REVEAL: 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

Sponsor

Nektar Therapeutics (Industry)

Overall Status

Terminated

CT.gov ID

NCT03435640

Collaborator

(none)

Enrollment

Locations

Arms

49.8

Actual Duration (Months)

4.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
Melanoma Merkel Cell Carcinoma Triple Negative Breast Cancer Head and Neck Squamous Cell Carcinoma Renal Cell Carcinoma Colorectal Cancer Sarcoma	Drug: NKTR-262 Drug: bempegaldesleukin 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, 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 Design

Study Type:

Interventional

Actual Enrollment :

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

Actual Study Start Date :

Mar 15, 2018

Actual Primary Completion Date :

May 9, 2022

Actual Study Completion Date :

May 9, 2022

Arms and Interventions

Arm	Intervention/Treatment
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.	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.
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.	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 Names: Opdivo®

Arm

Intervention/Treatment

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.

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.

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.

Drug: NKTR-262

Drug: bempegaldesleukin

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 Names:

Opdivo®

Outcome Measures

Primary Outcome Measures

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 [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 [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 [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key 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 1-10, 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).

Key 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 general and tumor specific inclusion and exclusion criteria will apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth	Scottsdale	Arizona	United States	85258
2	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
3	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
4	Emory University Hospital	Atlanta	Georgia	United States	30322
5	University of Kansas Hospital	Kansas City	Kansas	United States	66160
6	Henry Ford Hospital	Detroit	Michigan	United States	48202
7	University of Minnesota	Minneapolis	Minnesota	United States	55455
8	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
9	Duke Cancer Institute	Durham	North Carolina	United States	27710
10	Cleveland Clinic	Cleveland	Ohio	United States	44195
11	Providence Portland Medical Center	Portland	Oregon	United States	97213
12	University of Texas Southwestern Medical Center	Dallas	Texas	United States	72501
13	MD Anderson Cancer Center	Houston	Texas	United States	77030
14	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109