Activating TP53 by Dual Inhibition of MDMX and MDM2
TP53 is often inactivated by mutations or other mechanisms in human cancers. Recent work has demonstrated that its endogenous inhibitor MDMX (or MDM4) is frequently overexpressed in patients with hematologic malignancies including AML, lymphoid malignancies, as well as other cancers. Pharmacological disruption of the interactions of TP53 with both its endogenous inhibitors (MDMX and MDM2) has long been sought after as an attractive strategy to restore p53-dependent tumor suppressor activity. However, selective targeting of this pathway has previously been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. More recently, pharmacological dual targeting of MDMX/MDM2 has become feasible through stapled peptides and is currently being tested in clinical trials. This presentation will discuss such MDMX/MDM2 dual-targeting strategies as well as new insights into MDMX-mediated mechanisms of tumor progression at the stem cell level, which have emerged from recent studies. Disclosures Steidl: Aileron Therapeutics: Consultancy, Research Funding; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; Celgene: Consultancy; BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding.
Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.
Abstract Background. Patients with aggressive hematologic malignancies failing at least two lines of therapy are without further standard treatment options and have a poor prognosis. Identifying effective therapies with genomic-based precision medicine is hampered by intratumor heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Next-generation functional drug screening (ngFDS) in patient samples promises to overcome these challenges, however, proof of its clinical utility is limited. Methods. We investigated the feasibility and clinical impact of ngFDS measured at single-cell resolution using high-throughput automated microscopy in blood, bone marrow, pleural effusions, or excised lymph node biopsies (Figure 1A and Valdimer G et al. Nat Chem Biol. 2017). First, the accuracy of ngFDS to predict clinical outcome was evaluated in a retrospective cohort of 20 previously untreated patients with acute myeloid leukemia (AML). Then, 48 patients with aggressive hematologic malignancies failing at least two lines of treatment were prospectively evaluated for ngFDS guided therapy, of which 17 could receive ngFDS-guided treatment. Individual ngFDS-guided treatment regimens were selected by a committee (EXALT-board) of hemato-oncologists, pathologist, and pharmacists based on top-candidate treatments identified by ngFDS, considering drug availability as well as safety profiles of single agents and previously reported combinations (Figure 1B). The majority of these patients (12/17) presented with aggressive lymphoma and had seen in median three (2-7) prior treatment lines (Figure 2A). Overall response rate (ORR) and progression-free survival (PFS) of ngFDS-guided treatment were compared with ORR and PFS for the most recent regimen (MRR) on which patients had previously progressed. Results. ngFDS accurately predicted individual clinical response of AML patients to initial therapy. From prospectively analyzed patients receiving ngFDS guided treatment the ORR-ngFDS was 88% (15/17) compared to ORR-MRR of 24% (4/17; P<0.0004). Twelve (70%) of 17 patients had a PFS ratio of ≥1.3 and the mean PFS increased 3.9-fold, from 5.7 weeks to 22.6 weeks (P<0.007) (Figure 2B). Furthermore, analysis of an independent cohort revealed that ngFDS could positively and negatively predict patients' outcome to drug treatment. Conclusions. Automatedmicroscopy-based ngFDS is feasible and accurately predicts clinical response. It can successfully guide personalized treatment of aggressive refractory hematological malignancies. Figure 1 Figure 1. Disclosures Staber: Takeda: Honoraria; Abbie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria; Amgen: Honoraria; Gilad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Snijder: Allcyte: Equity Ownership, Other: founder and shareholder of Allcyte GmbH that holds a worldwide exclusive license for and commercializes the Pharmacoscopy high content imaging technology.. Vladimer: Allcyte Gmbh: Equity Ownership. Krall: Allcyte Gmbh: Equity Ownership. Hoermann: Ariad: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Research Funding. Sperr: Teva: Honoraria; Meda: Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Phadia: Research Funding; Novartis: Other: Register. Gisslinger: Janssen Cilag: Honoraria; Takeda: Honoraria; Shire: Honoraria; PharmaEssentia: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria. Valent: Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Teva: Honoraria; Celgene: Honoraria, Research Funding; Blueprint: Research Funding. Jaeger: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Superti-Furga: Allcyte GmbH: Equity Ownership.
Background: Measuring residual disease during the continuum of care is fundamental to oncology practice. In particular, minimal residual disease (MRD) assessments and trends over time can help inform clinical management, including change in treatment regimen or treatment discontinuation. In patients (pts) with plasma cell and lymphoid malignancies, next-generation sequencing (NGS)-MRD is a valuable tool for assessing MRD and depth of response to treatment. MRD status is strongly prognostic of time to relapse and overall survival in multiple myeloma (MM), acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL). In this report, we summarize our 2-year experience with clinical implementation of NGS-MRD (clonoSEQ®) testing across a spectrum of plasma cell and lymphoid disease. Methods: This retrospective analysis summarizes our experience using the NGS-MRD Assay (Adaptive Biotechnologies, Seattle, WA) in plasma cell and lymphoid malignancies. The assay uses multiplex polymerase chain reaction (PCR) and NGS to identify, characterize, and monitor unique disease-associated sequence rearrangements or clonotypes of immunoglobulin (Ig) IgH (V-J), IgH (D-J), IgK, and IgL receptor gene sequences, and translocated BCL1/IgH (J) and BCL2/IgH (J) sequences in DNA extracted from high disease burden diagnostic (ID) and post-treatment (MRD) samples. PCR amplification bias control ensures a quantitative read-out of the full B-cell receptor repertoire present in the ID sample and provides direct measure of tumor burden. Our study included pts with plasma cell and lymphoid malignancies, including MM, ALL, CLL, and MCL treated at the Moffitt Cancer Center between March 2017 and March 2019 who had provided at least an ID sample for NGS-MRD testing. Results: A total of 423 ID tests using DNA from bone marrow (BM; n=407) or peripheral blood (PB; n=16) and 384 MRD tracking tests (BM, n=321; PB, n=63) were performed in 297 pts (Table). The median turnaround time from shipment arrival to assay initiation was 2.1 hours and from activation to report date was 7.1 days. For MM, ALL, MCL, and CLL, the numbers of tests ordered, calibration rates (defined as proportion of ID samples with trackable sequence[s]), and mean number of trackable sequences are shown in the Table. More ID tests were ordered than number of pts (range: 108-178%) due to multiple tests performed for each patient. Sequences analyzed for MRD tests included IgH, IgK/IgL, and T-cell receptors β and γ. The proportion of pts with detectable MRD is shown by indication in the Table. In MM, autologous stem cell transplant (autoSCT)-eligible pts or those who achieved excellent initial responses but were transplant-ineligible, were primarily considered for NGS-MRD testing as part of standard of care. NGS-MRD testing was performed prior to autoSCT and post-SCT before initiation of maintenance therapy for prognostication. More than 90% of MM cases with successful NGS-MRD results had trackable clones. Negative NGS-MRD assured excellent disease control and supported the decision to discontinue therapy in some pts with significant toxicities. In pts with ALL, treatment response after induction and/or consolidation guided decision-making for allogeneic (allo) SCT at first remission. MRD burden prior to alloSCT could potentially guide the decisions and timing on performing SCT or conditioning regimen intensity. In pts with MCL, treatment response evaluated by NGS-MRD following 6 cycles of therapy was a decision point in a randomized trial of auto-transplant + rituximab vs rituximab alone (ClinicalTrials.gov: NCT03267433). MRD is also being used to guide the duration of rituximab maintenance therapy. Updated data analysis for all indications, including CLL, is underway and will be presented at the meeting. Conclusions: The NGS-MRD Assay is a highly sensitive diagnostic tool for the observation of deeper disease response to therapy in multiple specimen types and in various lymphoid and plasma cell malignancies. NGS-MRD may assist in therapeutic decision-making or prognostication. NGS-MRD is a sensitive and powerful prognostic tool available for the majority of pts, which will help our understanding of the role of MRD in clinical management of plasma cell and lymphoid malignancies. Table Disclosures Srivastava: Adaptive Biotechnologies: Employment, Equity Ownership. Lee:Adaptive Biotechnologies: Employment, Equity Ownership. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Shah:AstraZeneca: Honoraria; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding. Alsina:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Bristol-Myers Squibb: Research Funding. Baz:Merck: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Pinilla Ibarz:Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau. Shain:Adaptive Biotechnologies: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.
Abstract Introduction: The rapid technological advances in next generation sequencing (NGS) have allowed oncologists to sequence tumorexomesin a clinically meaningful period of time. NGS allows for identification of alterations that may be potentially targetable by already available Food and Drug Administration (FDA) approved drugs, providing a biologic rational for consideration of therapies and/or experimental treatments (clinical trials) that would not have otherwise been contemplated. Here we report our experience using NGS in a cohort of 60 patients with various lymphoid malignancies. Methods: We retrospectively reviewed the medical charts of 60 patients with various lymphoid malignancies who had undergone NGS. Patients were seen at the UCSD Moores Cancer Center (La Jolla, CA) from October 2012 until March 2016. We collected tumor samples from tissue (Table 1) or peripheral blood from 60 patients that were submitted for testing to Foundation Medicine, a clinical laboratory improvement amendments (CLIA)-certified lab. Hybrid capture based NGS (405 gene panel) was performed (http://www.foundationone.com/). The methods used in this assay have been described in detail in a previous report (He, J. et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016. 127:3004-3014.). Results: Sixty patients including 35 men (58%) and 25 women (42%), were identified with lymphoid malignancies (Table 1). A total of 224 alterations were found by NGS in the entire cohort of 60 individuals. Types of alterations identified included substitutions, indels, copy number alterations (CNAs), and gene fusions. Figure 1 demonstrates the 15 most frequent alterations among the cohort: TP53 mutations (10 patients), IGH rearrangements (9 patients), loss of CDKN2A/B (8 patients), and BCL2 mutations (8 patients). The median number of alterations detected per patient was 3 (range, 0 to 14). Shown in Figure 2, 7 patients (12%) had no reportable alterations, 10 patients (17%) had 1 alteration, and 43 (71%) patients had 2 or more alterations. The maximum number of alterations identified was 14, which occurred in two patients (3%), one with chronic lymphocytic leukemia (CLL) and the other with diffuse large B-cell lymphoma (DLBCL). A total of 49 patients (82%) had potentially actionable alterations using FDA approved drugs and/or experimental therapies (clinical trials) while 11 patients (18%) had no theoretically actionable alterations. Only 3 patientshad an alteration for which an approved drug in the disease is available (on-label) while 45 patients (75%) had an alteration for which an approved drug is available in another disease (off-label). Twenty-three patients (38%), 12 patients (20%), and 10 patients (17%) had 1, 2 and³ 3 FDA targetable alterations, respectively. The median number of theoretical FDA actionable alterations was 1. Conclusions:Most patients with lymphoid malignancies will have alterations that are potentially pharmacologically identified by NGS; however, only a minority of patients will have alterations for which an approved drug in the disease is available (on-label). Patients with lymphoid malignancies who have exhausted standard therapy or who are unable to tolerate chemotherapy may be excellent candidates for matched targeted therapies, ideally administered in the context of a clinical trial. Figure 1 The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 1. The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 2 Figure 2. Disclosures Goodman: Pfizer: Other: Fellowship funding. Costello:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kurzrock:Serono: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Actuate Therapeutics: Research Funding; Sequenom: Research Funding; X Biotech: Research Funding; Genentech: Research Funding; Curematch: Equity Ownership; Novena: Equity Ownership.
Abstract Introduction: Umbralisib (UMB) is a next generation, once daily, PI3Kδ/CK1ε inhibitor, active in patients with relapsed or refractory (rel/ref) hematologic malignancies that, in long-term follow-up, has demonstrated a uniquely differentiated safety profile from prior PI3Kδ inhibitors (Davids, 2018). Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UMB + UTX (U2) is tolerable and active in patients with rel/ref hematologic malignancies and registration directed trials for patients with CLL & NHL are ongoing. This Phase 1 trial evaluates the safety and efficacy of U2 + Benda in patients with advanced diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Methods: Eligible patients had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (cohort escalation group only). Patients refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. UMB was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 patients. Benda was dosed at 90 mg/m2 on Days 1 & 2 of Cycles 1-6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Thirty-nine patients were evaluable for safety: 26 DLBCL and 13 FL. Med age 67 yo (range 31-81); 23 M/16 F; median prior treatment regimens = 2 (range 1-6); 22 pts (56%) were refractory to prior treatment and 6 patients had progressed post-transplant; ECOG PS 0/1/2 (12/25/2). Initially 2/4 patients at 800 mg UMB experienced AE's in Cycle 1 that led to treatment interruption (rash, neutropenia) thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded and the 800 mg UMB dose was evaluated with the use of growth factor support in cycle 1 permitted. The most common AE's regardless of causality included diarrhea (54%; G3/4 15%), nausea (49%; G3/4 5%), vomiting (38%; G3/4 0%), neutropenia (33%; G3/4 33%) and pyrexia (31%; G3/4 0%). Thirty-eight patients (25 DLBCL/13 FL) were evaluable for efficacy (1 DLBCL patient came off study for G4 neutropenia prior to first assessment). ORR in the respective groups is shown in Table 1. The median time to response was 8 weeks. The median DOR was 9.6 months (95% CI: 2.5-NR) for patients with DLBCL, and was not reached (95% CI: 8.0-NR) for patients with FL, at a median duration of follow-up for responders of 11.5 months (range 2.9 - 30+ mos). Conclusions: The combination of U2 + bendamustine has exhibited manageable toxicity with significant activity in advanced DLBCL and FL patients, including an encouraging CR rate in advanced patients. Based upon the early activity of the triplet, a registration directed study is underway for patients with rel/ref DLBCL (UNITY-NHL). Disclosures Lunning: Gilead: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Bayer: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Genzyme: Consultancy; Kite: Consultancy; Juno: Consultancy; Genentech: Consultancy; Portola: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Flowers:Abbvie: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Gilead: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Janssen Pharmaceutical: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding. Cohen:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Cutter:TG Therapeutics, Inc.: Consultancy. Pauli:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Vose:Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Roche: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Acerta Pharma: Research Funding; Epizyme: Honoraria; Celgene: Research Funding.
Abstract Introduction: The intratumoral heterogeneity of Acute Myeloid Leukemia (AML) and other hematologic malignancies presents a challenge in developing effective single-agent targeted treatments. Furthermore, the emergence of genetically heterogeneous subclones leading to relapse suggests that effective therapies associated with discrete genotypes may require drug combinations, each of which modulates distinct pathways. In addition, microenvironmental rescue signals as well as tumor-intrinsic feedback pathways in AML and other hematologic malignancy subsets will necessitate combinatorial therapy approaches. Towards the goal of identifying new therapeutic combinations for AML and other hematologic malignancies, we assessed the sensitivity of primary patient samples to various drug combinations using an ex vivo functional platform. Methods: We have previously screened over 1000 primary patient specimens against a panel of single-agent small-molecule inhibitors. Using these historical drug sensitivity data, we ranked drugs by their IC50, and used these rankings to assemble an initial panel (1) of 44 drug combinations consisting primarily of kinase inhibitors with non-overlapping pathways. Primary patient samples (n = 74) with various hematologic malignancies were assessed for sensitivities to these combinations by culturing cells in the presence of fixed molar concentrations of the drugs over a dose series. Sensitivity was assessed by a viability assay on day 3 using a tetrazolium reagent. IC50 values for samples sensitive to a combination were sorted according to disease type and compared to those for each single agent to derive an index of effectiveness. Based on data from panel 1, we generated a second panel (2) consisting of 44 drug combinations, including new combinations of kinase inhibitors as well as combinations of drugs from different classes, such as bromodomain inhibitors, BH3 mimetics, proteasome inhibitors, IDH1/2 inhibitors coupled with kinase inhibitors. Primary patient samples (n = 78) were assessed for sensitivities to these combinations. Results: The performance of drug combinations across AML, ALL, CLL, CML or other MDS/MPN specimens are displayed in a heat map (Figure 1) representing the sensitivities of each drug combination relative to either of the single agents comprising that combination (the combination IC50 divided by the lowest single agent IC50 is our combination ratio). For each combination, we then compared the combination ratio of each individual specimen to the median combination ratio across all specimens tested, and cases with a combination ratio value less than 20% of the median were considered hypersensitive to that combination. We calculated the percentage of cases that were sensitive to each combination within the diagnostic subsets of AML, ALL, CLL, CML, and MDS/MPN and subsets with the most frequent sensitivity to a drug combination are indicated on the heat map (<20%, dark red; 20-50%, dark pink; 50-80%, light pink; and >80%, white). Combinations of two kinase inhibitors that included the p38MAPK inhibitor, doramapimod, were generally more effective on AML and CLL samples than other diagnostic subsets (panel 1). For CLL sample, combinations including midostaurin and either alisertib, ruxolitinib or sorafenib were particularly effective. Among combinations on panel 2, doramapimod coupled with an apoptosis inducer (ABT-199) exhibited broad efficacy on AML samples. In addition, combinations with the bromodomain inhibitor, JQ1, or the BH3 mimetic, ABT-199, were more broadly effective across diagnostic subsets than many of the kinase-kinase pairs tested. To validate the apparent synergies observed with patient samples, we tested selected combinations on AML-derived cell lines and observed synergies, which were supported with combination indices derived by the Chou-Talalay method. Conclusions: These data suggest that specific drug combinations formed either with two kinase inhibitors or with two compounds from different drug classes are effective in a patient-specific manner with enrichment for certain drug pairs within specific diagnostic subsets. While a secondary evaluation is necessary to validate the initial observation of sensitivity, linking this methodology with genetic attributes for patient samples will identify effective combinations of targeted agents and add therapeutic options for AML treatment. Figure 1. Figure 1. Disclosures Pandya: Microsoft: Employment, Equity Ownership. Bolosky:Microsoft: Employment, Equity Ownership. Druker:Oregon Health & Science University: Patents & Royalties; Henry Stewart Talks: Patents & Royalties; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Millipore: Patents & Royalties; AstraZeneca: Consultancy; Oncotide Pharmaceuticals: Research Funding; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fred Hutchinson Cancer Research Center: Research Funding; ARIAD: Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sage Bionetworks: Research Funding. Tyner:Incyte: Research Funding; Janssen Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding.
Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with high-risk or relapsed hematologic malignancies. Development of acute graft-vs-host disease (aGVHD) is a risk factor for nonrelapse mortality after allo-HSCT. Systemic corticosteroids (CS) are recommended first-line treatment for aGVHD, but <50% of patients (pts) achieve sustained responses, and there are no approved therapies for steroid-refractory (SR) aGVHD. Ruxolitinib (RUX) is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 signaling, implicated in GVHD pathogenesis. Retrospective studies showed clinical benefit from RUX in pts with SR aGVHD. Here, we report results from the REACH1 trial (NCT02953678) evaluating RUX plus CS in SR aGVHD. Methods: REACH1 was an open-label, single-cohort, multicenter, phase 2 study. Eligible pts were ≥12 years old, had an allo-HSCT from any donor source for hematologic malignancies, developed grade II-IV SR aGVHD per Mount Sinai Acute GVHD International Consortium criteria, and had ≤1 systemic treatment in addition to CS for aGVHD. SR aGVHD was defined as GVHD that progressed after 3 days or had not improved after 7 days of primary treatment with methylprednisone ≥2 mg/kg/d (or equivalent), development of GVHD in another organ after receiving CS (≥1 mg/kg/d methylprednisone) for skin or skin plus upper gastrointestinal GVHD, or inability to tolerate CS taper. Pts received RUX 5 mg twice daily (BID), with optional increase to 10 mg BID in the absence of cytopenias. The primary endpoint was overall response rate (ORR) at Day 28, defined as the proportion of pts having complete response (CR), very good partial response, or partial response (PR). The key secondary endpoint was 6-month duration of response (DOR; time from first response to GVHD progression or death). Results: At the primary analysis of ORR (02 Apr 2018), 71 pts received ≥1 dose of RUX. Mean (range) age was 52.9 (18-73) years; 49.3% of pts were men. Acute myeloid leukemia (AML) and myelodysplastic syndrome were the most common primary malignancies (28.2% each). Most pts (80.3%) received peripheral blood stem cells; 18.3% received bone marrow, and 1.4% received cord blood as the stem cell source. Treatment was ongoing in 17 pts (23.9%) at data cutoff. At baseline, 23 pts (32.4%) had grade II aGVHD, 34 (47.9%) had grade III, and 14 (19.7%) had grade IV; 36 pts (50.7%) had ≥2 organs involved. Before starting RUX, 19 pts (26.8%) had progressive aGVHD after 3 days of CS treatment, 30 (42.3%) had no response after 7 days of CS, 8 (11.3%) developed new organ involvement on CS <2 mg/kg, and 14 (19.7%) were taper intolerant. At Day 28, ORR (95% CI) was 54.9% (42.7%-66.8%) with responses observed irrespective of grade or SR criteria (Table 1). Median DOR among Day 28 responders has not been reached (lower limit, 159 days; Figure 1). Event-free probability estimates (95% CI) for Day 28 responders at 3 and 6 months were 79.0% (62.3%-88.9%) and 67.0% (47.3%-80.7%), respectively. Best ORR at any time was 73.2% (CR, 56.3%). Median (range) time to response was 7.0 (6-49) days. Two pts had malignancy relapse (AML in both). At Day 28, 43 pts were on RUX and CS treatment; 55.8% (24/43) of these pts had a 50% reduction from baseline in CS dose (Figure 2). Most pts (69/71) initiated RUX at 5 mg BID. At Day 28, 46.5% of pts (20/43) received RUX 10 mg BID. The most common treatment-emergent adverse events (TEAEs; any grade, grade 3/4) were anemia (60.6%, 46.5%), hypokalemia (47.9%, 18.3%), decreased platelet count (43.7%, 38.1%), peripheral edema (43.7%, 11.3%), and decreased neutrophil count (36.6%, 31.0%). Cytomegalovirus (CMV) infection, viremia, and chorioretinitis occurred in 9 (12.7%), 4 (5.6%), and 1 (1.4%) pts, respectively (43.7% of pts were CMV+ at baseline). Fatal treatment-related TEAEs were sepsis and pulmonary hemorrhage (1 pt each) and were attributed to both RUX and CS. Conclusion: In this first prospective trial of RUX in pts with SR aGVHD, RUX treatment resulted in overall responses in 54.9% of pts with SR aGVHD by Day 28, many of whom (68%) had grade III/IV disease at baseline. Best ORR at any time was 73.2% (CR, 56.3%). Responses were rapid and durable. Most pts achieved sustained reductions in CS dose. The AE profile was consistent with expectations for RUX and pts with SR aGVHD. RUX represents a promising therapeutic strategy; a phase 3 trial of RUX vs best available therapy in SR aGVHD is underway. Disclosures Jagasia: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Perales:Merck: Other: Personal fees; Abbvie: Other: Personal fees; Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support. Schroeder:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Shah:Lentigen Technology: Research Funding; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Geron: Equity Ownership; Exelexis: Equity Ownership; Oncosec: Equity Ownership. Chen:Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; REGiMMUNE: Consultancy. Arbushites:Incyte Corporation: Employment, Equity Ownership. Dawkins:Incyte Corporation: Employment. Tian:Incyte Corporation: Employment. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for pediatric patients with hematologic malignancies. Historically, matched sibling donors (MSD) have been the preferred donor source given ease of availability and lower rates of graft-versus-host-disease (GVHD). However, only 30% of patients have a MSD and relapse rates are high after MSD HSCT, raising the question of best donor choice. As conditioning regimens evolve, GVHD management improves and supportive care advances, it is important to evaluate the role of donor source on short and long-term clinical outcomes to inform donor selection. We performed a single-center retrospective analysis comparing post-HSCT outcomes in a cohort of pediatric patients undergoing MSD, matched unrelated donor (MUD), and umbilical cord blood (CB) transplants from 2006 to 2018. Methods: A retrospective analysis was performed on an IRB-approved protocol through Fred Hutchinson Cancer Research Center. 232 patients were included who received MSD (n=56), MUD (n=89) or CB (n=87) transplants. Of note, 24 CB patients received expanded CB cells in addition to unmanipulated unit(s). GVHD prophylaxis in all patients consisted of a calcineurin inhibitor and MMF or methotrexate. The vast majority received a high-intensity conditioning regimen (86%, 96%, and 82% respectively for MSD, MUD and CB). Overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method. Probabilities of non-relapse mortality (NRM), relapse, and acute GVHD were evaluated using cumulative incidence (CI) estimates with appropriate competing risks. The Cox regression model was used for adjusted analysis for age, year of transplant, sex, CMV status, MRD status, disease risk, and conditioning regimen. Results: Patient/treatment/donor demographics are shown in Table 1. Median follow-up was 2.6, 3.7 and 3.1 years for MSD, MUD and CB respectively. Patient diagnosis, disease risk, gender, age, and CMV serology were balanced between groups. CI of engraftment was similar as well, with only one graft failure in the MUD group (Fig 1). Median time to platelet recovery was significantly faster in MUD and MSD groups as compared to the CB group (p<0.0001; p<0.0001). There was no difference in unadjusted 5 year OS (Fig 2) and NRM (Fig 3) between groups. Five-year DFS was significantly higher in CB v. MSD (71% v. 54%, p=0.03) but not between CB v. MUD (71% v. 61%, p=0.18) or between MSD and MUD (p=0.38) (Fig 4). The CI of relapse at 5 years was 20% for CB patients, significantly lower than that of MSD recipients (49%, p=0.003) and not different from MUD (32%, p=0.11) (Fig 5). After adjusted analysis, the risk of DFS failures was higher among recipients of MSD than CB [HR: 1.88 (CI 95%: 1.01-3.47), p=0.04]. When CB versus MUD groups were compared, there was a trend of higher risk of DFS failures in the MUD group [HR: 1.28 (CI 95%: 0.96-1.66), p=0.09]. No difference was observed in risk of DFS failures between MSD versus MUD groups [HR:0.77 (CI 95%: 0.44-1.4), p=0.43]. Incidence of grade II-IV acute GVHD was 90% (95%CI: 82-95%), 75% (95%CI: 61-84%) and 88% (95%CI: 80-94%), for CB, MSD and MUD, respectively (p=0.25). Incidence of grade III-IV acute GVHD was 33% (95%CI: 23-43%) for CB, 9% (95%CI: 3-18%) for MSD, and 11% (95%CI: 5-18%) for MUD. Incidence of grade III-IV was significantly higher for the CB group compared to the other groups (p=0.001); however, nearly 60% of CB recipients with grade III-IV acute GVHD were diagnosed before engraftment had occurred and in retrospect met criteria for pre-engraftment syndrome. Among surviving patients, 23 CB recipients developed chronic GVHD (26% - 15 mild, 4 moderate, 4 severe) as compared to 14 MSD patients (25% - 13 mild, 1 moderate) and 40 MUD patients (45% - 27 mild, 11 moderate, 2 severe). Conclusions: Our data demonstrate no difference in unadjusted OS between MSD, MUD and CB recipients. Importantly, despite this equivalence, 5-year DFS was significantly better in the CB v. MSD group, reflecting the lower relapse rate observed in CB patients and seen previously by us and others. CB continues to be viewed as an "alternative" donor for HSCT due to the low stem cell dose in a CB graft resulting in delayed neutrophil recovery, primary graft failure and increased NRM. However, this was not observed herein, supporting the use of CB for pediatric HSCT perhaps especially in patients at high risk of post-transplant relapse. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Bleakley:HighPass Biotherapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
Abstract INTRODUCTION: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in a spectrum of solid tumors and hematologic malignancies, with mutations in DNMT3A and NPM1 co-occurring with IDH1 most frequently (Molenaar et al. Leukemia 2015). AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme being evaluated in an ongoing, first-in-human, phase 1, open-label study (NCT02074839). We report data, including clinical activity and safety, based on patients from the completed dose escalation phase. Molecular profiling, including observations of co-occurring genomic alterations at baseline, and relationship with clinical activity is also presented. METHODS: Patients with advanced IDH1 mutation-positive hematologic malignancies, diagnosed by local evaluation, receive AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously, in 28-day cycles. Bone marrow is examined on Days 15, 29, 57, and every 56 days thereafter. Primary objectives are safety, determination of maximum tolerated dose (MTD) and selection of a dose schedule for expansion cohorts and future phase 2 studies. Secondary objectives include clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML (Cheson et al). Molecular profiling was performed with the FoundationOne Heme next-generation sequencing (NGS) test on bone marrow and/or peripheral blood from all patients at pre-defined time points throughout the study. RESULTS: As of July 1, 2015, 66 patients were treated in the dose escalation phase, of whom 25 remain on treatment. Therapy has been well tolerated and the MTD was not reached. Dosing in the first cohort was 100 mg BID. The long half-life of AG-120 supported QD dosing subsequently, and 1200 mg QD was the highest dose evaluated. Dose escalation is now closed. The majority of adverse events (AEs) were grade 1 and 2, the most common being diarrhea (23%), fatigue (22%), and pyrexia (22%); the most common Grade ≥3 AE was febrile neutropenia (11%). The majority of serious AEs were disease-related. Of the 66 patients, 61 are response evaluable (patients with a Day 28 or later response assessment or who discontinued earlier than Day 28 for any reason). In all response evaluable patients, an estimated 55% had treatment durations of at least 3 months. Objective responses have been observed in 22 subjects (11 complete remissions [CR], 1 CR with incomplete platelet recovery, 4 partial responses and 6 marrow CRs), with a CR rate of 18% and an overall response rate (ORR) of 36% (22/61). Responses are durable, with a median duration of response among responders of 5.6 months [1.9, NE], including responses ≥11 months. Molecular profiling data from screening bone marrow was available in 38 patients. Among these 38, the most common co-mutations associated with IDH1 mutation were DNMT3A (67%) and NPM1 (24%). Incidence of additional co-mutations was <22%, with FLT3 in 7 patients (21%). Additional samples for longitudinal NGS sequencing were further analyzed at specified time points throughout the study. Updates from the completed dose escalation phase and further molecular profiling analysis will be presented. Three dose expansion arms are currently enrolling at 500 mg QD in relapsed/refractory AML, untreated AML, or other IDH1 mutation-positive advanced hematologic malignancies (n=125, n=25, and n=25, respectively, as of July 1, 2015). In addition, safety and efficacy data from the ongoing study will be included as of an October 2015 data cut-off date. CONCLUSION: AG-120, a potent, selective, oral inhibitor of mutant IDH1, is well tolerated in patients with advanced hematologic malignancies, and induces objective durable responses, with an ORR of 36%, including complete remissions. Molecular profiling may provide insights into the mechanisms of response and resistance. The data support the efficacy of AG-120 and provide continued validation of mutant IDH1 as a therapeutic cancer target. Disclosures DiNardo: Novartis: Research Funding. de Botton:Agios pharmaceuticals: Research Funding. Pollyea:Glycomimetics: Other: Member of data safety monitoring board; Pfizer: Consultancy; Karyopharm: Consultancy; Agios Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Ariad: Consultancy. Stein:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: 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:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Altman:Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Derti:Agios Pharmaceuticals: Employment, Equity Ownership. Goldwasser:Agios Pharmaceuticals: Employment, Equity Ownership. Prahl:Agios Pharmaceuticals: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Agresta:Agios Pharmaceuticals: Employment, Equity Ownership. Stone:Agios: Consultancy; Novartis: Research Funding; AROG: Consultancy; Merck: Consultancy; Celator: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Juno: Consultancy.
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.
