Bempegaldesleukin and Pembrolizumab With or Without Chemotherapy in Locally Advanced or Metastatic Solid Tumors (PROPEL)
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| ClinicalTrials.gov Identifier: NCT03138889 |
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Recruitment Status :
Terminated
(Sponsor decision)
First Posted : May 3, 2017
Results First Posted : March 9, 2023
Last Update Posted : March 10, 2023
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Non-Small Cell Lung Cancer | Drug: NKTR-214 Drug: Pembrolizumab Drug: Cisplatin Drug: Carboplatin Drug: Nab paclitaxel Drug: Paclitaxel Drug: Pemetrexed Drug: Atezolizumab | Phase 1 Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 162 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | June 9, 2017 |
| Actual Primary Completion Date : | July 5, 2022 |
| Actual Study Completion Date : | August 24, 2022 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Dose Optimization, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®)
Cohort 1: NKTR-214 will be combined with pembrolizumab
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Drug: NKTR-214
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.
Other Name: CD122-Biased Cytokine Drug: Pembrolizumab Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.
Other Name: Keytruda® |
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Experimental: Dose Expansion, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®)
Cohort 2: NKTR-214 will be combined with pembrolizumab
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Drug: Pembrolizumab
Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.
Other Name: Keytruda® Drug: NKTR-214 NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.
Other Name: CD122-Biased Cytokine |
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Experimental: Dose Expansion, Combo of NKTR-214 + Pembrolizumab (KEYTRUDA®)
Cohort 3: NKTR-214 will be combined with pembrolizumab
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Drug: Pembrolizumab
Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.
Other Name: Keytruda® Drug: NKTR-214 NKTR-214: The dose will be 0.010 mg/kg intravenous (IV) infusion.
Other Name: CD122-Biased Cytokine |
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Experimental: Dose Expansion, NKTR-214 + Pembrolizumab and either Cisplatin, or Carboplatin and Pemetrexed
Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion
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Drug: Pembrolizumab
Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.
Other Name: Keytruda® Drug: NKTR-214 NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.
Other Name: CD122-Biased Cytokine Drug: Cisplatin Cisplatin will be dosed per the pharmacy manual
Other Name: Platinol® Drug: Carboplatin Carboplatin will be dosed per the pharmacy manual
Other Name: Paraplatin® Drug: Pemetrexed Pemetrexed will be dosed per the pharmacy manual
Other Name: Alimta® |
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Experimental: Dose Expansion, NKTR-214 + Pembrolizumab and Carboplatin and either Nab-paclitaxel or Paclitaxel
Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion
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Drug: Pembrolizumab
Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.
Other Name: Keytruda® Drug: NKTR-214 NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.
Other Name: CD122-Biased Cytokine Drug: Carboplatin Carboplatin will be dosed per the pharmacy manual
Other Name: Paraplatin® Drug: Nab paclitaxel Nab-paclitaxel will be dosed per local practice and label
Other Name: Abraxane® Drug: Paclitaxel Paclitaxel will be dosed per local practice and label
Other Name: Taxol® |
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Experimental: Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®) or Atezolizumab (TECENTRIQ®)
Cohort 0 (Before Protocol Amendment 5.0): NKTR-214 will be combined with pembrolizumab or atezolizumab
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Drug: Pembrolizumab
Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.
Other Name: Keytruda® Drug: NKTR-214 NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.
Other Name: CD122-Biased Cytokine Drug: Atezolizumab Atezolizumab will be dosed per current label indication
Other Name: Tecentriq® |
- Number of Participants Experiencing Dose-Limiting Toxicities in Dose Optimization Cohort 1a [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03138889
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| Study Director: | Study Director | Nektar Therapeutics |
Documents provided by Nektar Therapeutics:
| Responsible Party: | Nektar Therapeutics |
| ClinicalTrials.gov Identifier: | NCT03138889 |
| Other Study ID Numbers: |
16-214-05 |
| First Posted: | May 3, 2017 Key Record Dates |
| Results First Posted: | March 9, 2023 |
| Last Update Posted: | March 10, 2023 |
| Last Verified: | March 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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NKTR-214 Metastatic Non-Small Cell Lung Cancer Pembrolizumab |
Keytruda® NSCLC Bempegaldesleukin |
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Carcinoma, Non-Small-Cell Lung Lung Neoplasms Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms Paclitaxel Albumin-Bound Paclitaxel Carboplatin Pembrolizumab |
Pemetrexed Atezolizumab Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological Immune Checkpoint Inhibitors Enzyme Inhibitors Folic Acid Antagonists Nucleic Acid Synthesis Inhibitors |