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Clinical Trials

Date: 2017-02-18

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at ASCO GU 2017

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 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.

 

Is general: Yes