Bempegaldesleukin and Pembrolizumab With or Without Chemotherapy in Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2, Open-Label, Multicenter Study to Investigate the Safety and Preliminary Efficacy of Combined Bempegaldesleukin (NKTR-214) and Pembrolizumab With or Without Chemotherapy in Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: NKTR-214
* Drug: Pembrolizumab
* Drug: NKTR-214
* Drug: NKTR-214
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Nab paclitaxel
* Drug: Paclitaxel
* Drug: Pemetrexed
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Optimization, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®)<br>Cohort 1: NKTR-214 will be combined with pembrolizumab | Drug: NKTR-214<br>* NKTR-214: The dose will be 0.008 mg/kg intravenous (IV) infusion administered over 30 (± 5) minutes q3w. The maximum dose of NKTR-214 will be 0.012 mg/kg. This will include a fixed 3+3 dose escalation followed by intra-patient step-up dose escalation based on tolerability.<br>* Other names: CD122-Biased Cytokine;Drug: Pembrolizumab<br>* Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.<br>* Other names: Keytruda®;|
| Experimental: Dose Expansion, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®)<br>Cohort 2: NKTR-214 will be combined with pembrolizumab | Drug: Pembrolizumab<br>* Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.<br>* Other names: Keytruda®;Drug: NKTR-214<br>* NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.<br>* Other names: CD122-Biased Cytokine;|
| Experimental: Dose Expansion, Combo of NKTR-214 + Pembrolizumab (KEYTRUDA®)<br>Cohort 3: NKTR-214 will be combined with pembrolizumab | Drug: Pembrolizumab<br>* Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.<br>* Other names: Keytruda®;Drug: NKTR-214<br>* NKTR-214: The dose will be 0.010 mg/kg intravenous (IV) infusion.<br>* Other names: CD122-Biased Cytokine;|
| Experimental: Dose Expansion, NKTR-214 + Pembrolizumab and either Cisplatin, or Carboplatin and Pemetrexed<br>Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion | Drug: Pembrolizumab<br>* Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.<br>* Other names: Keytruda®;Drug: NKTR-214<br>* NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.<br>* Other names: CD122-Biased Cytokine;Drug: Cisplatin<br>* Cisplatin will be dosed per the pharmacy manual<br>* Other names: Platinol®;Drug: Carboplatin<br>* Carboplatin will be dosed per the pharmacy manual<br>* Other names: Paraplatin®;Drug: Pemetrexed<br>* Pemetrexed will be dosed per the pharmacy manual<br>* Other names: Alimta®;|
| Experimental: Dose Expansion, NKTR-214 + Pembrolizumab and Carboplatin and either Nab-paclitaxel or Paclitaxel<br>Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion | Drug: Pembrolizumab<br>* Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.<br>* Other names: Keytruda®;Drug: NKTR-214<br>* NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.<br>* Other names: CD122-Biased Cytokine;Drug: Carboplatin<br>* Carboplatin will be dosed per the pharmacy manual<br>* Other names: Paraplatin®;Drug: Nab paclitaxel<br>* Nab-paclitaxel will be dosed per local practice and label<br>* Other names: Abraxane®;Drug: Paclitaxel<br>* Paclitaxel will be dosed per local practice and label<br>* Other names: Taxol®;|
| Experimental: Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) or Atezolizumab (TECENTRIQ®)<br>Cohort 0 (Before Protocol Amendment 5.0): NKTR-214 will be combined with pembrolizumab or atezolizumab | Drug: Pembrolizumab<br>* Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.<br>* Other names: Keytruda®;Drug: NKTR-214<br>* NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.<br>* Other names: CD122-Biased Cytokine;Drug: Atezolizumab<br>* Atezolizumab will be dosed per current label indication<br>* Other names: Tecentriq®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-Limiting Toxicities in Dose Optimization Cohort 1a | 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. | DLTs were assessed at 21 days from Cycle 1 | 
| Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability] for Dose Optimization Cohort 1a. | 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. | 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. | 
| 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. | 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. | 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. | 
| 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. | 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bempegaldesleukin, NKTR-214, Metastatic Non-Small Cell Lung Cancer, Pembrolizumab, Keytruda®, NSCLC