A Study of NKTR-262 in Combination With NKTR-214 and With NKTR-214 Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies

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,
NKTR-214 monotherapy increases newly proliferative CD8+ T cells in tumors. NKTR-262 plus
NKTR-214 is expected to increase expansion of antigen-specific CD8+ T cells. In preclinical
studies, a single IT injection of NKTR-262 plus IV NKTR-214 resulted in complete abscopal
effects in tumor models. Preliminary clinical data show NKTR-214 plus nivolumab enhances
immune-stimulatory responses. The REVEAL trial will assess safety and anti-tumor activity of
NKTR-262 with NKTR-214 +/- nivolumab for the treatment of selected cancers.

- Melanoma (1st-line and relapsed/refractory)

- Merkel Cell Carcinoma (1st -line and relapsed/refractory)

- Triple Negative Breast Cancer (1st - and 2nd-line and relapsed/refractory)

- Ovarian Cancer (3rd-line and relapsed/refractory)

- Renal Cell Carcinoma (1st-line and relapsed/refractory)

- Colorectal Cancer (2nd-line and relapsed/refractory)

- Urothelial Carcinoma (1st-line and relapsed/refractory)

- Sarcoma (2nd-line and relapsed/refractory)

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),
ovarian carcinoma, renal cell carcinoma (RCC), colorectal cancer, urothelial
carcinoma, 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 1-5, 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).

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.