REVEAL Study of NKTR-262 in Combination With NKTR-214 and Nivolumab in Patients With Locally Advanced / Metastatic Solid Tumor Malignancies

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.