Clinical Trials /

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

NCT03435640

Description:

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 18 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.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Melanoma
  • Merkel Cell Carcinoma
  • Renal Cell Carcinoma
  • Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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: 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

Clinical Trial IDs

  • ORG STUDY ID: 17-262-01
  • SECONDARY ID: 2018-004625-84
  • NCT ID: NCT03435640

Conditions

  • Melanoma
  • Merkel Cell Carcinoma
  • Triple Negative Breast Cancer
  • Head and Neck Squamous Cell Carcinoma
  • Renal Cell Carcinoma
  • Colorectal Cancer
  • Sarcoma

Interventions

DrugSynonymsArms
NKTR-262Doublet: NKTR-262 + bempegaldesleukin
bempegaldesleukinDoublet: NKTR-262 + bempegaldesleukin
nivolumabOpdivo®Triplet: NKTR-262 + bempegaldesleukin + Nivolumab

Purpose

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)
    

Trial Arms

NameTypeDescriptionInterventions
Doublet: NKTR-262 + bempegaldesleukinExperimentalPhase 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.
  • NKTR-262
  • bempegaldesleukin
Triplet: NKTR-262 + bempegaldesleukin + NivolumabExperimentalPhase 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.
  • NKTR-262
  • bempegaldesleukin
  • nivolumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nektar Therapeutics

Trial Keywords

  • Bempegaldesleukin (NKTR-214)
  • NKTR-262
  • Nivolumab
  • Opdivo®
  • Metastatic
  • Locally advanced
  • Relapsed/Refractory
  • TLR7/8
  • CD122

Last Updated