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Trial record 2 of 4 for:    NKTR-214

A Dose Escalation and Cohort Expansion Study of CD122-Biased Cytokine (NKTR-214) in Combination With Anti-PD-1 Antibody (Nivolumab) in Patients With Select Advanced or Metastatic Solid Tumors (PIVOT-02)

This study is currently recruiting participants.
Verified November 2017 by Nektar Therapeutics
Sponsor:
ClinicalTrials.gov Identifier:
NCT02983045
First Posted: December 6, 2016
Last Update Posted: November 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Nektar Therapeutics
  Purpose
This study is to determine first, the recommended Phase 2 dose of NKTR-214 when administered in combination with nivolumab, and then, the clinical benefit, safety, and tolerability of combining NKTR-214 with nivolumab in select patients with Melanoma, Renal Cell Carcinoma, Non-Small Cell Lung Cancer, Urothelial Carcinoma, or Triple Negative Breast Cancer. Both drugs target the immune system and may act synergistically to promote anti-cancer effects.

Condition Intervention Phase
Non Small Cell Lung Cancer Renal Cell Carcinoma Melanoma Triple Negative Breast Cancer Urothelial Carcinoma Drug: Combination of NKTR-214 + nivolumab Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-214 and Nivolumab in Patients With Select Locally Advanced or Metastatic Solid Tumor Malignancies.

Resource links provided by NLM:


Further study details as provided by Nektar Therapeutics:

Primary Outcome Measures:
  • 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: 100 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: 100 days after last dose ]
  • Efficacy of NKTR-214 in combination with nivolumab as assessed by the Objective Response Rate (ORR) based on RECIST 1.1 [ Time Frame: Through study completion, an expected average of 2 years ]
    ORR will be measured by the number and percentage of patients achieving a complete or partial response as best overall response and as defined by RECIST 1.1


Secondary Outcome Measures:
  • 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 first 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 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

  • 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


Other Outcome Measures:
  • Efficacy of NKTR-214 in combination with nivolumab by immune-related RECIST (irRECIST) at the RP2D. [ Time Frame: Through study completion, an expected average of 2 years ]

Estimated Enrollment: 250
Actual Study Start Date: October 2016
Estimated Study Completion Date: October 2018
Estimated Primary Completion Date: October 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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 phase of the study is to find the recommended phase 2 dose.

For the second phase of the study, enrollment into a dose expansion cohort will commence once the Recommended Phase 2 Dose (RP2D) is established for this combination.

Patients may be discontinued from receiving study treatment based on the results of disease assessments or if experiencing intolerable side effects.

Drug: Combination of NKTR-214 + nivolumab

Phase 1: Patients with select tumor types will receive NKTR-214 doses administered either every 21 days or every 14 days, in combination with 240 mg nivolumab (Opdivo®) every 14 days or in combination with 360 mg of nivolumab every 21 days.

Phase 2: Additional patient cohorts with select tumor types will be dosed at the RP2D dose/schedule of NKTR-214 and nivolumab (as determined by Phase 1 of the trial).

Other Name: NKTR-214 + Opdivo®

Detailed Description:

NKTR-214 is a cytokine (investigational agent) that is 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 a molecule called PD-1 (programmed cell death protein 1) on immune cells and promotes anti-tumor effects.

A total of 38 eligible patients were enrolled in the Dose Escalation portion of the study (Phase 1) and were assigned to one of five dose regimens of NKTR-214 in combination with nivolumab (0.006 mg/kg NKTR-214 every 21 days with 240 mg nivolumab every 14 days, 0.003 mg/kg NKTR-214 every 14 days with 240 mg nivolumab every 14 days, 0.006 mg/kg NKTR-214 every 14 days with 240 mg nivolumab every 14 days, 0.006 mg/kg NKTR-214 every 21 days with 360 mg nivolumab every 21 days, 0.009 mg/kg NKTR-214 every 21 days with 360 mg nivolumab every 21 days). The first phase of the study evaluated the safety and efficacy profile of the combination and it was determined that a dose of 0.006 mg/kg NKTR-214 every 21 days with 360 mg nivolumab every 21 days, the Recommended Phase 2 Dose (RP2D), will be studied in Phase 2 of the overall study.

During the Dose Expansion portion of the study (Phase 2), a total of five specific tumor types (Melanoma, Renal Cell Carcinoma (RCC), Non-Small Cell Lung Cancer (NSCLC), Urothelial Carcinoma, and Triple Negative Breast Cancer (TNBC)) will be enrolled to receive the RP2D of NKTR-214 in combination with nivolumab. Approximately 250 eligible patients who are both Immuno-oncology (I-O) therapy naïve and I-O therapy relapsed/refractory will be enrolled in the Dose Expansion (Phase 2) into one of eight cohorts. The eight expansion cohorts include:

  • Melanoma:1st-line
  • Melanoma: 2nd- and 3rd-line I-O therapy relapsed/refractory
  • RCC: 1st- and 2nd-line I-O therapy naïve
  • RCC: 2nd- and 3rd-line I-O therapy relapsed/refractory
  • NSCLC: 1st- and 2nd-line I-O therapy naïve
  • NSCLC: 2nd- and 3rd-line I-O therapy relapsed/refractory
  • Urothelial Carcinoma (Bladder): 1st-line I-O therapy naïve, cisplatin ineligible
  • TNBC: 1st- and 2nd-line I-O therapy naïve

All patients enrolled in the study will be closely monitored to determine if there is response to the treatment as well as for any side effects that may occur. The efficacy of the combination will be assessed using objective response rate (ORR). Exploratory immunological biomarkers in plasma and tumor samples will evaluate immune activation.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

INCLUSION CRITERIA - For Dose Escalation (Phase 1) and Dose Expansion (Phase 2):

  • Willing and able to provide written informed consent
  • Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic melanoma, RCC, NSCLC, urothelial carcinoma, or TNBC
  • Male or female patients, age 18 years or older at the time of signing the informed consent form (ICF)
  • 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
  • Demonstrated adequate organ function within 14 days of treatment initiation
  • Oxygen saturation ≥ 92% on room air. NSCLC patients may use supplemental oxygen
  • Subjects must be recovered from the effects of any prior chemotherapy, immunotherapy, other prior system anticancer therapy, radiotherapy, or surgery. Clinically significant toxic effect(s) of the most recent prior chemotherapy must be resolved to Grade 1 or less (except alopecia and sensory neuropathy).
  • Women of childbearing potential must agree to use highly effective methods of birth control. All participants must agree to use double barrier contraception during study participation for at least 6 months after the last dose of study drugs.
  • Patients with stable brain metastases may be enrolled if certain criteria are met.
  • Fresh and archival tumor tissue available
  • Additional criteria may apply.

INCLUSION CRITERIA - For Dose Expansion (Phase 2):

  • MELANOMA:

    • Histologically confirmed stage III (unresectable) or stage IV melanoma, as per American Joint Committee on Cancer (AJCC) staging system
    • Ocular melanoma will be excluded
  • Melanoma Subpopulation A 1st-line (1L):

    • Have not received prior anti-cancer therapy for advanced or metastatic melanoma
    • Known BRAF status as per regionally acceptable V600 mutational status testing
  • Melanoma Subpopulation B (immuno-oncology [I-O] therapy relapsed/refractory):

    • 2nd- and 3rd-line (2-3L), patients must have received only 1 prior line of therapy with a checkpoint inhibitor (anti-PD-1 or anti-PD-L1), which must be their most recent anti-cancer treatment. Patients must have documented disease progression within 24 months during or following treatment with a checkpoint inhibitor.
    • Patients may have received only 1 prior line of therapy with molecular-targeted therapy. Patients who have not received prior molecular-targeted therapy and received only 1 prior regimen of cytotoxic chemotherapy are eligible.
  • RENAL CELL CARCINOMA (RCC):

    • Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC stage IV) RCC
    • Histologically confirmed RCC with a clear-cell component.
  • RCC Subpopulation A (I-O therapy naïve):

    • 1st- and 2nd-line (1-2L), patients may have received only 1 prior targeted or tyrosine kinase inhibitor therapy, or patient refuses standard of care.
  • RCC Subpopulation B (I-O relapsed/refractory):

    • 2-3L, patients must have received only 1 prior line of therapy with a checkpoint inhibitor (anti-PD-1 or anti-PD-L1), which must be their most recent anti-cancer treatment. Patients must have documented disease progression within 24 months during or following treatment with a checkpoint inhibitor.
    • Patients may have received no more than 1 prior anti-angiogenic therapy or cytotoxic chemotherapy regimen.
  • NON-SMALL CELL LUNG CANCER (NSCLC):

    • Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC lacking epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation
    • Patients may have experienced disease recurrence or progression during or after a prior platinum-based chemotherapy-containing regimen for advanced or metastatic disease, or patient refuses standard of care.
    • Patients who received platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation therapy given for locally advanced disease and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible.
  • NSCLC Subpopulation A (I-O therapy naïve):

    • 1-2L, patients must not have received any prior immune-oncology regimens, including but not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co stimulation or checkpoint pathways, indoleamine 2,3 dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies.
  • NSCLC Subpopulation B (I-O relapsed/refractory):

    • 2-3L, patients must have received only 1 prior line of therapy with a checkpoint inhibitor (anti-PD-1 or anti-PD-L1) alone or in combination with chemotherapy, which must be their most recent anti-cancer treatment. Patients must have documented disease progression within 24 months during or following treatment with a checkpoint inhibitor.
  • UROTHELIAL CARCINOMA (1L, I-O therapy naïve, cisplatin ineligible)

    • Histologically or cytologically documented locally advanced or transitional cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, urethra ineligible for cisplatin-based chemotherapy. Patients with mixed histologies are required to have a dominant transitional cell pattern.
    • No prior chemotherapy for inoperable locally advanced or metastatic urothelial carcinoma. Prior local intravesical chemotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment.
    • For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval of more than 12 months between the last treatment administration and the date of recurrence is required to be considered treatment naïve in the metastatic setting.
    • Patients must not have received any prior immune-oncology regimens, including but not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,3 dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies.
    • Patients must meet at least one of the following criteria:

      • Creatinine clearance (calculated or measured) < 60 mL/min
      • Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≥ 2 audiometric hearing loss
      • CTCAE v4.03 Grade ≥ 2 peripheral neuropathy
      • New York Heart Association (NYHA) Class III heart failure
      • Patient refuses standard of care
  • TRIPLE-NEGATIVE BREAST CANCER (1-2L, I-O therapy naïve)

    • Less than 1% of tumor cell nuclei test positive for estrogen and progesterone receptors determined by using standard immunohistochemistry (IHC)
    • Human epidermal growth factor 2 (HER2) negative as determined by local pathologist, using IHC or in situ hybridization
    • Patients may have received only 1 prior line of therapy with chemotherapy, adjuvant setting excluded, or patient refuses standard of care.
    • Must not have received any prior immune-oncology regimens, including but not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 2, 3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies.

EXCLUSION CRITERIA - For Dose Escalation (Phase 1) and Dose Expansion (Phase 2):

  • 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
  • History of allergy or hypersensitivity to study drug components
  • Active malignancy not related to the current diagnosed malignancy
  • Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis
  • Prior surgery or radiotherapy within 14 days of therapy
  • Participants who have had < 28 days since the last chemotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, sorafenib, vemurafenib, dabrafenib, cobimetinib), or systemic or inhaled steroid therapy at doses greater than 10mg of prednisone or equivalent before administration of the first dose of study medication
  • Participant's inability to adhere to or tolerate protocol or study procedures
  • Additional criteria may apply.
  Contacts and Locations
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
Contact: Nektar Recruitment 855-482-8676 StudyInquiry@nektar.com

  Show 63 Study Locations
Sponsors and Collaborators
Nektar Therapeutics
Bristol-Myers Squibb
Investigators
Study Director: Michael Imperiale, MD Nektar Therapeutics
  More Information

Responsible Party: Nektar Therapeutics
ClinicalTrials.gov Identifier: NCT02983045     History of Changes
Other Study ID Numbers: 16-214-02
First Submitted: November 23, 2016
First Posted: December 6, 2016
Last Update Posted: November 8, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Non-Small-Cell Lung
Carcinoma, Renal Cell
Triple Negative Breast Neoplasms
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Breast Neoplasms
Breast Diseases
Skin Diseases
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs