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

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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A Phase 1/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-262 in Combination With Bempegaldesleukin (NKTR-214) With or Without Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies

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

Intervention / Treatment
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* Drug: NKTR-262
* Drug: bempegaldesleukin
* Drug: nivolumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NKTR-262 + bempegaldesleukin or + bempegaldesleukin with nivolumab<br>Phase 1: NKTR-262 in escalating doses, combined with bempegaldesleukin. The goal of this dose escalation part of the study is to establish a recommended Phase 1b dose for NKTR-262 + bempegaldesleukin with nivolumab, followed by a dose-confirmation cohort. | Drug: NKTR-262<br>* During Phase 1 Doublet: Patients receive escalating doses of NKTR-262 IT (starting dose 0.03 mg) in 3-week treatment cycles. During Phase 1 Doublet (Cohort A), Phase 2 Doublet: Patients were to receive the RP2D of NKTR-262. During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients receive the RP2D of NKTR-262.<br>Drug: bempegaldesleukin<br>* During Phase 1 Doublet (Cohort A), and proposed Phase 2 Doublet: Patients receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles. During Phase 1 Triplet (Cohort B), and proposed Phase 2 Triplet: Patients receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.<br>* Other names: NKTR-214;Drug: nivolumab<br>* During Phase 1 Triplet (Cohort B), and proposed Phase 2 Triplet: Patients receive a nivolumab flat dose of 360 mg administered in 3-week treatment cycles.<br>* Other names: Opdivo®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | DLTs were assessed in Cohort 1 through Cohort 9, which had dose levels of NKTR-262 as 0.03mg, 0.06mg, 0.06mg, 0.12mg, 0.24mg, 0.48mg, 0.96mg, 1.92mg, and 3.84mg in combination with bempegaldesleukin (bempeg). There was only 1 DLT that occurred in one of the Cohort 9 patients. Therefore, the maximum tolerated dose (MTD) of NKTR 262 was not reached. | The DLT window is 21 days following NKTR-262 single agent administration (Cycle 1) and an additional 9 days when combined with bempeg for staggered dosing administration (Cohorts 1 and 2), or 7 days for the same day administration (Cohort 3 and higher). | 
| Objective Response Rate (ORR) Per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D) | Objective Response Rate (ORR) per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D). ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by Blinded Independent Central Review (BICR). | From Cycle 1 Day 1 to 100 days after the last dose of study drug or the date for new anti-cancer therapy, whichever is earlier. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bempegaldesleukin (NKTR-214), NKTR-262, Nivolumab, Opdivo®, Metastatic, Locally advanced, Relapsed/Refractory, TLR7/8, CD122