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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 : December 6, 2018
Sponsor:
Information provided by (Responsible Party):
Nektar Therapeutics

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Melanoma Merkel Cell Carcinoma Triple Negative Breast Cancer Ovarian Cancer Renal Cell Carcinoma Colorectal Cancer Urothelial Carcinoma Sarcoma Drug: NKTR-262 Drug: NKTR-214 Drug: nivolumab Phase 1 Phase 2

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)

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 393 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 15, 2018
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Doublet: NKTR-262 + NKTR-214

Phase 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.

Drug: NKTR-262

During Phase 1 Doublet: Patients will receive escalating doses of NKTR-262 (starting dose 0.03 mg) in 3-week treatment cycles.

During Phase 1 Triplet, Phase 2 Doublet, and Phase 2 Triplet: Patients will receive the RP2D of NKTR-262.


Drug: NKTR-214
During Phase 1 Doublet, Phase 1 Triplet, Phase 2 Doublet, and Phase 2 Triplet: Patients will receive 0.006 mg/kg NKTR-214 administered in 3-week treatment cycles.

Experimental: Triplet: NKTR-262 + NKTR-214 + Nivolumab

Phase 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.

Drug: NKTR-262

During Phase 1 Doublet: Patients will receive escalating doses of NKTR-262 (starting dose 0.03 mg) in 3-week treatment cycles.

During Phase 1 Triplet, Phase 2 Doublet, and Phase 2 Triplet: Patients will receive the RP2D of NKTR-262.


Drug: NKTR-214
During Phase 1 Doublet, Phase 1 Triplet, Phase 2 Doublet, and Phase 2 Triplet: Patients will receive 0.006 mg/kg NKTR-214 administered in 3-week treatment cycles.

Drug: nivolumab
During Phase 1 Doublet, Phase 1 Triplet, Phase 2 Doublet, and Phase 2 Triplet: Patients will receive a nivolumab flat dose of 360 mg administered in 3-week treatment cycles.
Other Name: Opdivo®




Primary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

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): NCT03435640


Contacts
Contact: Nektar Recruitment 855-482-8676 StudyInquiry@nektar.com
Contact: Justin Ney 855-482-8676

Locations
United States, Arizona
Local Institution - Scottsdale Recruiting
Scottsdale, Arizona, United States, 85258
United States, Connecticut
Local Institution - New Haven Recruiting
New Haven, Connecticut, United States, 06520
United States, Florida
Local Institution - Tampa Recruiting
Tampa, Florida, United States, 33612
United States, Georgia
Local Institution - Atlanta Recruiting
Atlanta, Georgia, United States, 30322
United States, New York
Local Institution - New York Recruiting
New York, New York, United States, 10065
United States, North Carolina
Local Institution - Durham Recruiting
Durham, North Carolina, United States, 27710
United States, Oregon
Local Institution - Portland Recruiting
Portland, Oregon, United States, 97213
United States, Texas
Local Institution - Dallas Recruiting
Dallas, Texas, United States, 72501
Local Institution - Dallas Recruiting
Dallas, Texas, United States, 75390
Local Institution - Houston Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Nektar Therapeutics
Investigators
Study Director: Mario Marcondes, MD, PhD Nektar Therapeutics

Responsible Party: Nektar Therapeutics
ClinicalTrials.gov Identifier: NCT03435640     History of Changes
Other Study ID Numbers: 17-262-01
First Posted: February 16, 2018    Key Record Dates
Last Update Posted: December 6, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nektar Therapeutics:
NKTR-214
NKTR-262
Nivolumab
Opdivo
Metastatic
Locally advanced
Relapsed/Refractory
TLR7/8
CD122

Additional relevant MeSH terms:
Carcinoma
Colorectal Neoplasms
Carcinoma, Renal Cell
Triple Negative Breast Neoplasms
Carcinoma, Transitional Cell
Carcinoma, Merkel Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Breast Neoplasms
Breast Diseases
Skin Diseases
Polyomavirus Infections
DNA Virus Infections
Virus Diseases