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A Study of NKTR-262 in Combination With NKTR-214 and With NKTR-214 Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies (REVEAL)

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ClinicalTrials.gov Identifier: NCT03435640
Recruitment Status : Recruiting
First Posted : February 16, 2018
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
Nektar Therapeutics

Tracking Information
First Submitted Date  ICMJE February 6, 2018
First Posted Date  ICMJE February 16, 2018
Last Update Posted Date August 13, 2019
Actual Study Start Date  ICMJE March 15, 2018
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
  • Safety of NKTR-262 in combination with NKTR-214/nivolumab as evaluated by incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs leading to discontinuation, deaths, and clinical laboratory abnormalities per CTCAE [ Time Frame: 30 days after last dose ]
  • Tolerability of NKTR-262 in combination with bempegaldesleukin / nivolumab as evaluated by incidence of Dose Limiting Toxicities (DLTs), drug-related AEs, SAEs, AEs leading to discontinuation, deaths, clinical laboratory abnormalities per CTCAE 4.03 [ Time Frame: Through study completion, an expected average of 2 years ]
  • Efficacy of NKTR-262 in combination with bempegaldesleukin / nivolumab as assessed by the Objective Response Rate (ORR) based on RECIST 1.1 [ Time Frame: Through study completion, an expected average of 2 years ]
    ORR will be measured by the number and percentage of patients achieving a complete or partial response as best overall response and as defined by RECIST 1.1
Original Primary Outcome Measures  ICMJE
 (submitted: February 9, 2018)
  • Safety of NKTR-262 in combination with NKTR-214 / nivolumab as evaluated by incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs leading to discontinuation, deaths, and clinical laboratory abnormalities per CTCAE 4.03 [ Time Frame: 30 days after last dose ]
  • Tolerability of NKTR-262 in combination with NKTR-214 / nivolumab as evaluated by incidence of Dose Limiting Toxicities (DLTs), drug-related AEs, SAEs, AEs leading to discontinuation, deaths, clinical laboratory abnormalities per CTCAE 4.03 [ Time Frame: Through study completion, an expected average of 2 years ]
  • Efficacy of NKTR-262 in combination with NKTR-214 / nivolumab as assessed by the Objective Response Rate (ORR) based on RECIST 1.1 [ Time Frame: Through study completion, an expected average of 2 years ]
    ORR will be measured by the number and percentage of patients achieving a complete or partial response as best overall response and as defined by RECIST 1.1
Change History Complete list of historical versions of study NCT03435640 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of NKTR-262 in Combination With NKTR-214 and With NKTR-214 Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies
Official Title  ICMJE A Phase 1/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-262 in Combination With NKTR-214 and in Combination With NKTR-214 Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies
Brief Summary Patients will receive intra-tumoral (IT) NKTR-262 in 3-week treatment cycles. During the Phase 1 dose escalation portion of the trial, NKTR-262 will be combined with systemic administration of bempegaldesleukin. After determination of the recommended Phase 2 dose (RP2D) of NKTR-262, between 6 and 12 patients may be enrolled at the RP2D to further characterize the safety and tolerability profile of the combination of NKTR 262 plus bempegaldesleukin (doublet) or NKTR 262 plus bempegaldesleukin in combination with nivolumab (triplet) in Cohorts A and B, respectively. In the Phase 2 dose expansion portion, patients will be treated with doublet or triplet in the relapsed/refractory setting and earlier lines of therapy.
Detailed Description

Cancer treatments that couple pharmacological activation of tumor antigen presentation with activation and expansion of CD8+ T and natural killer (NK) cells in the tumor environment have the potential to induce an effective anti-tumor immune response in patients. NKTR-262 is a small molecule agonist of toll-like receptors (TLRs) 7/8 designed to be retained in the tumor micro-environment in order to activate antigen-presenting cells (APC), such as dendritic cells, to create new antigen-specific cytotoxic T cells. As a CD122-biased agonist, bempegaldesleukin monotherapy increases newly proliferative CD8+ T cells in tumors. NKTR-262 plus bempegaldesleukin is expected to increase expansion of antigen-specific CD8+ T cells. In preclinical studies, a single IT injection of NKTR-262 plus IV bempegaldesleukin resulted in complete abscopal effects in tumor models. Preliminary clinical data show bempegaldesleukin plus nivolumab enhances immune-stimulatory responses. The REVEAL trial will assess safety and anti-tumor activity of NKTR-262 with bempegaldesleukin +/- nivolumab for the treatment of selected cancers.

  • Melanoma (1st-line and relapsed/refractory)
  • Merkel Cell Carcinoma (2nd-line and relapsed/refractory)
  • Triple Negative Breast Cancer (1st- and 2nd-line and relapsed/refractory)
  • Renal Cell Carcinoma (1st-line and relapsed/refractory)
  • Colorectal Cancer (2nd-line and relapsed/refractory; MSI non-high)
  • Colorectal Cancer (2nd 3rd-line+, I-O therapy naive; relapsed/refractory; MSI high)
  • Head and Neck Squamous Cell Carcinoma (2nd-line and relapsed/refractory)
  • Sarcoma (2nd-line and relapsed/refractory)
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Melanoma
  • Merkel Cell Carcinoma
  • Triple Negative Breast Cancer
  • Head and Neck Squamous Cell Carcinoma
  • Renal Cell Carcinoma
  • Colorectal Cancer
  • Sarcoma
Intervention  ICMJE
  • Drug: NKTR-262

    During Phase 1 Doublet: Patients will receive escalating doses of NKTR-262 IT (starting dose 0.03 mg) in 3-week treatment cycles. During Phase 1 Doublet (Cohort A), Phase 2 Doublet: Patients will receive the RP2D of NKTR-262.

    During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive the RP2D of NKTR-262.

  • Drug: bempegaldesleukin

    During Phase 1 Doublet (Cohort A), and Phase 2 Doublet: Patients will receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.

    During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.

  • Drug: nivolumab
    During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients will receive a nivolumab flat dose of 360 mg administered in 3-week treatment cycles.
    Other Name: Opdivo®
Study Arms  ICMJE
  • Experimental: Doublet: NKTR-262 + bempegaldesleukin

    Phase 1 Doublet: NKTR-262 in escalating doses, will be combined with bempegaldesleukin. The goal of this dose escalation part of the study is to establish a safe and tolerable RP2D for NKTR-262 in combination with bempegaldesleukin (Every Three Week [Q3W] fixed dose) in select tumor indications.

    Phase 2 Doublet: NKTR-262 RP2D will be combined with a Q3W dose of bempegaldesleukin in select tumor indications to evaluate anti-tumor activity and to obtain additional safety data.

    Patients may be discontinued from receiving study treatment based on the results of disease assessments or if experiencing intolerable side effects.

    Interventions:
    • Drug: NKTR-262
    • Drug: bempegaldesleukin
  • Experimental: Triplet: NKTR-262 + bempegaldesleukin + Nivolumab

    Phase 1 Triplet: The RP2D of NKTR-262 RP2D will be combined with a Q3W dose regimen of bempegaldesleukin plus nivolumab. The goal is to establish the safety and tolerability of the triplet regimen.

    Phase 2 Triplet: The RP2D of NKTR-262 will be combined with a Q3W dose regimen of bempegaldesleukin plus nivolumab in select tumor indications to evaluate anti-tumor activity and to obtain additional safety data.

    Patients may be discontinued from receiving study treatment based on the results of disease assessments or if experiencing intolerable side effects.

    Interventions:
    • Drug: NKTR-262
    • Drug: bempegaldesleukin
    • Drug: nivolumab
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: February 9, 2018)
393
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) metastatic cancer of the following histologies: melanoma (MEL), Merkel cell carcinoma (MCC), triple-negative breast cancer (TNBC), renal cell carcinoma (RCC), colorectal cancer, head and neck squamous cell carcinoma (HNSCC), or sarcoma.
  • Life expectancy > 12 weeks as determined by the Investigator.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Measurable disease per RECIST 1.1.
  • Patients enrolled in Cohorts 1-8, Cohort A, Cohort B and Phase 2 Doublet must be refractory to all therapies known to confer clinical benefit to their disease.
  • Fresh tumor tissue available for cellular characterization and programmed cell death protein 1 (PD-L1) status.
  • Injected lesions (up to two) must be between 20 mm and 90 mm in diameter for IT injection; lesions must be accessible for baseline and on-treatment biopsies. Any liver lesion targeted for injection must not exceed 50 mm at the time of injection.
  • Demonstrated adequate organ function within 14 days of Cycle 1 Day 1 (C1D1).

Exclusion Criteria:

  • Use of an investigational agent or an investigational device within 21 days before administration of first dose of study drug(s).
  • Patients treated with prior interleukin-2 (IL-2).
  • Patients who have been previously treated with a toll-like receptor (TLR) agonist (excluding topical agents) and patients who have received experimental cancer vaccines.
  • Patients who have received systemic interferon (IFN)α within the previous 6 months prior to enrollment to the study.
  • Other active malignancy, except non-melanomic skin cancer
  • Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
  • Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis.
  • Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at Screening.

History of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following:

  • Unstable angina or myocardial infarction.
  • Congestive heart failure (NYHA Class III or IV).
  • Uncontrolled clinically significant arrhythmias.
  • Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic retinopathy, retinal hemorrhage, macular degeneration).
  • Uveal melanoma will be excluded
  • Patients with tumor that invade the superior vena cava or other major blood vessels.

Additional inclusion and exclusion criteria for specific tumor types will 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: Mona Vimal 855-482-8676
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03435640
Other Study ID Numbers  ICMJE 17-262-01
2018-004625-84 ( EudraCT Number )
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 Not Provided
Responsible Party Nektar Therapeutics
Study Sponsor  ICMJE Nektar Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mario Marcondes, MD, PhD Nektar Therapeutics
PRS Account Nektar Therapeutics
Verification Date August 2019

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