A Dose Escalation and Cohort Expansion Study of NKTR-214 in Combination With Nivolumab and Other Anti-Cancer Therapies in Patients With Select Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
In this four-part study, NKTR-214 was administered in combination with nivolumab and with/without other anticancer therapies. Part 1 considered escalating doublet (NKTR 214 + nivolumab) doses to determine the RP2D. Part 2 considered dose expansion cohorts for the doublet (NKTR 214 + nivolumab ± chemotherapy). Part 3 was schedule-finding for a triplet therapy (NKTR 214 + nivolumab + ipilimumab). Part 4 dose expansion for the triplet (NKTR 214 + nivolumab + ipilimumab) was planned to further assess the efficacy of the RP2D triplet combination at dosing schedules from Part 3.

Detailed Description
-----------------
Part 1 enrolled patients with advanced or metastatic melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), urothelial carcinoma, or triple negative breast cancer (TNBC) to determine the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD) of NKTR 214 + nivolumab doublet therapy. Part 2 enrolled patients with advanced or metastatic solid tumor malignancies (including 9 tumor types consisting of the same 5 tumor types as in Part 1, plus hormone receptor positive human epidermal growth factor receptor 2 [HER 2] negative breast cancer [HR+ HER2- BC], gastric cancer, colorectal carcinoma, and small cell lung cancer [SCLC]) to assess the efficacy of the RP2D. Part 3 enrolled patients with advanced or metastatic melanoma, RCC, NSCLC, or urothelial carcinoma (UCC) in a first-line setting (1L) to assess the safety and tolerability of NKTR 214 + nivolumab + ipilimumab triplet therapy Three dosing schedules were evaluated to establish RP2D dosing schedules for Part 4 of the study. Part 4 planned to enroll patients with advanced or metastatic melanoma, RCC, NSCLC, or UCC to further assess the efficacy of the RP2D triplet combination at the 3 dosing schedules from Part 3. Patients were enrolled simultaneously to each tumor cohort. All patients enrolled in the study were closely monitored for safety, tolerability and response per RECIST criteria. The primary efficacy endpoint was objective response rate (ORR) using RECIST 1.1 at the RP2D doublet.

Official Title
-----------------
A Phase 1/2, Open-label, Multicenter Study of the Combination of NKTR-214 and Nivolumab or the Combination of NKTR-214, Nivolumab, and Other Anti-Cancer Therapies in Patients With Select Locally Advanced or Metastatic Solid Tumor Malignancies

Conditions
-----------------
Melanoma, Renal Cell Carcinoma, Non Small Cell Lung Cancer, Urothelial Carcinoma, Triple Negative Breast Cancer, HR+/HER2- Breast Cancer, Gastric Cancer

Intervention / Treatment
-----------------
* Drug: Dose Escalation Doublet: Combination of NKTR-214 + nivolumab
* Drug: Dose Expansion Doublet: Combination of NKTR-214 + nivolumab
* Drug: Schedule Finding Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab
* Drug: Dose Expansion Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA - For Parts 1-4: Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic solid tumors Life expectancy > 12 weeks Patients must not have received prior interleukin-2 (IL-2) therapy Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Measurable disease per RECIST 1.1 Patients with stable brain metastases under certain criteria Fresh and archival tumor tissue available Tumor specific inclusion criteria may apply. EXCLUSION CRITERIA - For Parts 1-4: Use of an investigational agent or an investigational device within 28 days before administration of first dose of NKTR--214 Females who are pregnant or breastfeeding Participants who have an active autoimmune disease requiring systemic treatment within the past 3 months or have a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents History of organ transplant that requires use of immune suppressive agents Active malignancy not related to the current diagnosed malignancy Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis Participants who have had < 28 days since the last chemotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy, or systemic or inhaled steroid therapy at doses greater than 10mg of prednisone Tumor specific exclusion criteria may apply. Other protocol defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: Combination of NKTR-214 + nivolumab<br>NKTR 214 + nivolumab at 5 dosage levels to determine the RP2D Part 1 of RP2D in patients with advanced or metastatic melanoma, RCC, NSCLC, urothelial carcinoma, or TNBC. | Drug: Dose Escalation Doublet: Combination of NKTR-214 + nivolumab<br>* NKTR 214 + nivolumab at 5 dosage levels.<br>* Other names: Bempegaldesleukin + Opdivo®;|
| Experimental: Dose Expansion: Combination of NKTR-214 + nivolumab<br>NKTR-214+nivolumab in patients with advanced or metastatic solid tumor malignancies to assess the efficacy of the RP2D. | Drug: Dose Expansion Doublet: Combination of NKTR-214 + nivolumab<br>* Select patient cohorts with select tumor types will be dosed with NKTR-214 + nivolumab at the RP2D + other anti-cancer therapies per institution standard.<br>* Other names: Paclitaxel (Taxol®);|
| Experimental: Experimental: Combination of NKTR-214 + nivolumab + ipilimumab<br>To assess the safety and tolerability of NKTR 214 + nivolumab + ipilimumab triplet therapy and establish RP2D dosing schedules for Part 4 in patients with advanced or metastatic melanoma, RCC, NSCLC, or UCC in a first-line setting (1L). | Drug: Schedule Finding Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab<br>* 1L patients with RCC, NSCLC, UCC, and melanoma received NKTR-214 0.006 mg/kg q3w in combination with nivolumab and ipilimumab according to 3 dosing schedules.<br>* Other names: Bempegaldesleukin+ Opdivo®+ Yervoy®;|
| Experimental: Experimental: Dose Expansion of Part 3<br>To further assess the RP2D triplet combination dosing schedules from Part 3 in 1L NSCLC and 1L RCC patients. | Drug: Dose Expansion Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab<br>* Combination of NKTR-214 + nivolumab + ipilimumab was administered at RP2D dose/schedules in select tumor types<br>* Other names: Bempegaldesleukin+ Opdivo®+ Yervoy®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Dose Escalation: Incidence of Dose-limiting Toxicity (DLT) During the DLT Evaluation Window | Part 1of the study was a dose-escalation phase that evaluated the safety and tolerability and defined the maximum tolerated dose or recommended Phase 2 dose of the NKTR-214/nivolumab doublet across 5 dosage/schedule levels. The results presented are for the DLT Population. | Includes DLTs that occurred within the DLT window of at least 21 days after the first dose of study treatment (28 days for every 2 weeks dosing; 21 days for every 3 weeks dosing). Patients were counted only once under each preferred term. | 
| Part 3 Schedule Finding: Incidence of Dose-limiting Toxicity (DLT) During the DLT Evaluation Window | Part 3 of the study was a schedule finding phase to establish the recommended phase 2 dosing schedules for Part 4 and assess the safety and tolerability for the NKTR-214/nivolumab/ipilimumab triplet combination. The results presented are for the DLT Population. | Dose-limiting toxicities (DLTs) were assessed during a 3-week (21-day) DLT evaluation period beginning with the first dose of ipilimumab. | 
| Part 2 and Part 4: Objective Response Rate (ORR) Per RECIST 1.1 at Recommended Phase 2 Dose (RP2D) | Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) at Recommended Phase 2 Dose (RP2D). ORR is defined as the percentage of enrolled participants who achieved a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR is calculated as the sum of CR and PR. | Tumor assessment at Screening then every 8 weeks (± 7 days) from Cycle 1 Day 1 and end of treatment (unless scan done within 4 weeks) up to approximately 27 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NKTR-214, Bempegaldesleukin, Nivolumab, Paclitaxel, Carboplatin, Cisplatin, Pemetrexed, Melanoma, Renal Cell Carcinoma, Non Small Cell Lung Cancer, Urothelial Carcinoma, Triple Negative Breast Cancer, HR+/HER2- Breast Cancer, Gastric Cancer, Colorectal Cancer, Metastatic, Advanced, Immunotherapy, Anti-PD-1, anti-CTLA-4