A Dose Escalation and Cohort Expansion Study of CD122-Biased Cytokine (NKTR-214) in Combination With Anti-PD-1 Antibody (Nivolumab) or in Combination With Nivolumab and Anti-CTLA4 Antibody (Ipilimumab) in Patients With Select Advanced or Metastatic Solid Tumors (PIVOT-02)

Study Description

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Brief Summary:

This study is to determine first, the recommended Phase 2 dose (RP2D) of NKTR-214 when administered in combination with nivolumab, and then, the clinical benefit, safety, and tolerability of combining NKTR-214 with nivolumab at the RP2D in select patients with Melanoma, Renal Cell Carcinoma, Non-Small Cell Lung Cancer, Urothelial Carcinoma, or Triple Negative Breast Cancer. The study will also determine the RP2D of NKTR-214 in combination with nivolumab and ipilimumab, and then the clinical benefit, safety, and tolerability of this triplet combination in select patients with RCC or NSCLC.Both All three drugs target the immune system and may act synergistically to promote anti-cancer effects.

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

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.

Part 1: Dose escalation of NKTR-214 in combination with nivolumab. A total of 38 eligible patients were enrolled into one of five dose regimens of NKTR-214 in combination with nivolumab (0.006 mg/kg NKTR-214 every 3 weeks (q3w) with 240 mg nivolumab every two weeks (q2w), 0.003 mg/kg NKTR-214 q2w with 240 mg nivolumab q2w, 0.006 mg/kg NKTR-214 q2w with 240 mg nivolumab q2w, 0.006 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w, 0.009 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w). The first part 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 q3w with 360 mg nivolumab q3w, was the Recommended Phase 2 Dose (RP2D), to be studied in Part 2 of the study.

Part 2: Dose expansion of NKTR-214 in combination with nivolumab. Patients across 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 350 eligible patients who are either Immuno-oncology (I-O) therapy naïve or anti-PD-1 or anti-PD-L1 relapsed/refractory will be enrolled in the Dose Expansion (Part 2) into one of thirteen cohorts as follows:

• Melanoma:1st-line
• Melanoma: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
• RCC: 1st-line I-O therapy naïve
• RCC: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
• NSCLC 1st-line (PD-L1 ≥ 50%)
• NSCLC 1st-line (PD-L1< 1%)
• NSCLC 1st-line (PD-L1 ≥ 1% - < 50%)
• NSCLC: 2nd-line I-O therapy naïve
• NSCLC: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
• Urothelial Carcinoma (Bladder): 1st-line I-O therapy naïve
• Urothelial Carcinoma (Bladder): 1st-line cisplatin-ineligible I-O therapy naïve
• Urothelial Carcinoma (Bladder): 3rd-Line anti-PD-1 or anti-PD-L1 relapsed/refractory
• TNBC: 1st- and 2nd-line I-O therapy naïve

Part 3: Schedule finding of NKTR-214 in combination with nivolumab and ipilimumab. During this part of the study, the safety and tolerability, and efficacy of the triplet combination will be evaluated in approximately 30 patients with metastatic RCC or NSCLC who are treatment naïve. The first schedule to be evaluated Cohort A, is NKTR-214 0.006 mg/kg and nivolumab 360 mg q3w with the addition of ipilimumab 1 mg/kg q6w.

Part 4: Dose expansion of NKTR-214 in combination with nivolumab and ipilimumab. Approximately 60 first line RCC or NSCLC patients (26-38 patients per indication) will be enrolled at the RP2D determined in Part 3 to further evaluate the safety, tolerability and efficacy of the triple combination.

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	480 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 Ipilimumab in Patients With Select Locally Advanced or Metastatic Solid Tumor Malignancies
Actual Study Start Date :	October 2016
Estimated Primary Completion Date :	June 2020
Estimated Study Completion Date :	June 2021

Arms and Interventions

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Arm	Intervention/treatment
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 Part 1 of the study is to find the RP2D. For Part 2 of the study, enrollment into a dose expansion cohort will commence once the RP2D is established for this doublet 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; Part 1: 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. Part 2: Additional patient cohorts with select tumor types will be dosed at the RP2D dose/schedule of NKTR-214 and nivolumab (as determined by Part 1 of the trial).; Other Name: NKTR-214 + Opdivo®
Experimental: Combination of NKTR-214 + nivolumab + ipilimumab; NKTR-214 will be combined with nivolumab and plus ipilimumab. The goal of theis dose escalation in Part 3 of the study is to find the RP2D and dose administration schedule. For Part 4 of the study, enrollment into a dose expansion cohort will commence once the RP2D is established for this triplet 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 + ipilimumab; Part 3: The first schedule to be evaluated, Cohort A, is NKTR-214 0.006 mg/kg and nivolumab 360 mg q3w with the addition of ipilimumab 1 mg/kg q6w. Upon review of safety, tolerability, PK, and pharmacodynamic data collected in Cohort A, alternative regimens may be considered where ipilimumab will be administered at a later cycle. Part 4: Additional patient cohorts with select tumor types will be dosed at the RP2D dose/schedule of NKTR-214 in combination with nivolumab and ipilimumab (as determined by Part 3 of the trial).; Other Name: NKTR-214 + Opdivo® + Yervoy®

Outcome Measures

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Primary Outcome Measures :

1. 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: 90 days after last dose ]
2. Safety of NKTR-214 in combination with nivolumab and ipilmumab as evaluated by incidence of drug-related AEs, SAEs, and adverse events leading to discontinuation, deaths, and clinical laboratory test abnormalities [ Time Frame: 90 days after last dose ]
3. 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: 90 days after last dose ]
4. Tolerability of NKTR-214 in combination with nivolumab and ipilmumab 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: 90 days after last dose ]
5. 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
6. Efficacy of NKTR-214 in combination with nivolumab and ipilmumab 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 :

1. Best Overall Response (BOR) in the population of interest [ Time Frame: Through study completion, an expected average of 2 years ]
2. 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.
3. 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
4. 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
5. 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
6. 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:

1. 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 ]
2. Efficacy of NKTR-214 in combination with nivolumab and ipilimumab by immune-related RECIST (irRECIST) at the RP2D. [ Time Frame: Through study completion, an expected average of 2 years ]

Eligibility Criteria

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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:

• 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.
• 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 Part 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, or consent to testing, as per regionally acceptable V600 mutational status testing

• Melanoma Subpopulation B (2nd- and 3rd-line (2-3L), anti-PD-1 or anti-PD-L1 therapy relapsed/refractory):

  • 2-3L, patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic progression.
  • Patients may have received no more than 1 prior anti-angiogenic therapy or cytotoxic chemotherapy regimen.

• 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 (1L):

  • 1L, patients may have not received prior anti-cancer therapy for advanced or metastatic RCC.

• RCC Subpopulation B (2-3L, anti-PD-1 or anti-PD-L1 relapsed/refractory):

  • 2-3L, patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic.
  • 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

    • Patients with nonsquamous NSCLC must lack epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation

• NSCLC Subpopulation A (1L):

  • 1L, patients must not have received prior anti-cancer therapy for advanced or metastatic NSCLC. Patients must have known PD-L1 status as per validated immunohistochemistry testing. Up to 20 patients will be enrolled in each subgroup:

    • PD-L1 negative (PD-L1 < 1%),
    • PD-L1 positive (PD-L1 ≥ 50%),
    • PD-L1 low/intermediate (PD-L1 ≥ 1% - < 50%).
  • For patients who do not have known PD-L1 status, testing must be done using an FDA-approved PD-L1 test.

• NSCLC Subpopulation B (2L, I-O therapy naïve):

  • 2L, patients must have experienced disease recurrence or progression during or after one prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease. 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. 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 C (2-3L, anti-PD-1 or anti-PD-L1 relapsed/refactory):

  • 2-3L, patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic.

• UROTHELIAL CARCINOMA (UC)

  • Histologically or cytologically documented locally advanced or transitional cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or urethra. Patients with mixed histologies are required to have a dominant transitional cell pattern.
  • 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 naive in the metastatic setting.

• UC Subpopulation A (1L)

  • Enrollment of urothelial carcinoma 1L patients will target accrual of up to 20 patients who are cis-ineligible and up to 20 patients, who after consultation with the Investigator, choose to forego front-line chemotherapy
  • Treatment naive and cisplatin-eligible patients who refuse standard of care.

• UC Subpopulation B (1L) cisplatin-ineligible

  • Treatment naive and cisplatin-ineligible patients who 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
  • 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.
  • 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.

• UC Subpopulation C (3L, anti-PD-1 or anti-PD-L1 relapse/refractory)

  • Patients must have progressed on only one prior line of therapy that contains platinum-based chemotherapy in the metastatic setting or post platinum-based chemotherapy in an adjuvant setting with progression < 6 months.
  • Patients must have received only one prior line of therapy with an anti-PD-1 or anti-PD-L1 containing regimen, which must be their most recent anti-cancer treatment.
  • Patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic.

• 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.

INCLUSION CRITERIA - For Parts 3 and 4:

• RENAL CELL CARCINOMA (1L):

  • Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC stage IV) RCC.
  • Histologically confirmed RCC with a clear-cell component.
  • Patients must not have received prior anti-cancer therapy for advanced or metastatic RCC

• NON-SMALL CELL LUNG CANCER (1L):

  • Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC
  • Patients with nonsquamous NSCLC must lack epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation.
  • Patients must not have received prior anti-cancer therapy for advanced or metastatic NSCLC.

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
• 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, erlotinib, gefitinib, afatinib, osimertinib), 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

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Contacts

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

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Sponsors and Collaborators

Nektar Therapeutics

Bristol-Myers Squibb

Investigators

Study Director:	Michael Imperiale, MD	Nektar Therapeutics

More Information

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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
Last Update Posted:	May 24, 2018
Last Verified:	May 2018
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