Immuno-oncology (IO) therapies, particularly immune checkpoint inhibitors (ICIs) such as nivolumab (anti-PD- 1) and ipilimumab (anti-CTLA-4) have made rapid advances in inducing remarkable response rates in patients in a variety of solid tumors. However, over 40% of melanoma patients develop secondary resistance to aPD-1- based therapy, and have limited treatment options. Integrins a4ß1 and aLß2 are crucial for antigen presentation, T cell priming and trafficking. 7HP349 is an oral allosteric agonist of a4ß1 and aLß2 integrins, that may potentially reverse anti-PD-1 resistance and increase ICI effectiveness in these patients, without elevating toxicity. 7HP349 shows augmented T cell activity in vitro, and enhanced antitumor efficacy and survival in tumor models, with increased T cell infiltration into tumors but not to normal tissues. We have made significant progress with 7HP349 development, including approval of Orphan Drug Designation (ODD) and Fast-Track Designation for melanoma, and completion of a first-in-human (FIH) Phase I study of the safety, tolerability and pharmacokinetics of 7HP349, with the optimal pharmacokinetic dose (OPD) defined for Phase Ib/IIa. Our hypothesis is that the augmentation of T cell responses with a standard regimen of ipilimumab in combination with 7HP349, followed by a maintenance regimen of nivolumab monotherapy will improve responses without added toxicity in solid tumor patients with secondary aPD-1 resistance. Here we propose a Phase Ib dose escalation study (7HP-111a) with 7HP349 to evaluate the safety, tolerability and PK of 7HP349 in combination with ipilimumab followed sequentially by nivolumab monotherapy in solid tumor patients (melanoma, pleural mesothelioma, renal cell carcinoma, MSI-high or mismatch repair-deficient colorectal cancer, hepatocellular carcinoma, and non-small cell lung cancer with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations) who have secondary aPD-1 resistance. T cell activation studies will also be performed on patient samples, and biopsies collected as part of this study. The proposed Phase Ib study will not only enable the subsequent design and conduct of a future Phase IIa dose expansion study to evaluate the preliminary efficacy of 7HP349 in combination with ipilimumab followed sequentially by nivolumab monotherapy in melanoma patients with secondary resistance to aPD-1 therapy, but potentially lay the foundation for novel treatment options in such patients.
Public Health Relevance Statement: PROJECT NARRATIVE A significant proportion of solid tumor patients are resistant to anti-PD-1 immune checkpoint therapy, largely due to insufficient priming and trafficking of tumor-targeted T cells. 7HP349 is an allosteric agonist of a4ß1 and aLß2 integrins that has shown enhanced T cell priming and activation, antitumor efficacy and survival in tumor models with increased T cell infiltration into tumors, and has the potential to significantly increase response rates in patients resistant to anti-PD-1 immune checkpoint therapy. This proposal is for a Phase Ib clinical study to evaluate 7HP349 in combination with anti-CTLA-4 followed by anti-PD-1 immune checkpoint blockade in solid tumor patients with secondary resistance to anti-PD-1.
Project Terms: Biopsy; Capital; Non-Small-Cell Lung Carcinoma; NSCLC; NSCLC - Non-Small Cell Lung Cancer; Non-Small Cell Lung Cancer; Nonsmall Cell Lung Carcinoma; Renal Cell Carcinoma; Grawitz Tumor; Hypernephroid Carcinoma; Hypernephroma; Nephroid Carcinoma; Renal Adenocarcinoma; Renal Cell Adenocarcinoma; Renal Cell Cancer; kidney adenocarcinoma; Clinical Research; Clinical Study; Complement; Complement Proteins; Orphan Drugs; Food; Foundations; Future; Goals; Primary carcinoma of the liver cells; Hepatocarcinoma; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; Liver Cells Carcinoma; liver carcinoma; In Vitro; Integrins; Integrins Extracellular Matrix; Maintenance; melanoma; Malignant Melanoma; Overdose; Patients; Drug Kinetics; Pharmacokinetics; Privatization; Epidermal Growth Factor Receptor; EGF Receptor; EGFR; ERBB Protein; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Urogastrone Receptors; HER1; TGF-alpha Receptor; Transforming Growth Factor alpha Receptor; Urogastrone Receptor; c-erbB-1; c-erbB-1 Protein; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; proto-oncogene protein c-erbB-1; Recommendation; Safety; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Mediating; improved; Phase; Medical; Antigen Presentation; CD49d-CD29; Integrin Heterodimer alpha4beta1; Integrin alpha(4)beta(1); Integrin a4ß1; VLA-4; Very Late Activation Antigen-4; Very Late Antigen-4; Integrin alpha4beta1; Malignant Tumor of the Lung; Pulmonary Cancer; Pulmonary malignant Neoplasm; lung cancer; Malignant neoplasm of lung; Funding; Agonist; ALK protein; Anaplastic Lymphoma Kinase Ki-1; CD246 Antigen; anaplastic lymphoma kinase; Metastatic Melanoma; Solid Tumor; Solid Neoplasm; Normal tissue morphology; Normal Tissue; Consensus; Oral; immunotoxicity; toxic reaction in immunology; trafficking; Toxic effect; Toxicities; In complete remission; complete response; Stable Disease; novel; Modeling; Sampling; response; Adverse event; Adverse Experience; Genomics; activate T cells; T-Cell Activation; Molecular Interaction; Binding; Effectiveness; Progressive Disease; Pleural Mesothelioma; Mesothelioma of the Pleura; Dose; Dose Limiting; Immunooncology; immune-oncology; immuno oncology; immunology oncology; oncoimmunology; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Small Business Technology Transfer Research; STTR; partial response; Development; developmental; Colorectal Cancer; Colo-rectal Cancer; safety study; designing; design; migration; resistant; Resistance; tumor; standard of care; in vitro activity; risk mitigation; Phase I Study; phase 1 study; Regimen; T cell response; check point immunotherapy; check point inhibitor therapy; check point inhibitory therapy; check point therapy; checkpoint immunotherapy; checkpoint inhibitor therapy; checkpoint inhibitory therapy; immune check point therapy; immune checkpoint therapy; checkpoint therapy; objective response rate; check point blockade; checkpoint blockade; immune check point blockade; immune checkpoint blockade; Checkpoint inhibitor; immune check point inhibitor; Immune checkpoint inhibitor; PD-1 antibody therapy; PD-1 therapy; PD1 antibody therapy; PD1 based treatment; aPD-1 therapy; aPD-1 treatment; aPD1 therapy; aPD1 treatment; anti-PD-1 therapy; anti-PD-1 treatment; anti-PD1 treatment; anti-programmed cell death 1 therapy; anti-programmed cell death protein 1 therapy; programmed cell death protein 1 therapy; anti-PD1 therapy; aPD-1; aPD1; anti programmed cell death 1; anti-PD1; anti-programmed cell death protein 1; antiPD-1; antiPD1; aPD-1; aPD1; anti-PD-1; first in man; first-in-human; aCTLA-4; aCTLA4; anti-CTLA-4; a-CTLA-4; a-CTLA4; aCTLA-4; aCTLA4; anti-CTLA4; Opdivo; Nivolumab; MMR deficiency; Mismatch Repair Deficiency; Yervoy; ipilimumab; Keytruda; pembrolizumab; autoimmune toxicity; pharmacologic; T cell infiltration
