ontorpacept (PF-07901800) / Pfizer - LARVOL DELTA

Mechanistic approach exploring combination agents to potentiate anti-leukemia activity of Hu8F4, a clinical stage T cell receptor mimic antibody (ASH 2025) - "Wealso tested recombinant SIRPα-Fc (TTI-621), another agent in clinical development designed to blockCD47. In pilot experiments anti-LRP1 antibodies improved ADCP effect of Hu8F4 byup to 80% (p<0.0001) in the presence of NSG BMDM, however the mechanism and in vivo activity of a-LRP1 antibodies are under investigation.In summary, we tested both well-known and novel regulators of ADCP, such as SIRPα, TREM2 and LRP1 incombination with Hu8F4. Understanding the mechanisms and potential contribution of these agents hasimplications not only for Hu8F4, but for other TCR-mimics and other antibodies that work through ADCPas well."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Dyslipidemia • Hematological Malignancies • Leukemia • Solid Tumor • GLI2 • LRP1 • SIRPA • TREM2

Anti-CD47 drug interference in pre-transfusion testing can be overcome by antigen masking. (PubMed, Transfusion) - "These findings emphasize the need for awareness and adaptation in immunohematology practices as anti-CD47 drugs continue to advance in clinical development, and highlight the utility of antigen masking strategies to enhance the safe administration of blood products to treated patients."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD47 • SIRPA

TTI-622 in Combination With Pembrolizumab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P2 | N=10 | Active, not recruiting | Sponsor: Mayo Clinic | Recruiting ➔ Active, not recruiting | N=41 ➔ 10 | Trial completion date: Nov 2027 ➔ Jul 2027 | Trial primary completion date: Nov 2026 ➔ Jul 2027

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type • Primary Mediastinal Large B-Cell Lymphoma • T Cell Histiocyte Rich Large B Cell Lymphoma • ALK • BCL2 • BCL6 • IRF4 • PD-L1

Advancements in Cutaneous T-Cell Lymphoma Treatment: Unveiling Novel Therapeutic Avenues and Clinical Implications. (PubMed, Am J Clin Oncol) - "This review emphasizes the necessity for ongoing research and individualized treatment plans while highlighting the promise of these cutting-edge techniques to enhance outcomes for patients with advanced CTCL."

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CCR4 • IL15 • IL9 • TNFRSF8

TTI-622 in Combination with Pembrolizumab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P2 | N=41 | Recruiting | Sponsor: Mayo Clinic | N=62 ➔ 41

Combination therapy • Enrollment change • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Histiocyte Rich Large B Cell Lymphoma • ALK • BCL2 • BCL6 • IRF4 • PD-L1

A Trial of PF-07901800 (TTI-621) for Patients With Hematologic Malignancies and Selected Solid Tumors (clinicaltrials.gov) - P1 | N=249 | Terminated | Sponsor: Pfizer | Phase classification: P1a/1b ➔ P1

Phase classification • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Indolent Lymphoma • Lung Cancer • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • Sezary Syndrome • Small Cell Lung Cancer • Solid Tumor

TTI-621-03: A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma (clinicaltrials.gov) - P2 | N=76 | Terminated | Sponsor: Pfizer | Phase classification: P1/2 ➔ P2 | Active, not recruiting ➔ Terminated; Pfizer decided to terminate the study for administrative reasons. The termination was neither due to safety concerns nor a request from the regulatory authorities.

Combination therapy • Metastases • Phase classification • Trial termination • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

TTI-621-03: A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma (clinicaltrials.gov) - P1/2 | N=76 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

Novel agents in relapsed/refractory diffuse large B-cell lymphoma (ICML 2023) - "In recent years, numerous agents have been approved specifically for patients with DLBCL (RED) including tafasitamab, loncastuximab tesirine, polatuzumab vedotin, selinexor, rituximab, and pembrolizumab (for patients with Primary Mediastinal B-cell lymphoma)...Significant grade 3-4 toxicities were neutropenia and thrombocytopenia with 48.6% of patients requiring dose modifications, and 22.9% discontinuing treatment for toxicity.12 Ongoing and planned trials with loncastuximab include a phase III trial with rituximab, gemcitabine, and oxaliplatin (R-GemOx) (Tables 1 and 3)...Encouraging clinical activity, without unanticipated toxicities was observed when polatuzumab was combined with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) with an ORR of 89% (CR 61%).24 Combination of polatuzumab with lenalidomide and rituximab (R2) in 49 patients demonstrated an ORR of 35% (CR 29%), with median DOR, PFS, and OS of 8.1, 6.3, and 10.9 months, respectively...One notable..."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • CARD11 • CD79B • CDKN1A • CRBN • CTLA4 • EZH2 • IKZF1 • IRAK4 • LYN • MALT1 • MCT1 • MYC • MYD88 • NF-κβ • PD-L1 • ROR1 • SIRPA • SYK • XPO1

Safety and clinical activity of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma: Results from the low-dose expansion cohort. (ASCO 2023) - P1/2 | "Addition of TTI-621 to doxorubicin showed promising clinical activity and a favorable safety profile among pts with advanced LMS, including those with prolonged exposure to TTI-621 ( > 360 d). Clinical trial information: NCT04996004."

Clinical • Combination therapy • Metastases • Hematological Disorders • Leiomyosarcoma • Neutropenia • Oncology • Pancreatitis • Sarcoma • Solid Tumor • CD47 • SIRPA

TTI-621-03: A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma (clinicaltrials.gov) - P1/2 | N=80 | Recruiting | Sponsor: Pfizer | Phase classification: P2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

TTI-621-03: A Trial of TTI-621 in Combination With Doxorubicin in Patients With Leiomyosarcoma (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Pfizer | Phase classification: P1/2 ➔ P2 | Trial completion date: Jul 2024 ➔ Jan 2024 | Trial primary completion date: Jun 2023 ➔ Nov 2023

Combination therapy • Phase classification • Trial completion date • Trial primary completion date • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

TTI-622 and TTI-621 in Combination With Pembrolizumab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P2 | N=62 | Recruiting | Sponsor: Mayo Clinic | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Histiocyte Rich Large B Cell Lymphoma • ALK • BCL2 • BCL6 • IRF4 • PD-L1

A Trial of TTI-621 for Patients With Hematologic Malignancies and Selected Solid Tumors (clinicaltrials.gov) - P1a/1b | N=250 | Terminated | Sponsor: Pfizer | Active, not recruiting ➔ Terminated

Trial termination • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Myelodysplastic Syndrome • Neuroendocrine Tumor • Oncology • Solid Tumor

Blockade of the Immune Checkpoint CD47 By TTI-621 Potentiates the Response to Anti-PD-L1 in Cutaneous T Cell Lymphoma (ASH 2022) - P1, P1/2 | "CTCL specimens at baseline and during treatment with anti-CD47/SIRPα (TTI621) and anti-PD-L1 (durvalumab) were used to analyze immune cell gene expression. Collectively, our findings demonstrate that CD47 and PD-L1 are critical regulators of the immune microenvironment in CTCL and that dual targeting of CD47 and PD-L1 may potentiate anti-tumor responses in CTCL."

IO biomarker • Cutaneous T-cell Lymphoma • Dermatology • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Transplantation • CD47 • CD8 • MYC • SIRPA

TTI-621 (SIRPαFc), an Immune Checkpoint Inhibitor Blocking the CD47 "Do Not Eat" Signal, Induces Objective Responses in Patients with Advanced, Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (ASH 2017) - P1a/1b; "Weekly IV dosing employing TTI-621 to block the CD47 “do not eat” signal as monotherapy or in combination with rituximab was well tolerated. Treatment was associated with preliminary and promising anti-tumor activity in pts with advanced DLBCL as evidenced by 2 CRs and 3 PRs among 14 pts."

Checkpoint inhibition • Clinical • Biosimilar • Diffuse Large B Cell Lymphoma • Inflammation

A Single Direct Intratumoral Injection of TTI-621 (SIRPαFc) Induces Antitumor Activity in Patients with Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Preliminary Findings Employing an Immune Checkpoint Inhibitor Blocking the CD47 “Do Not Eat” Signal (ASH 2017) - P1; "These preliminary Phase 1 data suggest that mycosis fungoides and its leukemic variant, Sézary syndrome, are highly responsive to a single dose of TTI-621 delivered by intratumoral injection. One pt achieved a complete response of the injected lesion and 5 additional pts experienced decreases in tumor size and/or decreased circulating Sézary cells. Intratumoral injections were well tolerated by all pts."

Biomarker • Checkpoint inhibition • Clinical • Biosimilar • Cutaneous T-cell Lymphoma • Indolent Lymphoma • Inflammation • Melanoma • Sarcoma • Uterine Leiomyoma

Effects of TTI-621 (SIRPαFc) on CD47 and serum cytokines associated with phagocytosis in subjects with relapsed, refractory hematologic malignancies: Pharmacodynamic findings from a first-in-human clinical trial. (ASCO-SITC 2017) - P1a/1b; "Systemic administration of TTI-621 leads to CD47 blockade and dose dependent increases in cytokines associated with phagocytosis, temporally associated with reversible thrombocytopenia, suggesting enhanced macrophage mediated clearance of circulating platelets followed by a robust marrow regenerative response. Enrollment into multiple expansion cohorts addressing a wide range of hematopoietic cancers is ongoing."

Clinical • Biosimilar • Hematological Malignancies • Oncology • Venous Thromboembolism

The CD47-blocking innate immune checkpoint inhibitor, TTI-621, triggers CD47-mediated tumor cell apoptosis (AACR 2018) - P1,P1a/1b; "Additionally, under conditions of cellular stress, TTI-621 may induce tumor cell death directly via binding to CD47 on malignant cells, in a cell-autonomous, cytotoxic mechanism. Thus, TTI-621 may employ multiple mechanisms to elicit its anti-tumor effects."

Checkpoint inhibition • IO biomarker • Diffuse Large B Cell Lymphoma • Solid Tumor

The anti-myeloma activity of TTI-621 (SIRPαFc), a CD47-blocking immunotherapeutic, is enhanced when combined with a proteasome inhibitor (AACR 2017) - P1a/1b; "In this study we investigated the anti-myeloma activity of TTI-621 as both a single agent and in combination with bortezomib or carfilzomib, two proteasome inhibitors that are approved for use in MM patients. TTI-621 monotherapy is currently being evaluated in a Phase 1b study in patients with MM and other hematological malignancies (NCT02663518). These data provide a rationale to evaluate a combination study of TTI-621 and a proteasome inhibitor in MM patients."

Acute Myelogenous Leukemia • Biosimilar • Gene Therapies • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology

Intratumoral delivery of TTI-621 (SIRPαFc), a CD47-blocking immunotherapeutic, inhibits tumor growth and prolongs animal survival in a subcutaneous B cell lymphoma model (AACR 2017) - P1; "Collectively, these results demonstrate that TTI-621 is efficacious when delivered intratumorally and can increase the phagocytosis of tumor cells by both M1 and M2 TAM populations. These data support the evaluation of intratumoral administration of TTI-621 in cancer patients, and a Phase I study of intratumorally delivered TTI-621 in patients with percutaneously accessible solid tumors and mycosis fungoides is ongoing (NCT02890368)."

Biosimilar • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Blockade of the Immune Checkpoint CD47 by TTI-621 Potentiates the Response to Anti-PD-L1 in Cutaneous T Cell Lymphoma. (PubMed, J Invest Dermatol) - "We investigated the relationship between MYC and CD47 and PD-L1 expression and found that MYC shRNA knockdown and MYC functional suppression by TTI-621 (SIRPαFc) and anti-PD-L1 (durvalumab) in CTCL cell lines reduced the expression of CD47 and PD-L1 mRNA and protein as measured by qPCR and flow cytometry, respectively. These effects were mediated by cell‒death-related pathways, including apoptosis, autophagy, and necroptosis. Collectively, our findings demonstrate that CD47 and PD-L1 are critical regulators of immune surveillance in CTCL and dual targeting of CD47 and PD-L1 will provide insight into tumor immunotherapy for CTCL."

IO biomarker • Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Immune Modulation • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CD47 • CD8 • SIRPA

"#tti621 #cd47 still in the first line of $pfe $tril …" (@FBosom)

Clinical

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies (ASH 2021) - P1a/1b | "Testing of TTI-621 in alternative dosing schedules is in progress. With demonstrated good tolerability and robust single agent antitumor activity in heavily pre-treated patients, additional testing of TTI-621 beyond relapsed/refractory lymphoma has started."

Clinical • P1 data • Cutaneous T-cell Lymphoma • Dermatology • Diffuse Large B Cell Lymphoma • Fatigue • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Mycosis Fungoides • Neutropenia • Oncology • Pain • Peripheral T-cell Lymphoma • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • Transplantation • CD47 • SIRPA

[VIRTUAL] Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies (ASH 2020) - P1a/1b | "Preliminary data from Part 4 dose optimization indicate that weekly infusions of TTI-621 up to 1.4 mg/kg are well-tolerated without dose limiting or cumulative thrombocytopenia. Antitumor activity was seen at 1 mg/kg; dose escalation is continuing at 2 mg/kg."

Clinical • P1 data • Cutaneous T-cell Lymphoma • Dermatitis • Dermatology • Diffuse Large B Cell Lymphoma • Fatigue • Hematological Disorders • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Leukemia • Lymphoma • Multiple Myeloma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • Transplantation