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 ) (PIVOT-02)

• ClinicalTrials.gov Identifier: NCT02983045
• Recruitment Status: Active, not recruiting
• First Posted: December 6, 2016
• Last Update Posted: January 5, 2021
• 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
• Last Update Posted Date: January 5, 2021
• Actual Study Start Date: December 19, 2016
• Estimated Primary Completion Date: November 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 31, 2019)

• Efficacy of NKTR-214 in combination with nivolumab as assessed by the Objective Response Rate (ORR) based on immune-related RECIST (irRECIST) at the RP2D. [ Time Frame: Through study completion, an expected average of 2 years ]
• Efficacy of NKTR-214 in combination with nivolumab and ipilimumab as assessed by the Objective Response Rate (ORR) based on immune-related RECIST (irRECIST) at the RP2D. [ Time Frame: Through study completion, an expected average of 2 years ]

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 (submitted: October 31, 2019)

• 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
• 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: 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) [ Time Frame: 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.

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 ( PIVOT-02 )
• 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 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 and ipilimumab 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), metastatic Breast Cancer (mBC) 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 triplet combination of NKTR-214 plus nivolumab and ipilimumab will be evaluated in select patients with RCC, NSCLC, Melanoma, and UC. In Part 4, the safety and efficacy of the triplet combination will be evaluated further in select patients with RCC, NSCLC, Melanoma and UC.

Detailed Description

NKTR-214 (investigational agent) is an IL-2 pathway agonist designed to target CD122, a protein which is found on certain immune cells (known as CD8+ T Cells and Natural Killer Cells) to expand these cells to promote their anti-tumor effects. Nivolumab is a full human monoclonal antibody that binds to PD-1 (programmed cell death protein 1) on immune cells and promotes anti-tumor effects. NKTR-214, nivolumab and ipilimumab each target the immune system differently and may act synergistically to promote anti-cancer effects.

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, mBC 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 include up to a total of 650 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 and ipilimumab. During this part of the study, the RP2D triplet combination schedules will be determined in the following tumor types: RCC, NSCLC, Melanoma, or UC.

Part 4: Dose expansion of triplet combinations of NKTR-214 in combination with nivolumab and ipilimumab 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 triplet 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 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
• Metastatic Breast Cancer
• Colorectal Cancer

Intervention

• 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 Name: NKTR-214 + Opdivo®
• 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:

  • NKTR-214 + Opdivo®
  • Carboplatin (Paraplatin®)
  • Cisplatin (Platinol®)
  • Pemetrexed (Alimta®)
  • Paclitaxel (Taxol®)
• Drug: Combination of NKTR-214 + nivolumab + ipilimumab
  Combination of NKTR-214 at 0.006 mg/kg q3w in combination with nivolumab and ipilimumab in up to three different dosing schedules to identify dose and schedules that will proceed into Part 4.
  Other Name: NKTR-214 + Opdivo® + Yervoy®
• Drug: Combination of NKTR-214 + nivolumab + ipilimumab
  Combination of NKTR-214 + nivolumab + ipilimumab will be administered at the RP2D dose/schedule in patient cohorts with select tumor types.
  Other Name: NKTR-214 + Opdivo® + Yervoy®

Study Arms

• 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.
  Intervention: Drug: Combination of NKTR-214 + nivolumab
• 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

  Intervention: Drug: Combination of NKTR-214 + nivolumab
• Experimental: Experimental: Combination of NKTR-214 + nivolumab + ipi
  NKTR-214 will be combined with nivolumab and ipilimumab. The goal of this dose schedule finding part of the study is to define the RP2D and administration schedule.
  Intervention: Drug: Combination of NKTR-214 + nivolumab + ipilimumab
• Experimental: Dose Expansion of the Part 3 RP2D
  Experimental Combination of NKTR-214 + nivolumab + ipilimumab that may enroll between 12-26 patients per tumor type
  Intervention: Drug: Combination of NKTR-214 + nivolumab + ipilimumab

• Publications *: 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). pii: e001591. doi: 10.1136/jitc-2020-001591. Erratum in: J Immunother Cancer. 2021 Feb;9(2):.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: May 29, 2020): 557
• Original Estimated Enrollment (submitted: December 1, 2016): 30
• Estimated Study Completion Date: December 2021
• Estimated Primary Completion Date: November 2021 (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: Undecided

• Responsible Party: Nektar Therapeutics
• Study Sponsor: Nektar Therapeutics
• Collaborators: Bristol-Myers Squibb

Investigators

• Study Director: Erika Puente, MD; Nektar Therapeutics

• PRS Account: Nektar Therapeutics
• Verification Date: January 2021