Clinical trial NCT02983045: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Melanoma
Renal Cell Carcinoma
Non Small Cell Lung Cancer
Urothelial Carcinoma
Triple Negative Breast Cancer
HR+/HER2- Breast Cancer
Gastric Cancer
Keywords: 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
Lead sponsor: Nektar Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2016-12-06
Enrollment: 557
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Part 1 Dose Escalation: Incidence of Dose-limiting Toxicity (DLT) During the DLT Evaluation Window
timeFrame: 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.
measure: Part 3 Schedule Finding: Incidence of Dose-limiting Toxicity (DLT) During the DLT Evaluation Window
timeFrame: Dose-limiting toxicities (DLTs) were assessed during a 3-week (21-day) DLT evaluation period beginning with the first dose of ipilimumab.
measure: Part 2 and Part 4: Objective Response Rate (ORR) Per RECIST 1.1 at Recommended Phase 2 Dose (RP2D)
timeFrame: 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.
Secondary outcomes:
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD, Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Denver
country: United States
facility: University of Colorado, Denver
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Orlando
country: United States
facility: Orlando Health Inc.
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Maywood
country: United States
facility: Loyola University Medical Center, Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Melvin & Bren Simon Cancer Center
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center - NYU Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Kortrijk
country: Belgium
facility: Vzw Az Groeninge
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: CHU de Liège
city: Wilrijk
country: Belgium
facility: GZA Ziekenhuizen Campus Sint-Augustinus
city: Vancouver
country: Canada
facility: BC Cancer Agency Vancouver Centre
state: British Columbia
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Marseille
country: France
facility: L'Institut Paoli - Calmettes
state: Brouches-duRhone
city: Saint-Herblain
country: France
facility: Institut de Cancerologie de l'Ouest
state: Loire-Atlantique
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille Cedex 20
country: France
facility: Assistance Publique Hopitaux de Marseille - Hopital Nord
city: Villejuif
country: France
facility: Gustave Roussy
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo-Forlanini
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese
city: Turin
country: Italy
facility: Institute for Cancer Research and Treatment (IRCC)
city: Brzozów
country: Poland
facility: Szpital Specjalistyczny w Brzozowie Podkarpacki Ośrodek Onkologiczny im. Ks. B. Markiewicza
city: Gdynia
country: Poland
facility: Szpitale Pomorskie Sp. z o.o.
city: Otwock
country: Poland
facility: Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy
city: Poznań
country: Poland
facility: Wielkopolskie Centrum Pulmonologii i Torakochirurgii
city: Poznań
country: Poland
facility: Med-Polonia Sp. z o.o.
city: Łódź
country: Poland
facility: Instytut Medyczny Santa Familia Sp. z o. o. w Łodzi
city: Barcelona
country: Spain
facility: Hospital Quirón Barcelona
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Centro Integral Oncológico Clara Campal (CIOCC)
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Sevilla
country: Spain
facility: Campus Hospital Universitario Virgen del Rocío - Instituto de Biomedicina de Sevilla (IBIS)
city: London
country: United Kingdom
facility: The Royal Marsden NHS Trust
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre
city: Withington
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Nektar Therapeutics
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Siefker-Radtke AO, Cho DC, Diab A, Sznol M, Bilen MA, Balar AV, Grignani G, Puente E, Tang L, Chien D, Hoch U, Choudhury A, Yu D, Currie SL, Tagliaferri MA, Zalevsky J, Hurwitz ME, Tannir NM. Bempegaldesleukin plus Nivolumab in First-line Metastatic Urothelial Carcinoma: Results from PIVOT-02. Eur Urol. 2022 Oct;82(4):365-373. doi: 10.1016/j.eururo.2022.05.002. Epub 2022 May 25.
citation: Diab A, Tykodi SS, Daniels GA, Maio M, Curti BD, Lewis KD, Jang S, Kalinka E, Puzanov I, Spira AI, Cho DC, Guan S, Puente E, Nguyen T, Hoch U, Currie SL, Lin W, Tagliaferri MA, Zalevsky J, Sznol M, Hurwitz ME. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma. J Clin Oncol. 2021 Sep 10;39(26):2914-2925. doi: 10.1200/JCO.21.00675. Epub 2021 Jul 13.
citation: Veatch JR, Singhi N, Jesernig B, Paulson KG, Zalevsky J, Iaccucci E, Tykodi SS, Riddell SR. Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab. J Immunother Cancer. 2020 Dec;8(2):e001591. doi: 10.1136/jitc-2020-001591.