Clinical Trials /

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

NCT03435640

Description:

Patients will receive intratumoral (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 NKTR-214. After determination of the recommended Phase 2 dose (RP2D) of NKTR-262, NKTR-262 will be combined with NKTR-214 (Cohort A) and with NKTR-214 plus nivolumab (Cohort B). In the Phase 2 dose expansion portion, patients will be treated with NKTR-262 and NKTR-214 (doublet) or NKTR-262 and NKTR-214 plus nivolumab (triplet) in the relapsed/refractory setting and earlier lines of therapy.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Melanoma
  • Merkel Cell Carcinoma
  • Ovarian Carcinoma
  • Renal Cell Carcinoma
  • Sarcoma
  • Urothelial Carcinoma
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
  • NCT ID: NCT03435640

Conditions

  • Melanoma
  • Merkel Cell Carcinoma
  • Triple Negative Breast Cancer
  • Ovarian Cancer
  • Renal Cell Carcinoma
  • Colorectal Cancer
  • Urothelial Carcinoma
  • Sarcoma

Interventions

DrugSynonymsArms
NKTR-262Doublet: NKTR-262 + NKTR-214
NKTR-214Doublet: NKTR-262 + NKTR-214
nivolumabOpdivo®Triplet: NKTR-262 + NKTR-214 + Nivolumab

Purpose

Patients will receive intratumoral (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 NKTR-214. After determination of the recommended Phase 2 dose (RP2D) of NKTR-262, NKTR-262 will be combined with NKTR-214 (Cohort A) and with NKTR-214 plus nivolumab (Cohort B). In the Phase 2 dose expansion portion, patients will be treated with NKTR-262 and NKTR-214 (doublet) or NKTR-262 and NKTR-214 plus nivolumab (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,
      NKTR-214 monotherapy increases newly proliferative CD8+ T cells in tumors. NKTR-262 plus
      NKTR-214 is expected to increase expansion of antigen-specific CD8+ T cells. In preclinical
      studies, a single IT injection of NKTR-262 plus IV NKTR-214 resulted in complete abscopal
      effects in tumor models. Preliminary clinical data show NKTR-214 plus nivolumab enhances
      immune-stimulatory responses. The REVEAL trial will assess safety and anti-tumor activity of
      NKTR-262 with NKTR-214 +/- nivolumab for the treatment of selected cancers.

        -  Melanoma (1st-line and relapsed/refractory)

        -  Merkel Cell Carcinoma (1st -line and relapsed/refractory)

        -  Triple Negative Breast Cancer (1st - and 2nd-line and relapsed/refractory)

        -  Ovarian Cancer (3rd-line and relapsed/refractory)

        -  Renal Cell Carcinoma (1st-line and relapsed/refractory)

        -  Colorectal Cancer (2nd-line and relapsed/refractory)

        -  Urothelial Carcinoma (1st-line and relapsed/refractory)

        -  Sarcoma (2nd-line and relapsed/refractory)
    

Trial Arms

NameTypeDescriptionInterventions
Doublet: NKTR-262 + NKTR-214ExperimentalPhase 1 Doublet: NKTR-262 in escalating doses, will be combined with NKTR-214. The goal of this dose escalation part of the study is to establish a safe and tolerable recommended phase 2 dose (RP2D) for NKTR-262 in combination with NKTR-214 in an Every Three Week (Q3W) fixed dose. Phase 2 Doublet: NKTR-262 RP2D will be combined with a Q3W dose of NKTR-214 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
  • NKTR-214
Triplet: NKTR-262 + NKTR-214 + NivolumabExperimentalPhase 1 Triplet: The RP2D of NKTR-262 RP2D will be combined with a Q3W dose regimen of NKTR-214 plus nivolumab. The goal of this arm is to establish the safety and tolerability of the triplet. Phase 2 Triplet: The RP2D of NKTR-262 will be combined with a Q3W dose regimen of NKTR-214 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
  • NKTR-214
  • 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),
             ovarian carcinoma, renal cell carcinoma (RCC), colorectal cancer, urothelial
             carcinoma, 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 1-5, 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.

          -  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.

          -  Need for > 2 antihypertensive medications for management of hypertension (including
             diuretics).

          -  Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic
             retinopathy, retinal hemorrhage, macular degeneration).
      
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 4.03
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

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

Last Updated

April 30, 2018