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 (PIVOT-02)

• ClinicalTrials.gov Identifier: NCT02983045
• Recruitment Status: Completed
• First Posted: December 6, 2016
• Results First Posted: March 13, 2023
• Last Update Posted: March 13, 2023
• Sponsor: Nektar Therapeutics
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Nektar Therapeutics

Tracking Information

• First Submitted Date: November 23, 2016
• First Posted Date: December 6, 2016
• Results First Submitted Date: November 29, 2022
• Results First Posted Date: March 13, 2023
• Last Update Posted Date: March 13, 2023
• Actual Study Start Date: December 19, 2016
• Actual Primary Completion Date: April 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 9, 2023)

• Part 1 Dose Escalation: Incidence of Dose-limiting Toxicity (DLT) During the DLT Evaluation Window [ Time Frame: 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 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.
• Part 3 Schedule Finding: Incidence of Dose-limiting Toxicity (DLT) During the DLT Evaluation Window [ Time Frame: Dose-limiting toxicities (DLTs) were assessed during a 3-week (21-day) DLT evaluation period beginning with the first dose of ipilimumab. ]
  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.
• Part 2 and Part 4: Objective Response Rate (ORR) Per RECIST 1.1 at Recommended Phase 2 Dose (RP2D) [ Time Frame: 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. ]
  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.

Original Primary Outcome Measures (submitted: December 1, 2016)

• Safety of NKTR-214 in combination with nivolumab as evaluated by incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and adverse events leading to discontinuation, deaths, and clinical laboratory test abnormalities [ Time Frame: 30 days after last dose ]
• Tolerability of NKTR-214 in combination with nivolumab as evaluated by incidence of Dose Limiting Toxicities (DLTs), drug-related AEs, SAEs, adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities [ Time Frame: 30 days after last dose ]

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: December 1, 2016)

• Objective Response Rate (ORR) of NKTR-214 with nivolumab based on RECIST 1.1 [ Time Frame: Through study completion, an expected average of 2 years ]
  ORR will be measured and defined three ways: the percentage of patients achieving a confirmed complete or partial response, as defined by RECIST 1.1; the percentage of patients achieving a confirmed complete or partial response, as defined by immune-related RECIST 1.1; and the percentage of patients achieving a confirmed complete or partial response, as defined by immune-related response criteria (irRC)
• Best Overall Response (BOR) in the population of interest [ Time Frame: Through study completion, an expected average of 2 years ]
• Duration Of Response (DOR) [ Time Frame: Through study completion, an expected average of 2 years ]
  It is defined as time between the date of first radio-graphic images that documented objective response and the date of the radio-graphic images that documented disease progression.
• Progression-Free Survival (PFS) [ Time Frame: 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) [ Time Frame: Through study completion, an expected average of 2 years ]
  Clinical benefit rate will be assessed as the number of subjects with confirmed 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
• Median Time to Response (MTR) [ Time Frame: Through study completion, an expected average of 2 years ]
  The median time to response will be summarized descriptively for subjects who have a CR or PR
• Overall Survival (OS) [ Time Frame: Within 3 years from study start ]
  Overall survival is defined as the time from date of first dose to the date of death
• Maximum observed plasma concentration (Cmax) of NKTR-214 [ Time Frame: Cycle 1 and 2 Day 1: 0.25 hr., 1.5 hr, 3 hr., 6 hr., Days 2, 3, 4, 5, 8, 11, and 15. Cycles ≥ 3 Day 1: 0.25 hour on Day 8 ]
• Time of maximum observed plasma concentration (Tmax) of NKTR-214 [ Time Frame: Cycle 1 and 2 Day 1: 0.25 hr., 1.5 hr, 3 hr., 6 hr., Days 2, 3, 4, 5, 8, 11, and 15. Cycles ≥ 3 Day 1: 0.25 hour on Day 8 ]
• Area under the plasma concentration time curve in the dosing interval Area Under the Curve (AUC) of NKTR-214 [ Time Frame: Cycle 1 and 2 Day 1: 0.25 hr., 1.5 hr,, 3hr., 6 hr., Days 2, 3, 4, 5, 8, 11, and 15 for cycle 1 and 2. Cycles ≥ 3 Day 1: 0.25 hour on Day 8 ]
• Half-life (t½) of NKTR-214 [ Time Frame: Cycle 1 and 2 Day 1: 0.25 hr., 1.5 hr., 3hr., 6 hr. Days 2, 3, 4, 5, 8, 11, and 15 for cycle 1 and 2. Cycles ≥ 3 Day 1: 0.25 hour on Day 8 ]
• Changes in blood immune cells by flow cytometry [ Time Frame: Day 1 and Day 8 of Cycle 1 and 2 ]
• Changes in soluble cytokines and chemokines by multiplexed ELISA [ Time Frame: Day 1 and Day 8 of Cycle 1 and 2 ]
• Functional and phenotypic characterization of tumor immune infiltrates by flow cytometry [ Time Frame: Pre-dose and week 3 after first dose ]
• Functional and phenotypic characterization of tumor immune infiltrates by next generation sequencing [ Time Frame: Pre-dose and week 3 after first dose ]
• Functional and phenotypic characterization of tumor immune infiltrates by immunohistochemistry (IHC) [ Time Frame: Pre-dose and week 3 after first dose ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Dose Escalation Doublet: Combination of NKTR-214 + nivolumab
  NKTR 214 + nivolumab at 5 dosage levels.
  Other Name: Bempegaldesleukin + Opdivo®
• Drug: Dose Expansion Doublet: 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®)
• Drug: Schedule Finding Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab
  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.
  Other Name: Bempegaldesleukin+ Opdivo®+ Yervoy®
• Drug: Dose Expansion Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab
  Combination of NKTR-214 + nivolumab + ipilimumab was administered at RP2D dose/schedules in select tumor types
  Other Name: Bempegaldesleukin+ Opdivo®+ Yervoy®

Study Arms

• Experimental: Dose Escalation: Combination of NKTR-214 + nivolumab
  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.
  Intervention: Drug: Dose Escalation Doublet: Combination of NKTR-214 + nivolumab
• Experimental: Dose Expansion: Combination of NKTR-214 + nivolumab
  NKTR-214+nivolumab in patients with advanced or metastatic solid tumor malignancies to assess the efficacy of the RP2D.
  Intervention: Drug: Dose Expansion Doublet: Combination of NKTR-214 + nivolumab
• Experimental: Experimental: Combination of NKTR-214 + nivolumab + ipilimumab
  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).
  Intervention: Drug: Schedule Finding Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab
• Experimental: Experimental: Dose Expansion of Part 3
  To further assess the RP2D triplet combination dosing schedules from Part 3 in 1L NSCLC and 1L RCC patients.
  Intervention: Drug: Dose Expansion Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab

Publications *

• 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.
• 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.
• 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. Erratum In: J Immunother Cancer. 2021 Feb;9(2):

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 29, 2020): 557
• Original Estimated Enrollment (submitted: December 1, 2016): 30
• Actual Study Completion Date: April 28, 2022
• Actual Primary Completion Date: April 28, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Italy, Poland, Spain, United Kingdom, United States
• Removed Location Countries: Ukraine

Administrative Information

• NCT Number: NCT02983045
• Other Study ID Numbers: 16-214-02
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Nektar Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Nektar Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb

Investigators

• Study Director: Study Director; Nektar Therapeutics

• PRS Account: Nektar Therapeutics
• Verification Date: March 2023