Bempegaldesleukin and Pembrolizumab With or Without Chemotherapy in Locally Advanced or Metastatic Solid Tumors
- Conditions
- Non-Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT03138889
- Lead Sponsor
- Nektar Therapeutics
- Brief Summary
This study is to assess the safety and tolerability, and to assess the preliminary clinical benefit of NKTR-214 when combined with pembrolizumab (KEYTRUDA®) with or without chemotherapy.
The study is comprised of two groups; dose optimization and dose expansion cohorts.
Dose Optimization included first-line and second-line advanced or metastatic solid tumors including non-small cell lung cancer (NSCLC)
The dose expansion cohort will include first-line NSCLC patients.
- Detailed Description
NKTR-214 is a cytokine (investigational agent) that is designed to target CD122, a protein which is found on certain immune cells (known as CD8+ T Cells and Natural Killer Cells) to expand these cells to promote their anti-tumor effects. Pembrolizumab is a programmed death receptor -1 (PD-1) blocking, fully humanized, engineered monoclonal antibody of IgG1 isotype that promotes anti-tumor effects.
The study will evaluate the clinical benefit, safety and tolerability of combining NKTR-214 with pembrolizumab with or without chemotherapy. Each dose expansion cohort will enroll approximately 100 new patients.
Dose Optimization evaluated an every three-week dose regimen (q3w) of NKTR-214 in combination with pembrolizumab given that the optimal dose and dosing schedule of NKTR-214 in combination with pembrolizumab remains unknown. The previously established recommended Phase 2 dose (0.006 mg/kg) of NKTR-214 was studied in combination with nivolumab.
Dose Expansion: NKTR-214 in combination with pembrolizumab will be evaluated in first-line non-small cell lung cancer (NSCLC). The NKTR-214 dose to be studied is 0.006 mg/kg q3w. This dose is based on the recommended phase 2 dose noted in the monotherapy trial with NKTR-214 (Study 15-214-01, NCT02869295) and an ongoing combination trial (16-214-02, NCT02983045). Pembrolizumab will be administered at a dose of 200mg q3w. Following data review for safety and efficacy, additional patients may be dosed using the findings from the dose optimization cohorts.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 162
Dose Optimization and Dose Expansion Inclusion Criteria:
- Willing and able to provide written informed consent.
- Male or female patients, age 18 years or older at the time of signing the informed consent form (ICF).
- Life expectancy > 12 weeks from the time of enrollment as determined by the Investigator.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Oxygen saturation ≥ 92% on room air for all indications.
- Measurable disease per RECIST 1.1.
- Patients with brain metastases are eligible if certain criteria are met.
- Availability of fresh or archival tumor tissue
- Patients must have a minimum of 6 months of response to any nonpalliative cancer-directed treatment
Dose Expansion Inclusion Criteria (Non-Small Cell Lung Cancer):
- Histologically confirmed diagnosis of stage IV NSCLC.
- Patients must have a minimum of 6 months of response to any nonpalliative cancer-directed treatment.
- Patients with actionable mutations with approved targeted therapy in NSCLC are excluded. Testing for mutations should be performed per standard of care.
- Must not have received anti-cancer therapy for treatment of metastatic lung cancer
- Must not have received prior immunotherapy
- Use of an investigational agent or an investigational device within 28 days before administration of first dose of study drug(s).
- Females who are pregnant or breastfeeding.
- Patients who have an active autoimmune disease
- History of allergy or hypersensitivity to study drug components
- Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
- Prior surgery or radiotherapy within 14 days of therapy.
- For Dose Optimization Cohort 1 only: Chemotherapy or biological therapy within 28 days of enrollment. Targeted therapy (e.g., tyrosine kinase inhibitors) within 14 days of enrollment. Patients with ongoing AEs related to prior cancer therapies will be excluded.
- Participant's inability to adhere to or tolerate protocol or study procedures
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dose Expansion, NKTR-214 + Pembrolizumab and Carboplatin and either Nab-paclitaxel or Paclitaxel Nab paclitaxel Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion Dose Optimization, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) NKTR-214 Cohort 1: NKTR-214 will be combined with pembrolizumab Dose Expansion, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) NKTR-214 Cohort 2: NKTR-214 will be combined with pembrolizumab Dose Expansion, Combo of NKTR-214 + Pembrolizumab (KEYTRUDA®) NKTR-214 Cohort 3: NKTR-214 will be combined with pembrolizumab Dose Expansion, Combo of NKTR-214 + Pembrolizumab (KEYTRUDA®) Pembrolizumab Cohort 3: NKTR-214 will be combined with pembrolizumab Dose Expansion, NKTR-214 + Pembrolizumab and Carboplatin and either Nab-paclitaxel or Paclitaxel NKTR-214 Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) or Atezolizumab (TECENTRIQ®) NKTR-214 Cohort 0 (Before Protocol Amendment 5.0): NKTR-214 will be combined with pembrolizumab or atezolizumab Dose Expansion, NKTR-214 + Pembrolizumab and either Cisplatin, or Carboplatin and Pemetrexed NKTR-214 Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion Dose Optimization, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) Pembrolizumab Cohort 1: NKTR-214 will be combined with pembrolizumab Dose Expansion, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) Pembrolizumab Cohort 2: NKTR-214 will be combined with pembrolizumab Dose Expansion, NKTR-214 + Pembrolizumab and either Cisplatin, or Carboplatin and Pemetrexed Pembrolizumab Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion Dose Expansion, NKTR-214 + Pembrolizumab and either Cisplatin, or Carboplatin and Pemetrexed Cisplatin Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion Dose Expansion, NKTR-214 + Pembrolizumab and either Cisplatin, or Carboplatin and Pemetrexed Carboplatin Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion Dose Expansion, NKTR-214 + Pembrolizumab and Carboplatin and either Nab-paclitaxel or Paclitaxel Pembrolizumab Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion Dose Expansion, NKTR-214 + Pembrolizumab and either Cisplatin, or Carboplatin and Pemetrexed Pemetrexed Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion Dose Expansion, NKTR-214 + Pembrolizumab and Carboplatin and either Nab-paclitaxel or Paclitaxel Carboplatin Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) or Atezolizumab (TECENTRIQ®) Pembrolizumab Cohort 0 (Before Protocol Amendment 5.0): NKTR-214 will be combined with pembrolizumab or atezolizumab Dose Expansion, NKTR-214 + Pembrolizumab and Carboplatin and either Nab-paclitaxel or Paclitaxel Paclitaxel Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) or Atezolizumab (TECENTRIQ®) Atezolizumab Cohort 0 (Before Protocol Amendment 5.0): NKTR-214 will be combined with pembrolizumab or atezolizumab
- Primary Outcome Measures
Name Time Method Number of Participants Experiencing Dose-Limiting Toxicities in Dose Optimization Cohort 1a DLTs were assessed at 21 days from Cycle 1 DLTs were assesses in the Dose Optimization Cohort 1 a, which had doses of NKTR-214 as 0.008 mg/kg, 0.010 mg/kg, and 0.012 m/kg, I combination with pembrolizumab at 200 mg.
A single DLT (hypotension) was reported in 1 patient in dose optimization Cohort 1a.Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability] for Dose Optimization Cohort 1a. AEs reported starting immediately after first dose of study drug(s) until 100 days after the last dose of all study drugs, up to approximately 28 months. Safety and Tolerability of NKTR-214 (starting at dose of 0.008 mg/kg) in combination with pembrolizumab (Keytruda®) as evaluated by incidence of drug-emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs leading to drug discontinuation, and fatal AEs.
Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) by RECIST 1.1 of NKTR-214 Plus Pembrolizumab for Dose Expansion Cohorts 2 and 3. Until disease progression, death, unacceptable toxicity, symptomatic deterioration, Investigator's decision to discontinue treatment, patient withdrew consent or lost to follow-up, or study terminated by Sponsor; or until maximum of 2 years. ORR per BICR by RECIST 1.1 for the Response Evaluable Population dose expansion Cohorts 2 and 3.
ORR is defined as the proportion of enrolled participants who achieved a Best Overall Response (BOR) of CR or PR. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR is calculated as the sum of CR and PR.
The Response Evaluable Population was subjects who received at least 1 dose (or partial dose) of study drug, had measurable disease (per RECIST 1.1) at baseline, and had at least 1 post-baseline assessment of tumor response.Objective Response Rate (ORR) Per Investigator's Assessment by RECIST 1.1 of NKTR-214 at a Dose of 0.006 mg/kg With Pembrolizumab and Platinum-based Chemotherapy for Dose Expansion Cohorts 4+5. Until disease progression, death, unacceptable toxicity, symptomatic deterioration, Investigator's decision to discont. treatment, patient withdrew consent or lost to follow-up, or study terminated by Sponsor; or until maximum of 2 years. ORR per Investigator's Assessment\* by RECIST 1.1 for the Response Evaluable Population dose expansion Cohorts 4 +5. The Response Evaluable Population was subjects who received at least 1 dose (or partial dose) of study drug, had measurable disease (per RECIST 1.1) at baseline, and had at least 1 post-baseline assessment of tumor response.
Objective response is the sum of confirmed complete response and confirmed partial response.
\*Efficacy endpoint for Cohort 4 +5 is per Investigator's Assessment due to the early termination of the study and incompleteness of BICR data for these cohorts.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (38)
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Lungenklinik Hemer
🇩🇪Hemer, Germany
Highlands Oncology Group, PA - North Hills
🇺🇸Fayetteville, Arkansas, United States
Ochsner Medical Center
🇺🇸New Orleans, Louisiana, United States
Augusta University - Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Park Nicollet - Frauenshuh Cancer Center
🇺🇸Saint Louis Park, Minnesota, United States
Washington University School of Medicine in St. Louis
🇺🇸Saint Louis, Missouri, United States
St. Vincent Frontier Cancer Center
🇺🇸Billings, Montana, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
New York University Langone Medical Center
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
West Cancer Center
🇺🇸Germantown, Tennessee, United States
Inova Melanoma and Skin Cancer Center
🇺🇸Fairfax, Virginia, United States
Blue Ridge Cancer Care
🇺🇸Roanoke, Virginia, United States
Northwest Medical Specialties
🇺🇸Tacoma, Washington, United States
Epworth HealthCare
🇦🇺Richmond, Victoria, Australia
Vivantes Klinikum Spandau
🇩🇪Berlin, Germany
Centre Hospitalier de Saint-Quentin
🇫🇷Saint Quentin, France
LungenClinic Grosshansdorf
🇩🇪Grosshansdorf, Germany
Asklepios Fachkliniken München-Gauting
🇩🇪Gauting, Germany
Universitätsklinikum Schleswig-Holstein
🇩🇪Lübeck, Germany
Robert-Bosch-Krankenhaus
🇩🇪Stuttgart, Germany
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario Insular de Gran Canaria
🇪🇸Las Palmas De Gran Canaria, Spain
Hospital Clínico San Carlos
🇪🇸Madrid, Spain
Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
HM Universitario Sanchinarro
🇪🇸Madrid, Spain
Hospital Universitari i Politècnic La Fe
🇪🇸Valencia, Spain
California Pacific Medical Center
🇺🇸San Francisco, California, United States
Comprehensive Cancer Centers of Nevada (CCCN) - Central Valley
🇺🇸Las Vegas, Nevada, United States
Sarah Cannon Research Institute (SCRI) (The SCRI Oncology Research Consortium)
🇺🇸Nashville, Tennessee, United States
Duke Clinical Research Institute
🇺🇸Durham, North Carolina, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
University of Colorado Anschutz Medical Campus
🇺🇸Aurora, Colorado, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Froedtert & the Medical College of Wisconsin Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States