Colorectal Cancer, Head and Neck Squamous Cell Carcinoma, Melanoma, Merkel Cell Carcinoma, Renal Cell Carcinoma, Sarcoma, Triple Negative Breast Cancer
Conditions
Keywords
Bempegaldesleukin (NKTR-214), NKTR-262, Nivolumab, Opdivo®, Metastatic, Locally advanced, Relapsed/Refractory, TLR7/8, CD122
Brief summary
Patients received intratumoral (IT) injections of NKTR-262 in 3-week cycles for up to 3 cycles; bempegaldesleukin with or without nivolumab was administered every 3 weeks (q3w), and treatment continued until unacceptable toxicity, death, or disease progression per RECIST 1.1. Based on Phase 1 results of the study, the decision was made not to start the Phase 2 part of the study and the study was terminated.
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)
Interventions
DRUGNKTR-262
During Phase 1 Doublet: Patients 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 were to receive the RP2D of NKTR-262. During Phase 1 Triplet (Cohort B), and Phase 2 Triplet: Patients receive the RP2D of NKTR-262.
During Phase 1 Doublet (Cohort A), and proposed Phase 2 Doublet: Patients receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles. During Phase 1 Triplet (Cohort B), and proposed Phase 2 Triplet: Patients receive 0.006 mg/kg bempegaldesleukin administered in 3-week treatment cycles.
DRUGnivolumab
During Phase 1 Triplet (Cohort B), and proposed Phase 2 Triplet: Patients receive a nivolumab flat dose of 360 mg administered in 3-week treatment cycles.
Sponsors
Nektar Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | The DLT window is 21 days following NKTR-262 single agent administration (Cycle 1) and an additional 9 days when combined with bempeg for staggered dosing administration (Cohorts 1 and 2), or 7 days for the same day administration (Cohort 3 and higher). | DLTs were assessed in Cohort 1 through Cohort 9, which had dose levels of NKTR-262 as 0.03mg, 0.06mg, 0.06mg, 0.12mg, 0.24mg, 0.48mg, 0.96mg, 1.92mg, and 3.84mg in combination with bempegaldesleukin (bempeg). There was only 1 DLT that occurred in one of the Cohort 9 patients. Therefore, the maximum tolerated dose (MTD) of NKTR 262 was not reached. |
| Objective Response Rate (ORR) Per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D) | From Cycle 1 Day 1 to 100 days after the last dose of study drug or the date for new anti-cancer therapy, whichever is earlier. | Objective Response Rate (ORR) per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D). ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by Blinded Independent Central Review (BICR). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 NKTR-262 (0.03 mg) + Bempegaldesleukin (Administered Staggered) Phase 1 (dose escalation) Cohort 1 Patients received NKTR-262 intratumorally at 0.03 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) (administered staggered \[Day 3\] in Cycles 2-3). The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 3 |
| Cohort 2 NKTR-262 (0.06 mg) + Bempegaldesleukin (Administered Staggered) Phase 1 (dose escalation) Cohort 2 Patients received NKTR-262 intratumorally at 0.06 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) (administered staggered \[Day 3\] in Cycles 2-3). The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 3 |
| Cohort 3 NKTR-262 (0.06 mg) + Bempegaldesleukin (Administered the Same Day) Phase 1 (dose escalation) Cohort 3 Patients received NKTR-262 intratumorally at 0.06 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) administered on the same day. The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 4 |
| Cohort 4 NKTR-262 (0.12 mg) + Bempegaldesleukin (Administered the Same Day) Phase 1 (dose escalation) Cohort 4 Patients received NKTR-262 intratumorally at 0.12 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) administered on the same day. The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 3 |
| Cohort 5 NKTR-262 (0.24 mg) + Bempegaldesleukin (Administered the Same Day) Phase 1 (dose escalation) Cohort 5 Patients received NKTR-262 intratumorally at 0.24 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) administered on the same day. The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 4 |
| Cohort 6 NKTR-262 (0.48 mg) + Bempegaldesleukin (Administered the Same Day) Phase 1 (dose escalation) Cohort 6 Patients received NKTR-262 intratumorally at 0.48 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) administered on the same day. The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 4 |
| Cohort 7 NKTR-262 (0.96 mg) + Bempegaldesleukin (Administered the Same Day) Phase 1 (dose escalation) Cohort 7 Patients received NKTR-262 intratumorally at 0.96 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) administered on the same day. The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 4 |
| Cohort 8 NKTR-262 (1.92 mg) + Bempegaldesleukin (Administered the Same Day) Phase 1 (dose escalation) Cohort 8 Patients received NKTR-262 intratumorally at 1.92 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) administered on the same day. The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 3 |
| Cohort 9 NKTR-262 (3.84 mg) + Bempegaldesleukin (Administered the Same Day) Phase 1 (dose escalation) Cohort 9 Patients received NKTR-262 intratumorally at 3.84 mg (in Cycles 1 through 3) plus bempegaldesleukin IV at 0.006 mg/kg (starting in Cycle 2) every 3 weeks (q3w) administered on the same day.The number of patients to be enrolled per cohort was dependent the on the 3+3 study design and continued until RP2D was determined. | 8 |
| Cohort A NKTR-262 (3.84 mg) + Bempegaldesleukin (Administered the Same Day) Cohort A explored same-day administration of NKTR-262 at the RP2D (3.84 mg) and bempegaldesleukin (0.006 mg/kg) q3w. | 14 |
| Cohort B NKTR-262 (3.84 mg) + Bempegaldesleukin + Nivolumab Cohort B explored same-day administration of NKTR-262 at the RP2D (3.84 mg) and bempegaldesleukin (0.006 mg/kg) q3w plus nivolumab (360 mg) q3w, starting in Cycle 1. | 14 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 2 | 0 | 0 | 3 | 0 | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | Cohort 2 NKTR-262 (0.06 mg) + Bempegaldesleukin (Administered Staggered) | Cohort 3 NKTR-262 (0.06 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort 4 NKTR-262 (0.12 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort 5 NKTR-262 (0.24 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort 6 NKTR-262 (0.48 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort 7 NKTR-262 (0.96 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort 1 NKTR-262 (0.03 mg) + Bempegaldesleukin (Administered Staggered) | Cohort 8 NKTR-262 (1.92 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort 9 NKTR-262 (3.84 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort A NKTR-262 (3.84 mg) + Bempegaldesleukin (Administered the Same Day) | Cohort B NKTR-262 (3.84 mg) + Bempegaldesleukin + Nivolumab | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 4 Participants | 6 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 8 Participants | 10 Participants | 8 Participants | 43 Participants |
| Age, Continuous | 53.0 years | 51.5 years | 56.3 years | 57.0 years | 68.0 years | 55.3 years | 66.0 years | 59.0 years | 49.0 years | 57.7 years | 60.3 years | 57.4 years |
| ECOG Performance Status ECOG 0 | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 6 Participants | 7 Participants | 5 Participants | 34 Participants |
| ECOG Performance Status ECOG 1 | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 7 Participants | 9 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 3 Participants | 3 Participants | 8 Participants | 13 Participants | 13 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 8 Participants | 11 Participants | 14 Participants | 59 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 3 participants | 4 participants | 4 participants | 4 participants | 3 participants | 3 participants | 8 participants | 14 participants | 14 participants | 64 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants | 4 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 10 Participants | 7 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 3 | 3 / 4 | 1 / 3 | 4 / 4 | 4 / 4 | 1 / 4 | 2 / 3 | 5 / 8 | 9 / 14 | 5 / 14 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 4 / 4 | 4 / 4 | 4 / 4 | 3 / 3 | 8 / 8 | 14 / 14 | 14 / 14 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 1 / 4 | 1 / 3 | 1 / 4 | 1 / 4 | 1 / 4 | 3 / 3 | 3 / 8 | 2 / 14 | 5 / 14 |
Outcome results
Primary
Number of Participants Experiencing Dose-Limiting Toxicities (DLTS)
DLTs were assessed in Cohort 1 through Cohort 9, which had dose levels of NKTR-262 as 0.03mg, 0.06mg, 0.06mg, 0.12mg, 0.24mg, 0.48mg, 0.96mg, 1.92mg, and 3.84mg in combination with bempegaldesleukin (bempeg). There was only 1 DLT that occurred in one of the Cohort 9 patients. Therefore, the maximum tolerated dose (MTD) of NKTR 262 was not reached.
Time frame: The DLT window is 21 days following NKTR-262 single agent administration (Cycle 1) and an additional 9 days when combined with bempeg for staggered dosing administration (Cohorts 1 and 2), or 7 days for the same day administration (Cohort 3 and higher).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 NKTR-262 (0.03 mg) + Bempegaldesleukin (Administered Staggered) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 2 NKTR-262 (0.06 mg) + Bempegaldesleukin (Administered Staggered) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 3 NKTR-262 (0.06 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 4 NKTR-262 (0.12 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 5 NKTR-262 (0.24 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 6 NKTR-262 (0.48 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 7 NKTR-262 (0.96 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 8 NKTR-262 (1.92 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort 9 NKTR-262 (3.84 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 1 Participants |
| Cohort A NKTR-262 (3.84 mg) + Bempegaldesleukin (Administered the Same Day) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
| Cohort B NKTR-262 (3.84 mg) + Bempegaldesleukin + Nivolumab | Number of Participants Experiencing Dose-Limiting Toxicities (DLTS) | 0 Participants |
Primary
Objective Response Rate (ORR) Per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D)
Objective Response Rate (ORR) per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D). ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by Blinded Independent Central Review (BICR).
Time frame: From Cycle 1 Day 1 to 100 days after the last dose of study drug or the date for new anti-cancer therapy, whichever is earlier.
Population: safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 NKTR-262 (0.03 mg) + Bempegaldesleukin (Administered Staggered) | Objective Response Rate (ORR) Per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D) | 0 percentage of participants |
| Cohort 2 NKTR-262 (0.06 mg) + Bempegaldesleukin (Administered Staggered) | Objective Response Rate (ORR) Per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D) | 14.3 percentage of participants |