Biopharmaceutical sponsor Nektar recently announced in a press release early results from the ongoing dose-escalation stage of the first-in-human REVEAL Phase 1/2 clinical study evaluating the safety and efficacy of NKRT-262, a novel toll-like receptor (TLR) 7/8 agonist, in combination with bempegaldesleukin* (NKTR-214 or bempeg) a CD122-preferential IL-2 pathway agonist. TrialSite News first introduces the trial and then summarizes the sponsor’s results reported in the CISION PR Newswire press release.
What is the REVEAL Trial?
As reported in ClinicalTrials.gov, REVEAL is a study of Nektar’s NKTR-262 in combination with NKRT-214 and with NKTR-214 plus nivolumab in patients with locally advanced or metastatic solid tumor malignancies. Patients will receive intratumoral (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 NKTR-214. After determination of the recommended Phase 2 dose (RP2D) of NKTR-262, NKTR-262 will be combined with NKTR-214 (Cohort A) and with NKTR-214 plus nivolumab (Cohort B). In the Phase 2 dose expansion portion, patients will be treated with NKTR-262 and NKTR-214 (doublet) or NKTR-262 and NKTR-214 plus nivolumab (triplet) in the relapsed/refractory setting and earlier lines of therapy.
The sponsor targeted a total of 393 non-randomized participants. The study started in 2018 and is targeted for completion in December, 2020.
Study outcome measures include:
- 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 4.03 [ Time Frame: 30 days after last dose ]
- Tolerability of NKTR-262 in combination with NKTR-214 / 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 ]
- Efficacy of NKTR-262 in combination with NKTR-214 / 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
Nektar precludes the names of the research institutions participating but they are located in a handful of states across America. Nektar’s study lead is Mario Marcondes, MD, PhD.
What is NKTR-262?
NKTR-262 is a novel small molecule agonist designed to activate toll-like receptors (TLRs). As Nektar itself describes, Intratumoral delivery of NKTR-262 promotes TLR activation to induce the development of antigen-specific immunity by initiating the process by which the immune system generates antigen-specific cytotoxic T cells to the patient’s specific tumor.1 NKTR-214 targets CD122 specific receptors found on the surface of these cancer-killing immune cells, known as CD8+ effector T cells. By first generating antigen-specific cytotoxic T cells with NKTR-262 and then growing these CD8+ effector T cells with NKTR-214, the patient’s entire immunity cycle can potentially be engaged to fight cancer. They note that 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.
What are the Trial Observations thus Far?
A participating investigator, Dr. Adi Diab (Assistant Professor of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center) presented the ongoing study at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Dr. Jonathan Zalevsky (Chief Scientific Officer at Nektar) notes “we’re excited by the preliminary data from the REVEAL study which demonstrate desirable changes in the tumor micro-environment consistent with the activation of both the innate and adaptive immune responses induced by NKTR-262 and bempeg.” A core summary of findings to date were included by the sponsor’s press release:
- Maximum tolerated dose has not been reached and the dose escalation stage of the study is continuing.
- Initial dose cohorts of NKTR-262 intra-tumoral injection combined with fixed dose of bempeg IV Q3W were well tolerated. Treatment-related adverse events were transient, characterized by Grade 1-2 flu-like symptoms (69.2%), rash (46.2%), fatigue (46.2%), pruritus (46.2%) and nausea (30.8%). There were no immune-mediated adverse events or study discontinuations due to TRAEs.
- Local gene expression analysis of the injected tumor along with analysis of blood cells in system circulation demonstrated comprehensive activation of the immune system, including increases in the Type I interferon pathway and induction of CD4+, CD8+ and NK cell proliferation.
- Early evidence of clinical benefit including abscopal responses in non-injected lesions was observed in the dose-escalation cohort. 11 of 13 patients in dose-escalation were evaluable for efficacy with at least one on treatment scan. 2 out of 5 evaluable patients with relapsed/refractory (R/R) melanoma who progressed on more than one prior checkpoint or I-O therapy experienced confirmed partial responses with 100% and 50% reductions in target lesions per RECIST 1.1, respectively. 2 out of 2 heavily pre-treated Stage IV leiomyosarcoma patients and 1 heavily pre-treated triple negative breast cancer patient experienced stable disease as best response.