7HP349, an Integrin Activator to Treat Patients With anti-PD-1 Resistant Solid Tumors - PROJECT SUMMARY/ABSTRACT 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 α4β1 and αLβ2 are crucial for antigen presentation, T cell priming and trafficking. 7HP349 is an oral allosteric agonist of α4β1 and αLβ2 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.
