PIVOT-02: 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

Sponsor

Nektar Therapeutics (Industry)

Overall Status

Completed

CT.gov ID

NCT02983045

Collaborator

Bristol-Myers Squibb (Industry)

557

Enrollment

Locations

Arms

64.3

Actual Duration (Months)

9.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In this four-part study, NKTR-214 will be administered in combination with nivolumab in Part 1, in combination with nivolumab with or without various chemotherapies in Part 2, and with nivolumab in Parts 3 & 4. In Part 1, the Recommended Phase 2 Dose (RP2D) of NKTR-214 in combination with nivolumab will be determined. In Part 2, NKTR-214 with nivolumab at the RP2D will be evaluated as first-line therapy and/or as second or third line therapy in select patients with Melanoma, Renal Cell Carcinoma (RCC), Non-Small Cell Lung Cancer (NSCLC), Urothelial Carcinoma (UC), triple negative Breast Cancer (TNBC), HR+/HER2- breast cancer, gastric cancer, and Colorectal Cancer (CRC). In addition, in Part 2, the RP2D of NKTR-214 with nivolumab and various chemotherapies and regimens in select cohorts of NSCLC patients will be determined. In Part 3, several different regimens of the doublet combination of NKTR-214 plus nivolumab will be evaluated in select patients with RCC, NSCLC, Melanoma, and UC. In Part 4, the safety and efficacy of the doublet combination will be evaluated further in select patients with RCC, NSCLC, Melanoma and UC.

Condition or Disease	Intervention/Treatment	Phase
Melanoma Renal Cell Carcinoma Non Small Cell Lung Cancer Urothelial Carcinoma Triple Negative Breast Cancer HR+/HER2- Breast Cancer Gastric Cancer	Drug: Combination of NKTR-214 + nivolumab Drug: Combination of NKTR-214 + nivolumab Drug: Combination of NKTR-214 + nivolumab Drug: Combination of NKTR-214 + nivolumab	Phase 1/Phase 2

Detailed Description

The study is designed in four parts.

Part 1: Dose escalation of NKTR-214 in combination with nivolumab. Part 1 has been completed and the recommended phase 2 dose (RP2D) has been identified, which is being studied further in Parts 2, 3 and 4 of the study.

Part 2: Dose expansion of NKTR-214 in combination with nivolumab. Patients with the following tumor types (Melanoma, RCC, NSCLC, UC, triple negative breast cancer (TNBC), HR+/HER2- breast cancer, gastric cancer, and CRC) will be enrolled to receive the RP2D of NKTR-214 in combination with nivolumab. In addition, NKTR-214 with nivolumab and other anti-cancer therapies including cytotoxic chemotherapy will be evaluated in select patients with NSCLC. Each cohort in Part 2 has a target enrollment of 12-36 patients and could add up to a total of 936 patients who are either checkpoint-therapy naïve or anti-PD-1 or anti-PD-L1 relapsed/refractory. One dedicated and separate cohort in Part 2 will evaluate NKTR-214 with nivolumab in an additional 100 second-line NSCLC patients previously treated with an anti-PD-1 or anti-PD-L1 in combination with doublet platinum-containing cytotoxic chemotherapy in first-line.

Part 3: Schedule and safety finding of NKTR-214 in combination with nivolumab. During this part of the study, the RP2D doublet combination schedules will be determined in the following tumor types: RCC, NSCLC, Melanoma, or UC.

Part 4: Dose expansion of doublet combinations of NKTR-214 in combination with nivolumab in select tumor types. Each cohort will enroll between 6-36 patients and could include up to 106 patients. Enrollment into Part 4 will commence once the RP2D for the doublet combination has been established in Part 3 for each respective tumor type.

All patients enrolled in the study will be closely monitored for safety, tolerability and response per RECIST criteria. The primary efficacy endpoint of the combination will be assessed using objective response rate (ORR). Exploratory immunological biomarkers in plasma and tumor samples will evaluate immune activation.

Study Design

Study Type:

Interventional

Actual Enrollment :

557 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 19, 2016

Actual Primary Completion Date :

Apr 28, 2022

Actual Study Completion Date :

Apr 28, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation: Combination of NKTR-214 + nivolumab NKTR-214 in escalating doses will be combined with one of the two proposed doses of nivolumab. The goal of this dose escalation Part 1 of the study is to find the RP2D.	Drug: Combination of NKTR-214 + nivolumab Patients with select tumor types will receive NKTR-214 doses administered either q3w or q2w, in combination with 240 mg nivolumab q2w or in combination with 360 mg of nivolumab q3w. Other Names: Bempegaldesleukin + Opdivo®
Experimental: Dose Expansion: Combination of NKTR-214 + nivolumab Combination of NKTR-214+nivolumab in combination with cytotoxic chemotherapies for the following 2 cohorts of the Part 2: NSCLC 1L nonsquamous plus platinum/pemetrexed NSCLC 1L squamous plus platinum/taxane	Drug: Combination of NKTR-214 + nivolumab Select patient cohorts with select tumor types will be dosed with NKTR-214 + nivolumab at the RP2D + other anti-cancer therapies per institution standard. Other Names: Bempegaldesleukin+ Opdivo® Carboplatin (Paraplatin®) Cisplatin (Platinol®) Pemetrexed (Alimta®) Paclitaxel (Taxol®)
Experimental: Experimental: Combination of NKTR-214 + nivolumab NKTR-214 will be combined with nivolumab. The goal of this dose schedule finding part of the study is to define the RP2D and administration schedule.	Drug: Combination of NKTR-214 + nivolumab Combination of NKTR-214 at 0.006 mg/kg q3w with nivolumab in up to three different dosing schedules to identify dose and schedules that will proceed into Part 4. Other Names: Bempegaldesleukin+ Opdivo®
Experimental: Dose Expansion of the Part 3 RP2D Experimental Combination of NKTR-214 + nivolumab that may enroll between 12-26 patients per tumor type	Drug: Combination of NKTR-214 + nivolumab Combination of NKTR-214 + nivolumab will be administered at the RP2D dose/schedule in patient cohorts with select tumor types. Other Names: Bempegaldesleukin + Opdivo®

Outcome Measures

Primary Outcome Measures

Incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs leading to discontinuation, deaths, and laboratory abnormalities associated with use of NKTR-214 in combination with nivolumab and or other anti-cancer therapies [Through study completion, an expected average of 2 years]
Maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of NKTR-214 in combination with nivolumab or in combination with nivolumab and other anti-cancer therapies [Through study completion, an expected average of 2 years]
Efficacy of NKTR-214 in combination with nivolumab or in combination with nivolumab and other anti-cancer therapies [Through study completion, an expected average of 2 years]

Secondary Outcome Measures

Overall Survival (OS) [Within 3 years from study start]
Overall survival is defined as the time from date of first dose to the date of death
Progression-Free Survival (PFS) [Through study completion, an expected average of 2 years]
PFS is defined as the time from date of first dose to the date of the first objectively documented tumor progression or death due to any cause.
Clinical Benefit Rate (CBR) [Within 3 years from study start]
CBR will be assessed as the number of subjects with a BOR of Complete Response (CR), confirmed Partial Response (PR), or Stable Disease (SD) (where the duration of SD should be ≥ 84 days) divided by the total number of subjects in the Response Evaluable Population
Duration of Response (DOR) [Through study completion, an expected average of 2 years]
DOR is defined as time between the date of first radiographic images that documented objective response and the date of the first radiographic images that documented disease progression.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD, Moores Cancer Center	La Jolla	California	United States	92093
2	UCLA	Los Angeles	California	United States	90095
3	Stanford Cancer Institute	Stanford	California	United States	94305
4	University of Colorado, Denver	Denver	Colorado	United States	80045
5	Yale School of Medicine	New Haven	Connecticut	United States	06473
6	University of Florida	Gainesville	Florida	United States	32610
7	Orlando Health Inc.	Orlando	Florida	United States	32806
8	Emory University Hospital	Atlanta	Georgia	United States	30322
9	Loyola University Medical Center, Chicago	Maywood	Illinois	United States	60153
10	Indiana University Health Melvin & Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
11	University of Kansas Cancer Center	Kansas City	Kansas	United States	66205
12	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
13	Henry Ford Hospital	Detroit	Michigan	United States	48202
14	Washington University School of Medicine in St. Louis	Saint Louis	Missouri	United States	63110
15	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
16	New York University Langone Medical Center - NYU Cancer Institute	New York	New York	United States	10016
17	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
18	Providence Portland Medical Center	Portland	Oregon	United States	97213
19	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
20	Inova Fairfax Hospital	Fairfax	Virginia	United States	22031
21	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
22	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
23	Antwerp University Hospital	Edegem		Belgium	02650
24	Vzw Az Groeninge	Kortrijk		Belgium	08500
25	UZ Leuven	Leuven		Belgium	03000
26	CHU de Liège	Liège		Belgium	04000
27	GZA Ziekenhuizen Campus Sint-Augustinus	Wilrijk		Belgium	02610
28	BC Cancer Agency Vancouver Centre	Vancouver	British Columbia	Canada	H3T1E2
29	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N3M5
30	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G2M10
31	Jewish General Hospital	Montréal	Quebec	Canada	H3T1E2
32	L'Institut Paoli - Calmettes	Marseille	Brouches-duRhone	France	13009
33	Institut de Cancerologie de l'Ouest	Saint-Herblain	Loire-Atlantique	France	44805
34	Centre Léon Bérard	Lyon		France	69008
35	Assistance Publique Hopitaux de Marseille - Hopital Nord	Marseille Cedex 20		France	13915
36	Gustave Roussy	Villejuif		France	94805
37	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano		Italy	20133
38	Istituto Europeo di Oncologia	Milano		Italy	20141
39	Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"	Napoli		Italy	80131
40	Azienda Ospedaliera San Camillo-Forlanini	Roma		Italy	00152
41	Azienda Ospedaliera Universitaria Senese	Siena		Italy	53100
42	Institute for Cancer Research and Treatment (IRCC)	Turin		Italy	10060
43	Szpital Specjalistyczny w Brzozowie Podkarpacki Ośrodek Onkologiczny im. Ks. B. Markiewicza	Brzozów		Poland
44	Szpitale Pomorskie Sp. z o.o.	Gdynia		Poland	81519
45	Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy	Otwock		Poland	05400
46	Wielkopolskie Centrum Pulmonologii i Torakochirurgii	Poznań		Poland	60569
47	Med-Polonia Sp. z o.o.	Poznań		Poland	60693
48	Instytut Medyczny Santa Familia Sp. z o. o. w Łodzi	Łódź		Poland	93509
49	Hospital Quirón Barcelona	Barcelona		Spain	8023
50	Hospital Clínic de Barcelona	Barcelona		Spain	8036
51	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
52	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
53	Centro Integral Oncológico Clara Campal (CIOCC)	Madrid		Spain	28050
54	Clínica Universidad de Navarra	Pamplona		Spain	31008
55	Campus Hospital Universitario Virgen del Rocío - Instituto de Biomedicina de Sevilla (IBIS)	Sevilla		Spain	41013
56	The Royal Marsden NHS Trust	London		United Kingdom	SM25PT
57	Mount Vernon Cancer Centre	Northwood		United Kingdom	HA62RN
58	The Christie NHS Foundation Trust	Withington		United Kingdom	M204BX