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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)

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ClinicalTrials.gov Identifier: NCT02983045
Recruitment Status : Recruiting
First Posted : December 6, 2016
Last Update Posted : November 4, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Nektar Therapeutics

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.

Condition or disease Intervention/treatment Phase
Melanoma Renal Cell Carcinoma Non Small Cell Lung Cancer Urothelial Carcinoma Metastatic Breast Cancer Colorectal Cancer Drug: Combination of NKTR-214 + nivolumab Drug: Combination of NKTR-214 + nivolumab + ipilimumab Phase 1 Phase 2

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 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 5275 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 780 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 : October 2016
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021


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 Name: NKTR-214 + Opdivo®

Experimental: Dose Expansion: Combination of NKTR-214 + nivolumab

Combination of NKTR-214+nivolumab in combination with cytotoxic chemotherapies for the following 4 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:
  • NKTR-214 + Opdivo®
  • Carboplatin (Paraplatin®)
  • Cisplatin (Platinol®)
  • Pemetrexed (Alimta®)
  • Paclitaxel (Taxol®)

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.
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®

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
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®




Primary Outcome Measures :
  1. 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 ]
  2. 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 ]

Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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

  4. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02983045


Contacts
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Contact: Nektar Recruitment 855-482-8676 StudyInquiry@nektar.com

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Sponsors and Collaborators
Nektar Therapeutics
Bristol-Myers Squibb
Investigators
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Study Director: Corina Andresen, MD Nektar Therapeutics

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Responsible Party: Nektar Therapeutics
ClinicalTrials.gov Identifier: NCT02983045     History of Changes
Other Study ID Numbers: 16-214-02
First Posted: December 6, 2016    Key Record Dates
Last Update Posted: November 4, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nektar Therapeutics:
NKTR-214
Bempegaldesleukin
Nivolumab
Ipilimumab
Paclitaxel
Carboplatin
Cisplatin
Pemetrexed
Melanoma
Renal Cell Carcinoma
Non Small Cell Lung Cancer
Urothelial Carcinoma
Triple Negative Breast Cancer
Colorectal Cancer
Metastatic
Advanced
Immunotherapy
Anti-PD-1
anti-CTLA-4
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Non-Small-Cell Lung
Melanoma
Colorectal Neoplasms
Carcinoma, Renal Cell
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases