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 )

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 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 Phase

Phase 1/Phase 2

Study Type

Interventional

Primary Outcome

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.

Secondary Outcome

 Overall Survival (OS)

Condition

Melanoma

Intervention

Combination of NKTR-214 + nivolumab

Study Arms / Comparison Groups

 Dose Escalation: Combination of NKTR-214 + nivolumab

Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

557

Start Date

December 19, 2016

Completion Date

December 2021

Primary Completion Date

November 2021

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Erika Puente, MD, , 

Location Countries

Belgium

Location Countries

Belgium

NCT ID

NCT02983045

Organization ID

16-214-02

Responsible Party

Sponsor

Study Sponsor

Nektar Therapeutics

Collaborators

 Bristol-Myers Squibb

Study Sponsor

Erika Puente, MD, Study Director, Nektar Therapeutics

Verification Date

May 2021