Clinical Trials

Date: 2017-06-05

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago

Company: Nektar Therapeutics (USA - CA)

Product: NKTR-214

Action mechanism:

• cytokine/proteine/immunotherapy product. NKTR-214 is a CD122-biased immune-stimulatory cytokine, which is designed to stimulate the patient's own immune system to eliminate cancer cells. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase the proliferation of CD8-positive effector T cells, and these CD8-positive T cells comprise a key component of the tumor infiltrating lymphocytes that provide cell-mediated anti-tumor effects.
• By biasing activation to the CD122 receptor, NKTR-214 enhances CD8-positive T cells (tumor-killing cells) in the tumor. In preclinical studies, a single dose of NKTR-214 resulted in an approximate 400-fold AUC exposure within the tumor compared with an equivalent dose of aldesleukin, an existing IL-2 therapy. This increase potentially enables, for the first time, an antibody-like dosing regimen for a cytokine. In dosing studies in non-human primates, there was no evidence of low blood pressure or vascular leak syndrome with NKTR-214 at predicted clinical therapeutic doses.
• Nektar and BMS are collaborating to develop NKTR-214 as a potential combination treatment regimen with Opdivo® (nivolumab) in five tumor types and eight potential indications. The Phase 1/2 clinical program will enroll up to 260 patients and will evaluate the potential for the combination of Opdivo (nivolumab) and NKTR-214 to show improved and sustained efficacy and tolerability above the current standard of care in melanoma, kidney, triple-negative breast cancer, bladder and non-small cell lung cancer patients. The initial dose-escalation trial is underway with Opdivo (nivolumab) and NKTR-214 in the indications of first-line melanoma, second-line RCC checkpoint therapy-naïve, and second-line non-small cell lung cancer (NSCLC) checkpoint therapy-naïve.

Disease: solid tumors including melanoma, renal cell carcinoma (RCC), bladder cancer, colorectal cancer

Therapeutic area: Cancer - Oncology

Country:

Trial details:

• The Phase 1/2 study of NKTR-214 is designed to evaluate patients with advanced solid tumors, including melanoma, renal cell carcinoma and non-small cell lung cancer. The study is being conducted initially at two primary investigator sites: MD Anderson Cancer Center under Drs. Patrick Hwu and Adi Diab; and Yale Cancer Center, under Drs. Mario Sznol and Michael Hurwitz.

Latest news:

• • On June 5, 2017, Nektar Therapeutics announced that it presented new findings from two Phase 1 clinical studies of NKTR-214, Nektar's lead immuno-oncology candidate, a CD122-biased agonist, at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.  New findings were presented in patients from an ongoing Phase 1 dose-escalation study evaluating monotherapy NKTR-214 in patients with solid tumors in a poster session at the 2017 American Society of Clinical Oncology Annual Meeting in Chicago:
• - Confirmed partial responses (PRs) were observed in 3 of 4 patients with Stage IV renal cell carcinoma (RCC) who were immuno-oncology (I-O) treatment naïve who experienced stable disease (SD) with tumor shrinkage while on NKTR-214 monotherapy (range of 3-8 cycles) and then received sequential therapy with nivolumab.  All three patients with confirmed PRs experienced rapid responses at first 8-week scan after initiating sequential therapy with nivolumab. The fourth patient experienced SD at first 8-week scan.  All four patients had progressed on one or more prior tyrosine-kinase inhibitor (TKI) therapies and all are continuing on therapy with nivolumab.
• - Two heavily pre-treated Stage IV patients are continuing treatment with monotherapy NKTR-214.  One patient with BRAF-mutated melanoma, who was previously treated with ipilimumab and vemurafenib, continues on NKTR-214 therapy with SD for greater than 15 months.  One patient with RCC who was previously treated with high-dose IL-2 and subsequently refractory to single agent treatments with OX40 and nivolumab, continues on NKTR-214 therapy with SD for greater than 10 months.
• - NKTR-214 monotherapy demonstrated a favorable safety profile with no immune-related adverse events (AEs) (N=28, Stage IV patients)
• - Data from blood and tumor samples show that NKTR-214 increases immune cells in the blood and tumor microenvironment even in subjects who have failed multiple prior immunotherapeutic agents.
• Initial data were presented from the ongoing PIVOT dose-escalation trial evaluating NKTR-214 in combination with nivolumab in patients with melanoma, renal cell carcinoma and non-small cell lung cancer.  As of June 1, 2017, 20 patients were enrolled in the dose-escalation phase of the ongoing PIVOT study in a number of dose cohorts.  Findings from the first patients enrolled in the ongoing study are as follows:
• Clinical benefit data (evaluable scans) were available for initial patients enrolled in the trial:
• - Responses (RECIST 1.1) were observed in 3 of 4 patients with BRAF-mutated Stage IV melanoma (1 CR, 2 uPR).  Time to response for these patients, respectively, was 6 weeks, 7 weeks and 20 weeks.  All three patients with responses are ongoing treatment in the trial.
• - Two patients with RCC who were I-O naïve were evaluable for at least two scans.  A confirmed PR (-39%) was observed in one of these patients (PD-L1 negative) who progressed on prior TKI therapy.  Time to response was 15 weeks.  The second patient, who progressed on prior bevacizumab therapy, experienced SD and is continuing on treatment
• - 4 additional RCC IO naïve patients were evaluable for one scan.  All four had SD in their target lesions and are continuing on treatment in the study.
• On treatment tumor biopsies from the PIVOT trial show robust expansion of ICOS+ CD4 and CD8 T cells with the combination of NKTR-214 and nivolumab.
• All dose cohorts of NKTR-214 and nivolumab demonstrate a favorable safety profile and are well-tolerated.  In the study to-date, there are no dose-limiting toxicities, no grade 3 or higher treatment-related AEs, and no immune-related AEs (such as colitis, dermatitis, pneumonitis or endocrinopathies).
• The dose-escalation portion of the trial is enrolling with the last dose cohort recently initiated (NKTR-214 0.009 mg/kg q3w + nivo 360 mg q3w) in order to identify a recommended Phase 2 dose.
• Nektar Therapeutics is now looking forward to identifying a Phase 2 dose and initiating the expansion cohorts for the PIVOT trial in its 8 target indications in the third quarter of 2017.
• • On February 18, 2017, Nektar Therapeutics announced that positive Phase 1 clinical data for NKTR-214, in patients with renal cell carcinoma were presented at ASCO GU 2017. The results were presented by Michael Hurwitz, MD, PhD, Assistant Professor of Medicine, Department of Medical Oncology at Yale Cancer Center and were entitled "A Novel Immune Agonist, NKTR-214, Increases the Number and Activity of CD8+ Tumor Infiltrating Lymphocytes in Patients with Advanced Renal Cell Carcinoma." Clinical benefit and safety data were presented on 15 patients from the trial with renal cell carcinoma who were treated with single-agent NKTR-214: 6/15 (40%) patients with renal cell carcinoma had radiographic reductions in tumor size per RECIST 1.1 on NKTR-214, including: 3 patients who had progressed on 1 prior tyrosine kinase inhibitor (TKI) and had also progressed on 1 prior checkpoint therapy, 3 patients who had progressed on 1 prior tyrosine kinase inhibitor (TKI) and were checkpoint therapy naïve, including 1 patient who experienced an unconfirmed partial response.
• NKTR-214 continues to demonstrate a favorable safety and tolerability profile with convenient, outpatient q3w or q2w administration in all patients evaluable for safety to-date.
• Immune pheno-typing was conducted and biomarkers of immune activation were measured in patients with evaluable tumor biopsies and blood samples. Treatment with NKTR-214 produced a robust elevation in immune cell frequency and activation, including:
• Increase in total lymphocytes and newly proliferating (Ki67+) CD4+ T cells, CD8+ T cells, and NK cells, with increases greater than 50-fold observed Increase in CD8+ T cells of up to 10-fold in the tumor micro-environment in patients with evaluable tumor biopsies (pre-dose and post-dose at week 3) Increase in expression of cell-surface PD-1 on T cell subsets of up to 2-fold in the tumor micro-environment.
• • On November 9, 2016, Nektar Therapeutics announced that new Phase 1 clinical data for Nektar's lead immuno-oncology agent, NKTR-214, were presented at the SITC 2016 Annual Meeting. The results were presented by Adi Diab, MD, Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in an oral presentation during a session entitled "New Cancer Immunotherapy Agents in Development." Interim results presented were from the ongoing Phase 1 dose-escalation, first-in-human, trial of single-agent NKTR-214 in patients with locally advanced or metastatic solid tumors, including melanoma, renal cell carcinoma, bladder, colorectal and other solid tumor cancers. A total of 20 patients were treated in four separate every three-week (q3w) dose cohorts (ranging from 0.003 mg/kg q3w to 0.012 mg/kg q3w) with 18 of these patients evaluable for anti-tumor activity. Based upon encouraging anti-tumor activity and tolerability of NKTR-214 observed at the 0.006 mg/kg q3w dose, an every two week (q2w) cohort of the 0.006 mg/kg dose began enrolling in September 2016 with an additional 5 patients enrolled to this cohort, all of which are continuing on therapy. Preliminary encouraging evidence of anti-tumor activity has been observed to date in the ongoing study: 12/18 (67%) evaluable patients had stable disease at the initial 8 week scan 7/18 (39%) evaluable patients had radiographic reductions in tumor size per RECIST 1.1 on NKTR-214. One patient with metastatic melanoma (prior treatment with ipilimumab and a BRAF inhibitor) has received 13 cycles of treatment (0.003 mg/kg q3w) with stable disease and continues on therapy with NKTR-214 In the 18 evaluable patients, a total of 5 patients with metastatic RCC who had progressed on 1 prior tyrosine kinase inhibitor were treated with NKTR-214 at the 0.006 mg/kg q3w dose level: 1/5 (20%) of these RCC patients had a uPR per RECIST 1.1 (at 16 week scan) and treatment with NKTR-214 is ongoing 2/5 of these RCC patients had additional tumor reductions of 6% and 10% per RECIST 1.1 while on NKTR-214
• NKTR-214 also demonstrated a favorable safety and tolerability profile with convenient, outpatient q2w or q3w administration in 25 patients evaluable for safety to-date: No immune-related AEs were observed (e.g. colitis, dermatitis, hepatitis pneumonitis, adrenal insufficiency) No deaths or grade 4 AEs related to NKTR-214 No capillary leak syndrome was observed at any dose One patient experienced a dose-limiting toxicity (DLT) of hypotension/syncope at 0.012 mg/kg q3w and continued on treatment at 0.006 mg/kg q3w 3/25 patients experienced grade 3 hypotension, which was rapidly reversed with fluid administration and all patients continued on treatment with NKTR-214 Most common grade 1-2 adverse events were fatigue, pruritis, cough, decreased appetite, pyrexia, and hypotension
• Immune pheno-typing was conducted and biomarkers of immune activation were measured in patients with evaluable tumor biopsies and blood samples. Treatment with NKTR-214 produced a robust elevation in immune cell frequency and activation, including:
• Increase in total and newly proliferating (Ki67+) CD4+ T cells, CD8+ T cells, and Natural Killer (NK) cells in 9/9 patients with blood samples evaluated in the trial to-date, with increases of up to 30-fold observed Increase in frequency of PD-1+ T cell subsets of up to 9-fold in the blood
• Increase in CD8+ T cells and Natural Killer (NK) cells of up to 10-fold in the tumor micro-environment in patients with evaluable tumor biopsies (pre-dose and post-dose at week 3), with minimal intratumoral changes to T regulatory cells Increase in expression of cell-surface PD-1 on T cell subsets of up to 2-fold in the tumor micro-environment
• Induction of an activation gene signature in the tumor micro-environment, including increases of 5-fold or greater in expression of interferon ?, perforin and granzyme B genes.
• • On December 8, 2015, Nektar Therapeutics announced that dosing has commenced in the Phase 1/2 clinical study evaluating the efficacy and safety of NKTR-214 in the treatment of solid tumors.
• • On October  7, 2015, Nektar Therapeutics announced that it has submitted an Investigational New Drug (IND) application to the FDA for NKTR-214. The company plans to initiate a Phase 1/2 clinical study by the end of 2015. The study will evaluate the safety, tolerability and efficacy of NKTR-214 in patients with solid tumor malignancies and will include expansion cohorts that will evaluate NKTR-214 both as a single-agent and in combination with a checkpoint inhibitor.

 

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