reveal study of nktr-262 in combination with nktr-214 and nivolumab in patients with locally advanced / metastatic solid tumor malignancies

Conditions: Melanoma; Merkel Cell Carcinoma; Triple Negative Breast Cancer; Head and Neck Squamous Cell Carcinoma; Renal Cell Carcinoma; Colorectal Cancer; Sarcoma

Summary: patients received intratumoral (it) injections of nktr-262 in 3-week cycles for up to 3 cycles; bempegaldesleukin with or without nivolumab was administered every 3 weeks (q3w), and treatment continued until unacceptable toxicity, death, or disease progression per recist 1.1. based on phase 1 results of the study, the decision was made not to start the phase 2 part of the study and the study was terminated.

cancer treatments that couple pharmacological activation of tumor antigen presentation with activation and expansion of cd8+ t and natural killer (nk) cells in the tumor environment have the potential to induce an effective anti-tumor immune response in patients. nktr-262 is a small molecule agonist of toll-like receptors (tlrs) 7/8 designed to be retained in the tumor micro-environment in order to activate antigen-presenting cells (apc), such as dendritic cells, to create new antigen-specific cytotoxic t cells. as a cd122-biased agonist, bempegaldesleukin monotherapy increases newly proliferative cd8+ t cells in tumors. nktr-262 plus bempegaldesleukin is expected to increase expansion of antigen-specific cd8+ t cells. in preclinical studies, a single it injection of nktr-262 plus iv bempegaldesleukin resulted in complete abscopal effects in tumor models. preliminary clinical data show bempegaldesleukin plus nivolumab enhances immune-stimulatory responses. the reveal trial will assess safety and anti-tumor activity of nktr-262 with bempegaldesleukin +/- nivolumab for the treatment of selected cancers. * melanoma (1st-line and relapsed/refractory) * merkel cell carcinoma (2nd-line and relapsed/refractory) * triple negative breast cancer (1st- and 2nd-line and relapsed/refractory) * renal cell carcinoma (1st-line and relapsed/refractory) * colorectal cancer (2nd-line and relapsed/refractory; msi non-high) * colorectal cancer (2nd 3rd-line+, i-o therapy naive; relapsed/refractory; msi high) * head and neck squamous cell carcinoma (2nd-line and relapsed/refractory) * sarcoma (2nd-line and relapsed/refractory)

Eligibility criteria:
key inclusion criteria: * histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) metastatic cancer of the following histologies: melanoma (mel), merkel cell carcinoma (mcc), triple-negative breast cancer (tnbc), renal cell carcinoma (rcc), colorectal cancer, head and neck squamous cell carcinoma (hnscc), or sarcoma. * life expectancy \> 12 weeks as determined by the investigator. * eastern cooperative oncology group (ecog) performance status 0 or 1. * measurable disease per recist 1.1. * patients enrolled in cohorts 1-10, cohort a, cohort b and phase 2 doublet must be refractory to all therapies known to confer clinical benefit to their disease. * fresh tumor tissue available for cellular characterization and programmed cell death protein 1 (pd-l1) status. * injected lesions (up to two) must be between 20 mm and 90 mm in diameter for it injection; lesions must be accessible for baseline and on-treatment biopsies. any liver lesion targeted for injection must not exceed 50 mm at the time of injection. * demonstrated adequate organ function within 14 days of cycle 1 day 1 (c1d1). key exclusion criteria: * use of an investigational agent or an investigational device within 21 days before administration of first dose of study drug(s). * patients treated with prior interleukin-2 (il-2). * patients who have been previously treated with a toll-like receptor (tlr) agonist (excluding topical agents) and patients who have received experimental cancer vaccines. * patients who have received systemic interferon (ifn)α within the previous 6 months prior to enrollment to the study. * other active malignancy, except non-melanomic skin cancer * evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis. * prior surgery or radiotherapy within 14 days of initiating study drug(s). patients must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis. * prolonged fridericia's corrected qt interval (qtcf) \> 450 ms for men and \> 470 ms for women at screening. history of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following: * unstable angina or myocardial infarction. * congestive heart failure (nyha class iii or iv). * uncontrolled clinically significant arrhythmias. * patients with a history of any retinal disorders (e.g., retinal detachment, diabetic retinopathy, retinal hemorrhage, macular degeneration). * uveal melanoma will be excluded * patients with tumor that invade the superior vena cava or other major blood vessels. additional general and tumor specific inclusion and exclusion criteria will apply.

Keywords: bempegaldesleukin (nktr-214) nktr-262 nivolumab opdivo® metastatic locally advanced relapsed/refractory tlr7/8 cd122