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

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ClinicalTrials.gov Identifier: NCT03138889
Recruitment Status : Recruiting
First Posted : May 3, 2017
Last Update Posted : July 9, 2021
Sponsor:
Information provided by (Responsible Party):
Nektar Therapeutics

Tracking Information
First Submitted Date  ICMJE May 1, 2017
First Posted Date  ICMJE May 3, 2017
Last Update Posted Date July 9, 2021
Actual Study Start Date  ICMJE June 9, 2017
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2021)
  • Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of NKTR-214 in combination with pembrolizumab (Keytruda®) [ Time Frame: 100 days after last dose ]
    Safety and Tolerability of NKTR-214 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.
  • Recommended Phase 2 Dose (RP2D) or Maximum Tolerated Dose (MTD) or optimal dosing schedule of NKTR-214 in combination with pembrolizumab (Keytruda®) [ Time Frame: 100 days after last dose ]
    To define the Recommended Phase 2 Dose (RP2D), or Maximum Tolerated Dose (MTD), or optimal dosing schedule of NKTR-214 in combination with pembrolizumab (Keytruda®), by evaluating the incidence of Dose Limiting Toxicities (DLTs) within the DLT window (21 days after first dose), drug-related AEs, SAEs, adverse events leading to discontinuation, deaths and overall tolerability.
  • Objective response rate (ORR) per blinded independent central review (BICR) by RECIST 1.1 of NKTR-214 plus pembrolizumab with or without systemic chemotherapy in patients with untreated metastatic NSCLC [ Time Frame: 100 days after last dose ]
    ORR is defined as the proportion of enrolled participants who achieved a Best Overall Response (BOR) of CR or PR
Original Primary Outcome Measures  ICMJE
 (submitted: May 1, 2017)
  • Safety and Tolerability of NKTR-214 in combination with atezolizumab (Tecentriq) [ Time Frame: 100 days after last dose ]
    Safety and Tolerability of NKTR-214 in combination with atezolizumab (Tecentriq) as evaluated by incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and adverse events leading to discontinuation, deaths, and clinical laboratory test abnormalities
  • Recommended Phase 2 Dose (RP2D) of NKTR-214 in combination with atezolizumab (Tecentriq) [ Time Frame: 100 days after last dose ]
    To define the Recommended Phase 2 Dose (RP2D), or Maximum Tolerated Dose (MTD), of NKTR-214 in combination with atezolizumab (Tecentriq), by evaluating the incidence of Dose Limiting Toxicities (DLTs), drug-related AEs, SAEs, adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 27, 2021)
  • Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of NKTR-214 plus pembrolizumab (Keytruda®) with or without systemic chemotherapy in untreated metastatic NSCLC. [ Time Frame: 100 days after last dose ]
    Safety and Tolerability of NKTR-214 plus pembrolizumab (Keytruda®) with or without systemic chemotherapy as evaluated by incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and adverse events leading to discontinuation, deaths, and overall tolerability.
  • Objective response rate (ORR) per RECIST 1.1 in Dose Optimization [ Time Frame: Through study completion, an expected average of 2 years ]
    ORR is defined as the proportion of enrolled participants who achieved a Best Overall Response (BOR) of CR or PR
  • Duration of response (DOR) [ Time Frame: Through study completion, an expected average of 2 years ]
    DOR for patients who have confirmed complete response (CR) or confirmed partial response (PR) as the date from first documented CR or PR to the date of the first objectively documented disease progression per RECIST 1.1 or death due to any cause, whichever is earlier.
  • Clinical benefit rate (CBR) [ Time Frame: Through study completion, an expected average of 2 years ]
    CBR is defined as the number of patients with confirmed complete response, confirmed partial response, or stable disease (≥ 7 weeks).
  • Time to Response (TTR) [ Time Frame: Through study completion, an expected average of 2 years ]
    TTR will be defined for patients who had confirmed CR or confirmed PR as the time from the date of first dose to date of first documented CR or PR per RECIST 1.1.
  • Progression-Free Survival (PFS) [ Time Frame: Through study completion, an expected average of 2 years ]
    PFS is defined as the time from date of first dose to the date of the first objectively documented tumor progression or death due to any cause
  • Overall Survival (OS) [ Time Frame: Through study completion, an expected average of 2 years ]
    OS is defined as the time from date of first dose to the date of death.
  • To assess the association between efficacy measures and PD L1 expression in tumors. [ Time Frame: Through study completion, an expected average of 2 years ]
    Efficacy measures are defined as ORR and changes in PD-L1 expression from on treatment biopsy in Dose Optimization.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 1, 2017)
  • Efficacy of NKTR-214 in combination with atezolizumab (Tecentriq) [ Time Frame: Through study completion, an expected average of 2 years ]
    Efficacy, or the preliminary anti-tumor activity, of NKTR-214 in combination with atezolizumab (Tecentriq), as assessed by the Objective Response Rate (ORR) based on RECIST 1.1
  • Progression-Free Survival (PFS) [ Time Frame: Through study completion, an expected average of 2 years ]
    PFS is defined as the time from date of first dose to the date of the first objectively documented tumor progression or death due to any cause
  • Overall Survival (OS) [ Time Frame: Through study completion, an expected average of 2 years ]
    Overall survival is defined as the time from date of first dose to the date of death.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bempegaldesleukin and Pembrolizumab With or Without Chemotherapy in Locally Advanced or Metastatic Solid Tumors
Official Title  ICMJE 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
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 will include first-line and second-line melanoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), and hepatocellular carcinoma (HCC) regardless of PD-L1 expression status. This cohort will include patients enrolled in a 3 + 3 dose escalation and intra-patient step-up dose schemas.

The dose expansion cohort will include first-line NSCLC patients regardless of PD-L1 expression status.

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: will evaluate an every three-week dose regimen (q3w) of NKTR-214 in combination with pembrolizumab in approximately 40 patients 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. Tumors to be studied include first-line and second-line melanoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), and hepatocellular carcinoma (HCC). NKTR-214 will be administered at a starting dose of 0.008 mg/kg q3w. Pembrolizumab will be administered at a dose of 200 mg q3w. Patients will undergo a fixed 3+3 dose escalation followed by intra-patient step-up dose escalation at a dose determined by the safety review committee after reviewing the data in the fixed 3+3 dose escalation.

Dose Expansion: NKTR-214 in combination with pembrolizumab in approximately 58 patients 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Non-Small Cell Lung Cancer
  • Melanoma
  • Urothelial Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Hepatocellular Carcinoma
Intervention  ICMJE
  • 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®
  • Drug: NKTR-214
    NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion.
    Other Name: CD122-Biased Cytokine
  • Drug: NKTR-214
    NKTR-214: The dose will be 0.010 mg/kg intravenous (IV) infusion.
    Other Name: CD122-Biased Cytokine
Study Arms  ICMJE
  • Experimental: Dose Optimization, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®)
    Cohort 1: NKTR-214 will be combined with pembrolizumab
    Interventions:
    • Drug: NKTR-214
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Combo of NKTR-214 + Pembrolizumab(KEYTRUDA®)
    Cohort 2: NKTR-214 will be combined with pembrolizumab
    Interventions:
    • Drug: Pembrolizumab
    • Drug: NKTR-214
  • Experimental: Dose Expansion, Combo of NKTR-214 + Pembrolizumab (KEYTRUDA®)
    Cohort 3: NKTR-214 will be combined with pembrolizumab
    Interventions:
    • Drug: Pembrolizumab
    • Drug: NKTR-214
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 27, 2021)
240
Original Estimated Enrollment  ICMJE
 (submitted: May 1, 2017)
36
Estimated Study Completion Date  ICMJE January 2024
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 Optimization Inclusion Criteria (Multiple Solid Tumors):

  • Melanoma:

    • Histologically confirmed stage IV (metastatic) melanoma.
  • Non-small Cell Lung Cancer:

    • Histologically confirmed diagnosis of stage IV NSCLC
    • Must not have received systemic anti-PD-L1 therapy for metastatic disease.
    • Patients with actionable mutations with approved targeted therapy in NSCLC are excluded. Testing for mutations should be performed in accordance with standard of care.
  • Urothelial Carcinoma:

    • Histologically confirmed diagnosis of metastatic urothelial carcinoma
  • Head and Neck Squamous Cell Carcinoma (HNSCC)

    • Histologically confirmed diagnosis of metastatic HNSCC
  • Hepatocellular Carcinoma (HCC)

    • Histologically confirmed diagnosis of metastatic HCC

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nektar Recruitment 855-482-8676 StudyInquiry@nektar.com
Contact: Medical Affairs Department medicalaffairs@nektar.com
Listed Location Countries  ICMJE Australia,   France,   Germany,   Italy,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03138889
Other Study ID Numbers  ICMJE 16-214-05
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Nektar Therapeutics
Study Sponsor  ICMJE Nektar Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Nektar Therapeutics
PRS Account Nektar Therapeutics
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP