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

June 24, 2022 updated by: Nektar Therapeutics

A Phase 1/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-262 in Combination With Bempegaldesleukin (NKTR-214) and in Combination With Bempegaldesleukin Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies

Patients will receive intra-tumoral (IT) NKTR-262 in 3-week treatment cycles. During the Phase 1 dose escalation portion of the trial, NKTR-262 will be combined with systemic administration of bempegaldesleukin. After determination of the recommended Phase 2 dose (RP2D) of NKTR-262, between 6 and 18 patients may be enrolled at the RP2D to further characterize the safety and tolerability profile of the combination of NKTR 262 plus bempegaldesleukin (doublet) or NKTR 262 plus bempegaldesleukin in combination with nivolumab (triplet) in Cohorts A and B, respectively. In the Phase 2 dose expansion portion, patients will be treated with doublet or triplet in the relapsed/refractory setting and earlier lines of therapy.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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)

Study Type

Interventional

Enrollment (Actual)

64

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Scottsdale, Arizona, United States, 85258
        • HonorHealth
    • California
      • La Jolla, California, United States, 92093
        • UC San Diego Moores Cancer Center
    • Florida
      • Tampa, Florida, United States, 33612
        • H Lee Moffitt Cancer Center and Research Institute
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University Hospital
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • University of Kansas Hospital
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Henry Ford Hospital
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota
    • New York
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke Cancer Institute
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic
    • Oregon
      • Portland, Oregon, United States, 97213
        • Providence Portland Medical Center
    • Texas
      • Dallas, Texas, United States, 72501
        • University of Texas Southwestern Medical Center
      • Houston, Texas, United States, 77030
        • MD Anderson Cancer Center
    • Washington
      • Seattle, Washington, United States, 98109
        • Seattle Cancer Care Alliance

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Doublet: NKTR-262 + bempegaldesleukin

Phase 1 Doublet: NKTR-262 in escalating doses, will be combined with bempegaldesleukin. The goal of this dose escalation part of the study is to establish a safe and tolerable RP2D for NKTR-262 in combination with bempegaldesleukin (Every Three Week [Q3W] fixed dose) in select tumor indications.

Phase 2 Doublet: NKTR-262 RP2D will be combined with a Q3W dose of bempegaldesleukin in select tumor indications to evaluate anti-tumor activity and to obtain additional safety data.

Patients may be discontinued from receiving study treatment based on the results of disease assessments or if experiencing intolerable side effects.
Drug: NKTR-262

During Phase 1 Doublet: Patients will 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 will receive the RP2D of NKTR-262.

During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive the RP2D of NKTR-262.

Drug: bempegaldesleukin

During Phase 1 Doublet (Cohort A), and Phase 2 Doublet: Patients will receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.

During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.
Experimental: Triplet: NKTR-262 + bempegaldesleukin + Nivolumab

Phase 1 Triplet: The RP2D of NKTR-262 RP2D will be combined with a Q3W dose regimen of bempegaldesleukin plus nivolumab. The goal is to establish the safety and tolerability of the triplet regimen.

Phase 2 Triplet: The RP2D of NKTR-262 will be combined with a Q3W dose regimen of bempegaldesleukin plus nivolumab in select tumor indications to evaluate anti-tumor activity and to obtain additional safety data.

Patients may be discontinued from receiving study treatment based on the results of disease assessments or if experiencing intolerable side effects.
Drug: NKTR-262

During Phase 1 Doublet: Patients will 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 will receive the RP2D of NKTR-262.

During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive the RP2D of NKTR-262.

Drug: bempegaldesleukin

During Phase 1 Doublet (Cohort A), and Phase 2 Doublet: Patients will receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.

During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.

Drug: nivolumab
During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive a nivolumab flat dose of 360 mg administered in 3-week treatment cycles.
Other Names:
  • Opdivo®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety of NKTR-262 in combination with NKTR-214/nivolumab as evaluated by incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs leading to discontinuation, deaths, and clinical laboratory abnormalities per CTCAE
Time Frame: 30 days after last dose
30 days after last dose
Tolerability of NKTR-262 in combination with bempegaldesleukin / nivolumab as evaluated by incidence of Dose Limiting Toxicities (DLTs), drug-related AEs, SAEs, AEs leading to discontinuation, deaths, clinical laboratory abnormalities per CTCAE 4.03
Time Frame: Through study completion, an expected average of 2 years
Through study completion, an expected average of 2 years
Efficacy of NKTR-262 in combination with bempegaldesleukin / nivolumab as assessed by the Objective Response Rate (ORR) based on RECIST 1.1
Time Frame: Through study completion, an expected average of 2 years
ORR will be measured by the number and percentage of patients achieving a complete or partial response as best overall response and as defined by RECIST 1.1
Through study completion, an expected average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nektar Therapeutics

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 15, 2018

Primary Completion (Actual)

May 9, 2022

Study Completion (Actual)

May 9, 2022

Study Registration Dates

First Submitted

February 6, 2018

First Submitted That Met QC Criteria

February 9, 2018

First Posted (Actual)

February 19, 2018

Study Record Updates

Last Update Posted (Actual)

June 29, 2022

Last Update Submitted That Met QC Criteria

June 24, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 17-262-01
  • 2018-004625-84 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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