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Supplementary Table from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Supplementary Figure from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Supplementary Data from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Purpose:Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination.Patients and Methods:Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination.Results:In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD.Conclusions:The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.

Supplementary Figure 1 from Efficacious Immune Therapy in Chronic Myelogenous Leukemia (CML) Recognizes Antigens That Are Expressed on CML Progenitor Cells

Supplementary Tables 1-3, Figure Legend from Efficacious Immune Therapy in Chronic Myelogenous Leukemia (CML) Recognizes Antigens That Are Expressed on CML Progenitor Cells

TPS8071 Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don’t eat me" signal to suppress macrophage phagocytosis. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. CD47 is significantly increased in multiple myeloma (MM) bone marrow mononuclear cells and expression inversely correlates with survival in patients. Relapsed/Refractory (R/R) MM shows particularly high expression of CD47. Preclinical studies demonstrate that the addition of proteasome inhibitors to CD47 blockade significantly increases phagocytosis of MM cells in vitro and anti-myeloma activity in vivo. The ongoing phase 1a part of this study has been previously described. The phase 1b part of the study will determine the safety and efficacy of TTI-622 when given as monotherapy or in combination with selected approved anticancer treatments in patients with hematological malignancies where new treatments with novel mechanism of action are needed. Here we describe 5 RRMM cohorts within phase 1b of the study. Methods: TTI-622-01 is a multi-center Phase 1a/1b study. Phase 1a was designed to determine the MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of QW, Q2W, and Q3W single-agent TTI-622 in R/R lymphoma using a 3+3 dose escalation schema. Phase 1b, ongoing, will determine the safety and recommended dose of TTI-622 to be given as single agent and in combination with carfilzomib + dexamethasone (Kd) in RRMM and will evaluate the preliminary efficacy. Secondary objectives are to further characterize the safety, PK and immunogenicity of TTI-622 when combined with Kd. Patients will be enrolled in 5 separate cohorts: 3 cohorts will explore different doses and administration schedules of TTI-622 combined with the approved dose of Kd; 2 cohorts will explore different doses of TTI-622 monotherapy. Cohorts will be opened in a staggered manner. In each cohort 3 patients will be dosed and followed for 28 days (21 days in the monotherapy) before expanding enrolment to approximately an additional 27 patients. Key eligibility criteria include: relapse or progression following ≥3 prior lines of therapy (including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody), carfilzomib-refractory progressive and measurable disease per IMWG at study entry; age ≥18 years; ECOG performance status ≤2; adequate organ functions; no known CNS involvement; no prior anti-CD47 or anti-SIRPα therapy. Patient recruitment is planned or ongoing at 40 sites worldwide. Clinical trial information: NCT03530683.

TPS7595 Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don’t eat me" signal to suppress macrophage phagocytosis. Overexpression of CD47 on cancer cells serves as a mechanism of immune surveillance evasion, and is associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Preclinical studies demonstrate that TTI-622 induces macrophage-mediated phagocytosis of different malignant cell lines, including DLBCL cells, decreases tumor growth and improves survival in a DLBCL xenograft tumor model. Anti-CD47 antibody enhances rituximab stimulated macrophage-mediated phagocytosis of non-GCB DLBCL cell lines (Bouwstra et al, Cancer Immunol Res. 2019). The ongoing phase 1a part of this study has been previously described. Here we describe 2 cohorts within the phase 1b part of the study that are intended to determine the safety and preliminary efficacy of TTI-622 when given in combination with anti-CD20 targeting agent in patients with CD20+ relapsed/refractory (RR) DLBCL. Methods: TTI-622-01 is a multi-center Phase 1a/1b study. Phase 1a was designed to determine the MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of QW, Q2W, and Q3W single-agent TTI-622 in R/R lymphoma using a 3+3 dose escalation schema. Phase 1b, ongoing, will determine the safety, recommended dose and preliminary efficacy of TTI-622 in combination with select approved anticancer treatments for patients with hematological malignancies including, but not limited to anti-CD20 therapy in patients with CD20+ RR DLBCL. Secondary objectives are to further characterize safety, PK and immunogenicity of TTI-622 when combined with approved therapies. Patients will be enrolled in 2 cohorts exploring different doses of TTI-622 in combination with anti-CD20 therapy. Cohorts will open in a staggered manner. In each cohort 3 patients will be dosed and followed for 28 days before expanding enrolment to additional 27 patients per cohort. Key eligibility criteria include: age ≥18 years; relapsed and/or refractory disease after ≥1 prior line of therapy; not eligible for or have progressed after high dose chemotherapy (HDT)/auto-SCT; ≥1 site of measurable disease (Lugano 2014 classification); ECOG PS ≤2; adequate organ functions, no known CNS involvement; no prior anti-CD47 or anti-SIRPα therapy. Patient recruitment is planned or ongoing at 40 sites worldwide. Clinical trial information: NCT03530683.

TPS11593 Background: Doxorubicin is a standard of care agent for patients with advanced soft tissue sarcoma, with a response rate of around 15%, progression-free survival of 5-7 months and cumulative cardiac toxicity that limits its use. TTI-621 is a recombinant soluble fusion protein that combines the N-terminal portion of human SIRPα (the binding domain for CD47) with the Fc region of human IgG1, generating a decoy receptor for CD47 on the surface of tumor cells that both over-rides CD47-mediated inhibition of phagocytosis and provides a pro-phagocytic stimulation. Many solid tumors express high levels of CD47 which is associated with poor prognosis, thought to be the result of CD47-mediated inhibition of macrophage phagocytosis and escape of immune-mediated clearance. Interruption of the CD47-SIRPα signaling pathway using monoclonal antibodies to CD47 has shown anti-tumor activity in animal models and in some early clinical trials. The combination of doxorubicin with CD47-targeted antibodies results in enhanced anti-tumor activity and increased macrophage-mediated cell killing in animal models and macrophage-mediated phagocytosis of cancer cell lines in vitro, suggesting that combining TTI-621 with doxorubicin might be more effective than doxorubicin alone in tumor types that express CD47 and have high numbers of macrophages, such as LMS. Thus, a Phase 1/2 study was initiated to evaluate this combination in patients with advanced soft tissue sarcoma, including LMS. Methods: TTI-621-03 is a Phase 1/2, open-label study of TTI-621 in combination with doxorubicin in patients with anthracycline-naïve disease. The Phase 1 dose escalation evaluates doses of TTI-621 (0.2 to 2.0 mg/kg) in combination with doxorubicin at 75 mg/m2 in patients with high-grade soft tissue sarcomas. Expansion cohorts will evaluate TTI-621 (0.2 and 2.0 mg/kg) with doxorubicin in patients with LMS, with pathology confirmed at a central laboratory. The primary goals of this study are evaluation of safety of TTI-621 administered in combination with standard-of-care doxorubicin and to further evaluate clinical activity (ORR, PFS, OS), safety, PK and patient-reported quality of life in the LMS subpopulation. The dose escalation portion of the study has been completed without DLT. Enrollment to the expansion portion of the study is underway. Clinical trial information: NCT04996004.