O’Connor, Owen A.

Abstract Introduction The phagocytic activity of macrophages is regulated by activating ("eat") and inhibitory ("do not eat") signals. Under normal physiologic conditions, the ubiquitously expressed cell surface antigen CD47 suppresses phagocytosis by binding to signal regulatory protein alpha (SIRPα) on macrophages. It is hypothesized that overexpression of CD47 by cancer cells enables immune evasion. Blockade of CD47 results in phagocytosis of cells bearing "eat" signals and primes effective anti-tumor T cell responses. TTI-621(SIRPαFc)is a soluble recombinant fusion proteinconsisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1designed to both: 1) block the CD47 "do not eat" signal, and 2) engagemacrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity.In vitro, TTI-621 binds to normal human cells, platelets, a wide range of human primary tumor cells and cell lines, but only minimally to human erythrocytes. TTI-621 selectively promotes macrophage-mediated phagocytosis of hematologic and solid tumors over that observed with normal monocytes, and exhibits antitumor activity in xenograft mouse models. Methods A first-in-human, phase 1, open label, multicenter study (NCT02663518) is ongoing to evaluate the safety and tolerability, and to identify the maximum tolerated dose of TTI-621 in patients (pts) with relapsed/refractory lymphomas using a 3+3 dose-escalation design. Once the optimal dose has been determined in the dose-escalation phase, multiple expansion cohorts will be enrolled comprising pts with various relapsed/refractory hematologic malignancies. Assessments include peripheral receptor occupancy, serum cytokine levels, pharmacokinetics, and immunogenicity. Eligible pts are adults with advanced, measurable, hematologic malignancies, who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are required to have baseline hemoglobin ≥10 g/dL, platelets ≥75 x 109/L, and be transfusion- and growth factor-independent. Pts with cutaneous T-cell lymphoma, high-grade lymphoma, and acute promyelocytic leukemia are excluded. TTI-621 is administered IV once weekly at protocol-defined doses. Treatment may continue until disease progression or unacceptable toxicity. Results Eleven pts (6M/5F, age 21-72 years) have been enrolled as of the data cut-off date of 28 July 2016. Lymphoma diagnoses included Hodgkin (N=4), diffuse large B cell (DLBCL) (N=4), follicular (N=2), and mantle cell (N=1). Treatment has been reasonably well tolerated by pts in the 0.05 mg/kg (N=3), 0.1 mg/kg (N=3), and 0.3 mg/kg (N=5) dose cohorts. The majority of pts experienced mild to moderate infusion-related events. Hemoglobin levels have remained stable or improved with treatment. Transient, dose-dependent decreases in platelets and leukocytes occurred in the hours following infusion in all pts without clinical sequelae. The 0.3 mg/kg dose was associated with reversible, dose-limiting toxicity (DLT) in 2 of 5 pts: one pt with G3 elevated ALT/AST and G4 platelet count, and a second pt with G4 platelet count who was transfused. Dosing at 0.2 mg/kg is now being explored. Aside from the DLTs and 2 non-DLT G3 platelet count (all in 0.3 mg/kg cohort), treatment-related adverse events have been ≤G2. CD47 receptor occupancy increased with each cohort, peaking at the end of infusion and remaining detectable 24 hrs after the 1st infusion in Cohort 3. Macrophage-associated cytokines, including MIP-1α and MIP-1β, increased during the 4 hrs after infusion. Six pts continue to receive weekly infusions of TTI-621; one pt with DLBCL and another with FL have experienced progression-free intervals of 161 and 70 days, respectively. Conclusions TTI-621 has been reasonably well tolerated. Pts retained stable hemoglobin levels consistent with minimal drug binding to erythrocytes. Manageable, dose-dependent thrombocytopenia was likely due to increased phagocytic clearance of platelets. TTI-621 binds to CD47+ cells in a dose-dependent manner, potently yielding increases in cytokines associated with augmented phagocytic activity. Enrollment continues at the 0.2 mg/kg dose level; updated data will be provided at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. O'Connor:Bristol Myers Squibb: Research Funding; Spectrum: Research Funding; TG Therapeutics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; TG Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Irwin:Hoffmann La Roche: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Sievers:Seattle Genetics: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership; MEI Pharma: Consultancy.

Abstract INTRODUCTION: PR-171 is a novel, irreversible proteasome inhibitor under investigation for the treatment of hematological malignancies. In preclinical studies, PR-171 was well tolerated in rats and monkeys when given daily × 5 (QDx5), every two weeks. Proteasome inhibition determined in blood and other tissues one hour after dosing at the maximum tolerated dose (MTD) was >80%. Despite the irreversible mechanism of action, the half-life of recovery of proteasome inhibition in tissues was approximately 24 hours. PR-171 was effective in suppression of tumor growth in xenograft studies in mice when administered QDx2 every week for three weeks. Two phase I dose-escalation studies have been initiated, aimed at determining the safety, tolerability, and clinical response to PR-171. METHODS: Two different dose-intensive schedules were employed in these phase I studies. In PX-171-001, PR-171 was administered on a two week cycle, QDx5 with nine days rest, while in PX-171-002, PR-171 was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. The objective of these studies was to evaluate the safety and effectiveness of single-agent PR-171 administered according to a modified Fibonacci dose escalation scheme in cohorts of three. Patients with multiple myeloma (MM), non-Hodgkin Lymphoma (NHL), Hodgkin disease, or Waldenstrom’s Macroglobulinemia who received two or more prior treatments were eligible. RESULTS: Both studies were initiated with a dose of 1.2 mg/m2. Thus far, a total of 15 and 23 subjects have been enrolled in PX-171–001 and -002, respectively. PR-171 has been well tolerated at the highest doses thus far, 8.4 and 15 mg/m2, respectively. Proteasome inhibition in whole blood at the highest dose levels exceeded 75%, and in peripheral blood mononuclear cells inhibition exceeded 65%, one hour after the first dose. There have been no dose-limiting toxicities, no adverse events (AEs) considered probably related to study medication, no dose-related increases in the incidence or severity of AEs, and no incidence of painful peripheral neuropathy on either study. Although the MTD has not yet been identified on either study, preliminary evidence of efficacy has been observed with reduction in myeloma paraprotein levels and symptomatic improvement in patients on both protocols. Eleven subjects remain on study with stable disease (SD), which has been observed in MM and NHL patients on both studies, lasting up to eight months. CONCLUSION: PR-171 is well-tolerated in relapsed and refractory MM and NHL patients at proteasome inhibition levels of more than 75%. Several subjects have achieved long-lasting SD, reduction in paraprotein levels or symptomatic improvement. Further data from these ongoing trials will be discussed at the meeting.

Background:Despite advances in the treatment of lymphoma in recent years, unmet medical needs remain, particularly for patients with R/R disease and rarer subtypes of non‐Hodgkin lymphoma (NHL). The alkylating deacetylase inhibitor tinostamustine (EDO‐S101) is a novel multi‐action therapy that is designed to improve drug access to DNA strands, and at the same time induce DNA damage and counteract its repair in cancer cells.Aims:Here we report findings from the dose‐escalation stage of a Phase I first‐in‐human study to evaluate the safety and pharmacokinetics, and to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), of tinostamustine in patients with R/R lymphoid malignancies (NCT02576496).Methods:Patients were recruited using a standard 3+3 design, with the first cohort receiving 20 mg/m2 tinostamustine administered iv over 60 minutes, with six ascending cohorts, to a maximum dose of 120 mg/m2. Dose‐limiting toxicities (DLT) were defined as: any Grade (G) 3 or 4 non‐haematological toxicity (excluding alopecia and easily correctable electrolyte abnormalities); nausea, vomiting or diarrhoea ≥10 days despite aggressive symptomatic treatment; G4 neutropenia or thrombocytopenia for ≥7 days; any G2 or more toxicity for >3 weeks; any toxicity resulting in a delay of the next dose administration (Cycle 2 Day 1 ≥14).Results:A total of 27 patients with lymphoid malignancies were enrolled into the study, 10 of these patients were diagnosed with R/R Hodgkin lymphoma (HL) and 17 with NHL, including peripheral T‐cell lymphoma and diffuse large B‐cell lymphoma. The MTD of tinostamustine was determined to be 100 mg/m2; shorter infusion times were evaluated in three cohorts of patients, but the recommended infusion time was confirmed as 60 minutes. Safety findings for each dose cohort for HL and NHL patients were mainly haematological toxicities: G3/4 thrombocytopenia, neutropenia and leucopenia, with incidence increasing with increasing dose. One patient experienced a G3 allergic reaction. Signals of efficacy were observed among the 27 patients with lymphoma (overall response rate [ORR] 41% [11 patients]; clinical benefit rate [CBR] 67% [18 patients]). The best response, as determined by the Investigator, was complete response (CR; 3/27 patients [11%]), which was observed in one patient with HL and two with NHL; partial response (PR; 8/27 patients [30%]) and stable disease (SD; 7/27 patients [26%]) were also observed. Nine of the 27 patients (33%) had disease progression.Summary/Conclusion:Administration of tinostamustine on Day 1 of a 21‐day cycle was well tolerated with signals of efficacy in patients with both HL and NHL, including rare forms of NHL such as peripheral T‐cell lymphoma. The RP2D for tinostamustine in lymphoid malignancies, depending on patient platelet count at treatment initiation, was determined as 80 mg/m2 for those with >100 x 109/l platelets, and 100 mg/m2 for those with ≥200 x 109/l platelets. This will be applied in the second phase of this study, where patients will be recruited into one of five different cohorts.

Key PointsThe outpatient BV and bendamustine regimen is highly active as first salvage therapy in relapsed/refractory HL, with manageable toxicity. The CR rate of 73.6% exceeded those reported for standard chemotherapy regimens, and post-ASCT outcomes generally appeared excellent.

Abstract Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patientsmostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses 11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenstrm's macroglobulinemia). Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing. (Clin Cancer Res 2009;15(22):708591)