Clinical trial NCT03435640: REVEAL Study of NKTR-262 in Combination With NKTR-214 and Nivolumab in Patients With Locally Advanced / Metastatic Solid Tumor Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Melanoma
Merkel Cell Carcinoma
Triple Negative Breast Cancer
Head and Neck Squamous Cell Carcinoma
Renal Cell Carcinoma
Colorectal Cancer
Sarcoma
Keywords: Bempegaldesleukin (NKTR-214)
NKTR-262
Nivolumab
Opdivo®
Metastatic
Locally advanced
Relapsed/Refractory
TLR7/8
CD122
Lead sponsor: Nektar Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-02-19
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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)

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.

Primary outcomes:
measure: Number of Participants Experiencing Dose-Limiting Toxicities (DLTS)
timeFrame: 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).
measure: Objective Response Rate (ORR) Per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D)
timeFrame: 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.
Secondary outcomes:
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth
state: Arizona
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Center, Emory University Hospital
state: Georgia
city: Fairway
country: United States
facility: University of Kansas Research Center
state: Kansas
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: Nektar Therapeutics
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Rolig AS, Rose DC, McGee GH, Rubas W, Kivimae S, Redmond WL. Combining bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) improves systemic antitumor CD8+ T cell cytotoxicity over BEMPEG+RT. J Immunother Cancer. 2022 Apr;10(4):e004218. doi: 10.1136/jitc-2021-004218.