ALBERT

Description: Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope 〉 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb 〈 100 g/L in 38%, PLT 〈 100 x 109/L in 69% and 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in 〉 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

Description: Conventional therapy for acute myeloid leukemia (AML) consists of a combination of cytarabine and an anthracycline such as idarubicin. Currently, most patients ultimately fail treatment due to leukemia cell resistance to drug therapy. In vitro experiments have shown that the addition of a proteasome inhibitor to an anthracycline results in synergistic cytotoxicity to leukemia cells. Hence, we initiated this phase I trial in patients to see if bortezomib could be safely added to conventional treatment. Patients over age 60 with AML or any patient 18 or older with relapsed disease after a remission of at least 3 months (not refractory) were eligible. All patients received idarubicin 12 mg/m2 on days 1–3 and cytarabine 100 mg/m2 by continuous infusion days 1–7. In addition, patients received bortezomib by IV bolus on days 1, 4, 8, and 11. Cohorts of 3 to 6 patients were entered using increasing doses of bortezomib in order to determine the maximum tolerated dose (MTD). The first cohort received 0.7 mg/m2 of bortezomib with each bolus. If dose limiting toxicity (DLT) was encountered, then cohort advancement was restricted. DLTs included prolonged myelosuppression, neuropathy, and other grade 3 or 4 toxicities. Dose escalation would proceed to 1.0 mg/m2 and then to 1.3 mg/m2 if tolerated. No escalation was planned beyond 1.3 mg/m2. To date 14 patients have been entered on this study. In the first cohort of 3 patients with bortezomib at 0.7 mg/m2, a DLT due to prolonged neutropenia was encountered, so an additional 3 patients were entered at this dose level. No DLTs were encountered among these additional patients, so 3 more patients were entered with bortezomib at 1.0 mg/m2. One of these patients experienced prolonged thrombocytopenia and thus 3 additional patients were enrolled at 1.0 mg/m2. No DLTs were encountered among these additional patients, and thus the next cohort of patients with bortezomib at 1.3 mg/m2 was opened. To date, two patients have been enrolled at this dose level. The plan is to enroll a third patient at this level and to assess for possible DLTs. Among the 12 patients evaluable for response, there have been 4 patients achieving complete remission, 3 patients achieving remission without complete recovery of platelet count (CRp defined as having met criteria for CR but with 25,000–99,000 platelets/μl), 2 patients achieving a partial remission (CR but with 5–24% bone marrow blasts), and 3 patients failing to respond. In conclusion, bortezomib at 0.7 mg/m2 and 1.0 mg/m2 in the day 1, 4, 8, and 11 schedule can be added to idarubicin and cytarabine with acceptable toxicity. This study continues in an attempt to determine whether bortezomib can be escalated safely to 1.3 mg/m2 in this combination. Additional patients will be enrolled at the candidate MTD to gain confidence in the safety and activity at this level. Correlative science studies are planned.

Description: PRM-151 (PRM) is a recombinant form of Pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. PRM has broad anti-fibrotic activity in multiple preclinical models of established fibrotic diseases and no dose limiting toxicities in phase 1 trials. Myelofibrosis (MF: primary (PMF), post-essential thrombocythemia (post-ET MF), and post polycythemia vera (Post PV MF)) is a myeloid malignancy characterized by progressive bone marrow (BM) fibrosis with resultant anemia, abnormal platelet and leukocyte counts, extramedullary hematopoiesis, and a well-defined symptom complex. This study investigated the potential of PRM in MF to reduce BM fibrosis and to improve key disease features including abnormal blood counts, symptoms, and splenomegaly. MF patients (pts) with Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2, or high-risk disease and grade ≥ 2 BM fibrosis, either on no current therapy or on a stable dose of ruxolitinib (RUX) for ≥ 12 weeks and no improvement in spleen for ≥ 4 weeks, were eligible for stage 1 of this open-label adaptive trial. Assignment to one of the 4 treatment arms was per investigator and pt choice: PRM 10 mg/kg IV 1-hour infusion days 1, 3, 5, then weekly (QW) or every 4 weeks (Q4W), alone or with RUX, for 24 weeks. Primary endpoint was overall response rate by IWG-MRT (symptoms by MPN-SAF Total Symptom Score (TSS), spleen by palpation) and/or decrease in BM fibrosis by ≥ 1 grade with otherwise stable disease. BM biopsies were obtained at baseline, 3 and 6 months, and were evaluated centrally by two blinded hematopathologists. Pts with clinical benefit were allowed to continue treatment in an extension. At least one response in any arm was required for that regimen to be evaluated in Stage 2. Twenty seven pts were enrolled: 8 PRM QW, 7 PRM Q4W, 6 PRM QW + RUX, 6 PRM Q4W + RUX. Median age 67 years (52-85); 70% DIPSS Int-2 or High Risk; 52% PMF, 15% post-ET MF, 33% post-PV MF; 63% grade 3 BM fibrosis, Hemoglobin (Hgb) 〈 100 g/L in 56% and 〈 85 g/L in 26%, platelet count (PLT)〈 100 x 109/L in 52% and 〈 25 x 109/L in 30%; 22% were JAK inhibitor-naive and 52% had received a prior JAK inhibitor (not including ongoing RUX). Twenty pts completed 24 weeks of therapy; 18 continued extension treatment. PRM-151 was well-tolerated alone and with RUX; most adverse events (AEs) were Grade 1/2 and unrelated, with 3 Grade 3 possibly related AEs and 5 possibly related serious AEs. Nine of 26 evaluable pts responded, for an overall response rate (ORR) of 35%, with 4 IWG symptom clinical improvements (CI) and 6 BM fibrosis responses (Table 1), with ≥ 1 response in each arm. One pt had a CI and BM response. Reduction in BM fibrosis was associated with normal erythroid microarchitecture, normal or decreased myeloid:erythroid ratio, and fewer paratrabecular megakaryocytes, all potential surrogates of improved bone marrow microenvironment. IWG stable disease was observed in 77% of pts, with trends of clinical benefit in Hgb, PLT, peripheral blood blasts, spleen, and symptoms (Table 2). In 14 patients (54%), all parameters were stable or improved. Conclusion: PRM-151 was well-tolerated in patients with advanced MF, with no evidence of drug-related myelosuppression and encouraging trends in both clinical and histologic aspects of the disease. Reduction in BM fibrosis, stable to improved hematologic parameters, symptom responses, and stable to reduced spleen size support further development of PRM-151 in MF. Table 1 Two additional subjects had decrease in bone marrow fibrosis but progressive disease. Number of Patients BM Fibrosis Grade at Last Study Timepoint 3 2 1 BM Fibrosis Grade at Baseline 3 8 3 1 2 1 4 2 Abstract 713. Table 2 Outcome Parameter Denominator (n) Clinical Benefit Pts with Improvement (n/%) ORR (primary endpoint) All evaluable pts (26) IWG-MRT CI AND/OR reduction in BM fibrosis by ≥ 1 grade 9 (35%) Hgb Hgb 〈 100 g/L (15) ≥10 g/L increase from baseline AND no transfusions or 50% reduction in transfusions if transfusion dependent 6 (40%) PLT PLT 〈 100 x 109/L (13) 〉 100 x 109/L AND increase of ≥20 x 109/L ; increase of ≥20 x 109/L if baseline 〈 50, AND/OR increase of ≥ 10 x 109/L with discontinuation of transfusions 8 (62%) Blasts ≥ 1% peripheral blasts (14) No peripheral blasts 3 (21%) Symptoms All evaluable pts (26) ≥ 25% reduction in TSS ≥ 12 weeks 10 (38%) Spleen Palpable spleen (19) ≥ 25% decrease ≥ 4 weeks AND any decrease ≥ 12 weeks 5 (26%) Disclosures Verstovsek: Incyte: Research Funding; Astrazeneca: Research Funding; Lilly Oncology: Research Funding; Roche: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Promedior: Research Funding; Cell Therapeutics: Research Funding. Mesa:Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding; Promedior: Research Funding. Foltz:Janssen: Consultancy; Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Novartis Pharmaceuticals Corporation: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding. Ritchie:Celgene, Incyte: Speakers Bureau; Promedior: Research Funding. Hoffman:Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Pozdnyakova:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Hasserjian:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Gotlib:Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other; Sanofi: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Promedior: Research Funding.

Description: The aim of this study was to investigate whether interleukin (IL)-6 induces the production of IL-1 and tumor necrosis factor (TNF) antagonists. Serial plasma samples were obtained from cancer patients participating in phase I and II trials of recombinant IL-6 administered as a 120-hour continuous intravenous (IV) infusion. Plasma IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor p55 (TNFsRp55) levels were measured by specific radioimmunoassays (RIAs). IL-1Ra levels increased rapidly, reaching peak values (9.6 +/- 1.7 ng/mL) within 2 to 4 hours of beginning treatment. Thereafter, levels promptly declined, reaching near baseline within 24 hours despite continuation of IL-6. TNFsRp55 plasma levels increased within 4 to 8 hours after initiating treatment and increased progressively throughout the duration of therapy. IL-1 beta and TNF-alpha plasma levels were below the detection limit in all samples tested. Peripheral blood mononuclear cells (PBMC) exposed to IL-6 produced only small amounts (1.56 +/- 0.3 ng/mL) of IL-1Ra, even in the presence of exogenous soluble IL-6 receptor (gp80). TNFsRp55 levels measured in the supernatants of IL-6- stimulated PBMC were below the detection limit of the assay. Macrophages generated by culturing monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) were much more responsive to IL-6 than freshly isolated unfractionated or adherent PBMC and synthesized almost as much IL-1Ra when stimulated with IL-6 as with endotoxin. These results suggest that the antinflammatory properties of IL-6 may be due; in part, to the induction of IL-1Ra synthesis and the release of soluble TNF receptors. Our findings also suggest that tissue macrophages may be an important source of IL-6-induced IL-1Ra.

Description: Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

Description: The aim of this study was to investigate whether interleukin (IL)-6 induces the production of IL-1 and tumor necrosis factor (TNF) antagonists. Serial plasma samples were obtained from cancer patients participating in phase I and II trials of recombinant IL-6 administered as a 120-hour continuous intravenous (IV) infusion. Plasma IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor p55 (TNFsRp55) levels were measured by specific radioimmunoassays (RIAs). IL-1Ra levels increased rapidly, reaching peak values (9.6 +/- 1.7 ng/mL) within 2 to 4 hours of beginning treatment. Thereafter, levels promptly declined, reaching near baseline within 24 hours despite continuation of IL-6. TNFsRp55 plasma levels increased within 4 to 8 hours after initiating treatment and increased progressively throughout the duration of therapy. IL-1 beta and TNF-alpha plasma levels were below the detection limit in all samples tested. Peripheral blood mononuclear cells (PBMC) exposed to IL-6 produced only small amounts (1.56 +/- 0.3 ng/mL) of IL-1Ra, even in the presence of exogenous soluble IL-6 receptor (gp80). TNFsRp55 levels measured in the supernatants of IL-6- stimulated PBMC were below the detection limit of the assay. Macrophages generated by culturing monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) were much more responsive to IL-6 than freshly isolated unfractionated or adherent PBMC and synthesized almost as much IL-1Ra when stimulated with IL-6 as with endotoxin. These results suggest that the antinflammatory properties of IL-6 may be due; in part, to the induction of IL-1Ra synthesis and the release of soluble TNF receptors. Our findings also suggest that tissue macrophages may be an important source of IL-6-induced IL-1Ra.

Description: In vitro experiments have shown that the addition of a proteasome inhibitor to an anthracycline results in synergistic cytotoxicity to leukemia cells and, specifically, the leukemia stem cell. Hence, we initiated this phase I study to determine if the proteasome inhibitor, bortezomib, could be safely added to conventional treatment for acute myeloid leukemia (AML). Eligibility was restricted to patients ≥ 18 with relapsed disease after a remission of at least 3 months and patients ≥ 60 without prior treatment for AML. All patients were required to have an ECOG performance status of 0–3 and adequate cardiac, renal, and hepatic function. Patients with ≥ grade 2 peripheral neuropathy prior to enrollment were excluded. All patients received idarubicin 12 mg/m2 on days 1–3 and cytarabine 100 mg/m2 by continuous infusion days 1–7. Bortezomib was added to this regimen on days 1, 4, 8, and 11 by IV bolus. Cohorts of 3–6 patients were treated with the following doses of bortezomib: 0.7, 1.0, 1.3, and 1.5 mg/m2. An additional 6 patients were to be treated at the candidate maximally tolerated dose (MTD). Dose limiting toxicities (DLTs) were defined as prolonged myelosuppression, severe neuropathy, and other grade 3 or 4 toxicities. Dose escalation was permitted if 〈 2 DLTs were experienced in 3–6 patients at a given dose level. The study is now closed, with 30 patients entered and 24 patients evaluable at this time. The age range was 42–75 years, with a median of 65. There were 13 males and 11 females. Of these patients, 16 were ≥ 60 with previously untreated AML, of whom 4 had a prior history of MDS or MPD, 4 were ≥ 60 with relapsed AML, and 4 〈 60 with relapsed AML. Among the first 6 patients treated at 0.7 mg/m2, there was 1 DLT consisting of prolonged neutropenia. In the second cohort of 6 patients treated with 1.0 mg/m2 bortezomib, there was 1 DLT consisting of prolonged thrombocytopenia. No DLTs were encountered in 9 patients treated with 1.3 mg/m2 bortezomib. Because the MTD had not been reached, an additional cohort assessing 1.5 mg/m2 bortezomib was added. Three patients have completed treatment at this dose and no DLTs were experienced; a final 6 patients are currently undergoing treatment. There have been no significant neurologic or cardiac toxicities. There was one death within the first 45 days of protocol treatment. This occurred in the setting of febrile neutropenia in a patient previously transplanted for AML who received 1.5 mg/m2 bortezomib. Of the first 24 patients, 14 (58%) achieved complete remission (CR), 3 achieved remission without complete recovery of platelet count (CRp), 3 achieved a partial remission (6–24% BM blasts), and 4 patients failed to respond. In conclusion, bortezomib was well tolerated up to 1.3 mg/m2 in this regimen and this combination produced an encouraging remission frequency in this population of patients. A phase II study of this combination will proceed in the cooperative group setting.

Description: Introduction: The 26S proteasome is an important regulator of proteins involved in cell cycle progression, cell survival, and transcription of anti-apoptotic proteins via activation of NF-κB. Bortezomib, (VELCADE®) is a potent, selective, reversible inhibitor of the 26S proteasome with demonstrated clinical activity in multiple myeloma for which it gained FDA and EMEA approval. On the basis of encouraging phase I data in lymphoma, a phase II clinical study was undertaken to examine the efficacy and toxicity of bortezomib in pts with relapsed, refractory NHL and HD. Methods: 1.3 mg/m2 bortezomib was administered twice weekly for 2 of 3 weeks to pts who had adequate ECOG performance status (PS) 〉2, and haematological function with an absolute neutrophil count 〉1.0 x109/l (0.5 x109/l if bone marrow involvement) and platelets 〉30 x109/l. Pts were assessed for toxicity at each cycle, re-staged after 4 cycles and received up to 8 cycles of treatment. Results: 32pts, 20 male and 12 female with a median age of 58 yrs (35–75) received a total of 119 cycles of treatment. 11 pts had mantle cell lymphoma (MCL), 10 follicular lymphoma (FL), 4 Waldenstrom’s macroglobulinaemia (WM), and 1 lymphoplasmacytic lymphoma. Other diagnoses included HD (n=3), diffuse large B-cell lymphoma (n=1), ATL (n=1), and diffuse follicle centre lymphoma (n=1). Pts were heavily pre-treated with a median of 3.5 previous therapies (range 1–8) and 12 pts (38%) had received prior HDT. Sixteen pts (50%) had bone marrow involvement and 13 (40%) a raised LDH. 13 pts (40%) had a ECOG PS of 1 and 7 pts (22%) a PS of 2. The most common grade III-IV toxicities observed in patients, who received a median of 4 cycles of treatment (range 1–8), were thrombocytopenia in 14 pts (45%); fatigue in 8 pts (26%), anaemia in 5 pts (16%) and peripheral neuropathy in 2 pts (6%). Four of 11 pts with MCL initially responded to treatment, 3PR, 1 CR (ORR of 36%); one pt progressed at the end of 8 cycles having required 2 dose reductions. No patients with FL had an objective response at the outcome assessment after a median of 4 cycles (range 1–8) and within a month of completing therapy; however 4 had stable disease and 2 achieved a ‘late response’ with reduction in tumour volumes of 76.7% and 56.1% when assessed 3 mths later. Two pts with WM achieved a PR on the basis of 〉50% reduction in paraprotein, but with no change in the bone marrow. No patients with HD or other diagnoses responded to treatment. The sensitivity of tumour biopsy samples to bortezomib was examined in vitro in a CD40 ligand primary culture system in 5 pts on the clinical trial, where sensitivity correlated with clinical response. In a larger group of patients the median EC50 for MCL (n=5) was 209nM, and FL (n=8) 1311nM (p