatment Evaluation Program criteria. Serial plasma samples were collected up to 96 hours following a single PK test dose of panobinostat 30 mg and its concentrations assessed by liquid chromatography tandem mass spectrometry. PK parameters were derived from individual plasma concentrationtime data using non-compartmental analysis. One week after the PK test dose, patients started continuous panobinostat 30 mg 3 times per week every week. Dose was modified according to tolerability. Ten patients with normal, 6 mildly, and 3 moderately impaired hepatic function were enrolled. The median age was 58 years (10 male; 9 female), and 95 of the patients had PS 0 to 1. Thirteen patients (7 normal (70), 4 mild (67), and 2 moderate (67)) experienced grade 3 toxicity suspected to be drug related. Grade 3 or 4 thrombocytopenia occurred in 3 patients in the normal group (30). Grade 3 nonhematologic adverse events included fatigue (4 normal (40), 1 mild (17), 1 moderate (33)), diarrhea (2 normal (20), 1 mild (17)), nausea (3 normal (30), 1 mild (17)), and vomiting (1 normal (10), 1 mild (17)). One patient in the moderate group was discontinued from the study because of grade 3 vasculitis (purpuric rash, proteinuria, anemia, and renal dysfunction). In these heavily pretreated patients, disease stabilization was noted in 3 patients, one with endometrial cancer, one with adenocarcinoma of the lung, and one with prostate cancer. The PK results from 19 patients of this ongoing study are summarized in the table below. The currently available results suggest that the PK and safety of panobinostat are comparable between patients with normal hepatic function and those with mild or moderate liver dysfunction PK parameters, median range Normal hepatic function (n 10) Mild hepatic dysfunction (n 5TUF1-1) Moderate hepatic dysfunction (n 3) Tmax (hr) 2 0.5-7 2 0.5-2 2 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{1}{4}\) \end{document} Cmax (ng/mL) 19.0 6.9-61.8 27.0 17.4-56.3 31.2 15.1-37.3 AUC0-inf (nghr/mL) 184 42.7-347 285 75.8-342 276 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{161}{425}\) \end{document} t1/2 (hr) 28.9 14.2-36.6 25.0 17.5-39.3 23.6 16.3-40.6 One patient was excluded from the PK analysis because of emesis. AUC0-inf, area under the concentration-time curve from zero to infinity; Cmax, maximum concentration; t1/2, half-life; Tmax, time to maximum plasma concentration. Disclosures: Hess: Novartis: Equity Ownership. Porro:Novaratis Pharma AG: Employment. Hengelage:Novartis Pharma AG: Employment, Equity Ownership. St-Pierre:Novartis Pharma AG: Employment. Gazi:Novartis Pharma AG: Employment. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Woo:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Sharma:Novartis: Research Funding.

Abstract 5001 Panobinostat is a potent class I/II/IV oral pan-deacetylase inhibitor which has shown promising clinical activity in patients with multiple myeloma and myelofibrosis, some with compromised renal and hepatic functions. The metabolism mediated by cytochrome P450 3A4 (CYP3A4) and non-CYP pathways is the major clearance pathway of panobinostat, with drug and metabolites being excreted in nearly similar amounts by liver/bile (54.3) and kidneys (40.6). However, the effects of impaired renal and hepatic function on panobinostat pharmacokinetics (PK) have not been elucidated. This study was designed to assess the impact of renal dysfunction on the PK and safety of panobinostat when compared to that of patients with normal renal function. Patients with advanced cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2, AST/ALT 2.5 ULN, normal bone marrow, and varying degrees of renal function were enrolled. Renal function was categorized as normal (as control), mild, moderate, or severe according to baseline 24-hour urine creatinine clearance (CrCL). Serial blood and urine panobinostat samples collected up to 96 and 24 hours, respectively, following a single PK test dose of 30 mg panobinostat were assessed for plasma and urine concentrations by liquid chromatography tandem mass spectrometry. PK parameters were derived from individual plasma or urine concentrationtime data using non-compartmental analysis. The following week, patients continued to receive panobinostat 30 mg orally 3 times a week. Dose was modified according to tolerability. PK results from 19 patients (15 male, 4 female) in this ongoing study are tabulated below. Median age was 66 years, and 13/19 patients had ECOG PS 1. Safety results were available in 18 patients. The most frequent drug-related adverse events (AEs) were grade (Gr) 34 thrombocytopenia in 7 patients (2 normal, 2 mild, 3 moderate) and Gr 3 fatigue in 5 patients (1 normal, 1 mild, 3 moderate). Other drug-related Gr 3 AEs included nausea, diarrhea, and hyperphosphatemia (1 normal patient each); asthenia and anemia (1 mild patient each); and ventricular bigeminy and dehydration (1 moderate patient). Two deaths on therapy not suspected to be study drugrelated occurred in the normal group. Although efficacy is not the primary study objective, PR was noted in 1 moderate patient with bladder cancer while SD was noted in 5 patients (2 pancreatic, 1 ovarian, 1 bladder and 1 renal cancer) as best overall response in these heavily pre-treated patients. The currently available results unexpectedly showed that patients with renal dysfunction did not have higher panobinostat exposures than the control group and the PK of panobinostat did not seem to have a distinct rank-order relationship with the severity of renal dysfunctionPK parameters median rangeRenal Function ClassificationNormal n7(CrCL 80 mL/min)Mild n6(50 CrCL 80 mL/min)Moderate n6(30 CrCL 50 mL/min)Tmax (hr)1.0 0.5-41.0 0.5-41.0 0.5-2Cmax (ng/mL)36.7 30.0-107.014.4 5.8-33.522.8 9.5-52.3AUC0-inf (nghr/mL)371 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{180}{441}\) \end{document}108 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{76}{234}\) \end{document}202 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{78}{329}\) \end{document}t1/2(hr)32.9 25.2-42.836.0 23.7-55.634.3 31.4-35.4ClR/F (L/hr)1.6 0.4-2.71.4 0.5-2.82.1 0.2-3.8Xu0-24hr ( of dose)1.8 1.2-4.00.6 0.2-1.30.7 0.2-1.9 AUC0-inf, area under the concentration-time curve from zero to infinity; Cmax, maximum concentration; t1/2, half-life; Tmax, time to maximum plasma concentration; Xu0-24h, percentage of drug excreted in urine; ClR/F, apparent renal clearance. Disclosures: Sharma: Novartis: Research Funding. Valera:Novartis Pharmaceuticals: Employment. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Mires:Novartis Pharmaceuticals: Employment. Porro:Novaratis Pharma AG: Employment. Woo:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Hess:Novartis: Equity Ownership.

Background: AS703569 is a novel, orally bioavailable, potent ATP-competitive, small molecule that inhibits all three aurora kinase isoforms (A, B, and C), and shows inhibitory activity across other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK-2, and FGFR3. AS703569 has been tested as a single agent and in combination with standard-of-care anticancer agents in leukemia cell lines, freshly isolated leukemic cells, and tumor xenograft models. The strong inhibition of proliferation and the triggering of apoptosis induced by AS703569 lead to significant anti tumor activity resulting in tumor regression or growth delay, and prolongation of animal survival. AS703569 is currently being tested in phase I studies as a single agent and in combination; the main objectives are to establish the MTD (based on dose-limiting toxicities [DLTs]) and evaluate the safety and PK/PD effects of different regimens. Study design: This is an open-label, phase I, two-arm, dose-escalation study in patients (pts) with AML, CML, MDS, and MPD. Patients were sequentially assigned to one of two AS703569 dosing regimens: Regimen 1: once daily (QD), days 1–3 and 8–10 of a 21-day cycle; Regimen 2: QD, days 1–6 of a 21-day cycle. In both treatment arms, AS703569 was administered at escalating dose levels (DL; 3, 6, 10, 15, 21, 28, and 47 mg/m2/day) using a 3+3 cohort design. Repeated cycles were permitted until disease progression or unacceptable toxicity. Patient characteristics: Pt characteristics are summarized in the Table. Pts had primary AML (n=20), secondary AML (n=13), CML (n=6), MDS (n=5), and MPD (n=1). Pts were heavily pretreated and had failed previous chemotherapy. Safety: The median number of AS703569 cycles received per pt was 2 for Regimen 1 (range 1–7) and 1 for Regimen 2 (range 1–6). In Regimen 1, at DL 7 (47 mg/m2/day, n=3), 2 subjects reported DLTs: 1 case of grade 3 diarrhea with hyponatremia and sepsis with a fatal outcome, and 1 case of grade 3 diarrhea with GI bleeding. In Regimen 2, at DL 7 (n=5), 3 subjects reported DLTs: 2 cases of grade 4 mucositis and 1 case of neutropenic infection. Consequently, the dose was de-escalated to 37 mg/m2/day for both regimens and enrollment is ongoing at this DL to confirm the MTD. Grade ≥3 toxicities reported throughout the study mainly included infections (18 pts), neutropenia and febrile neutropenia (17 pts), thrombocytopenia (15 pts), anemia (11 pts), and GI disorders including mucositis, diarrhea and GI bleeding (8 pts). Alopecia was reported in some pts. PK: Preliminary data for 37 pts (DL 1–6) show an increased exposure with dose, a Tmax of 2–4 h (range 0.5–8 h), and an effective half-life of ~10–20 h. Activity (preliminary data): In Regimen 1, 1 pt with refractory CML (mut. T315I) has received 7 treatment cycles and shown a hematological and cytogenetic response; 5 pts with AML received 5–7 cycles, 3 achieved reduction in BM and/or peripheral blasts. In Regimen 2, 1 pt with MDS received 6 cycles and achieved a PR; 2 pts with AML received 3 cycles and did not progress. Conclusions: These data indicate that AS703569, QD, days 1–3 and 8–10 every 21 days or on days 1–6 every 21 days is generally well tolerated in pts with advanced hematological malignancies. Most grade 3/4 toxicities are commonly seen in pts with advanced hematological malignancies and are in part linked to the underlying disease. A DL with an unacceptable frequency of DLTs was reached and enrollment continues at a lower DL to confirm the MTD. Early evidence of activity was observed in pts with CML, AML, and MDS. Regimen 1 Regimen 2 N 24 21 Median (range) age, years 69.5 (48–83) 71 (49–82) Sex, M/F 15/9 12/9 ECOG PS, 0-1-2 5-12-7 3-12-6 Median (range) previous lines of therapy 3 (1–6) 2 (1–6)