ALT-803 Plus Nivolumab in Patients With Pretreated, Advanced or Metastatic Non-Small Cell Lung Cancer

A Phase IB/II Study of Nivolumab In Combination With ALT-803 In Patients With Pretreated, Advanced, or Metastatic Non-Small Cell Lung Cancer

The purpose of the study is to define the safety and tolerability of this drug combination. The study will also define the response rate of patients with advanced and unresectable NSCLC.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Biological: ALT-803; Biological: Nivolumab

Detailed Description

This study has a dose escalation (Ib) and dose expansion phase (II). The ALT-803 treatment in the Phase Ib portion of the study will escalate until a recommended dose level is decided. This dose level will be used in the phase II portion of the study. The Phase II potion of the study will include two groups: Nivolumab naive and Nivolumab progressing. Patients will be enrolled to one of the arms based on their previous treatment with Nivolumab.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of NSCLC who present with Stage IIIB/Stage IV disease (according to version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology) or recurrent disease following radiation therapy or surgical resection.

2. Patient must be eligible for treatment with nivolumab. Patients previously treated with nivolumab, pembrolizumab or atezolizumab, and who have progressed are eligible.

   Patients with targetable with EGFR or ALK mutations are eligible after disease recurrence or progression after at least one targeted therapy for advanced or metastatic disease.

3. Measurable disease as defined by RECIST 1.1 criteria.
4. Age ≥ 18 years
5. Performance status: ECOG performance status of ≤1 (Appendix A)

6. Adequate organ system function within 14 days of registration:

   ANC ≥ 750/μL (≥0.75 X 109/L) PLT ≥ 100,000/μL (≥ 30 X 109/L) HGB > 8g/dL Total bilirubin < 2.0 x ULN AST < 3.0 X ULN ALT < 3.0 X ULN eGFR* > 45mL/min

   *using Cockcroft & Gault equation (see Appendix B)

7. Negative serum pregnancy test if WOCBP (non-childbearing is defined as greater than one year postmenopausal or surgically sterilized).
8. Female participants of childbearing potential must adhere to using a medically accepted method of birth control up to 28 days prior to screening and agree to continue its use during the study or be surgically sterilized (e.g., hysterectomy or tubal ligation) and males must agree to use barrier methods of birth control while on study. WOCBP must agree to use effective contraception during treatment and for at least 5 months following the last dose of study treatment.
9. Prior to any study specific activities, the patient must be aware of the nature of his/her disease and willingly consent to the study after being informed of study procedures, the experimental therapy, possible alternatives, risks and potential benefits.

Exclusion Criteria:

1. While prior therapy with nivolumab, pembrolizumab, or atezolizumab is allowed, any prior therapy with other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) is not allowed.
2. NYHA Class III or IV heart failure (Appendix C), uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, or other clinical signs of severe cardiac dysfunction.
3. Symptomatic congestive heart failure, unstable angina pectoris, or myocardial infarction within 6 months of registration.
4. Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval greater than 500 milliseconds).
5. Patients with CNS metastases with the following exceptions: Patient untreated CNS metastases with 5 or fewer sites of disease, with no single site larger than 20mm, are eligible if they are asymptomatic and not requiring steroids at any dose. Patients with asymptomatic CNS metastases may be treated with radiosurgery before or during therapy on trial without treatment delays. Patients with treated, symptomatic CNS metastases are eligible if they are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to registration AND either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
6. Known autoimmune disease requiring active treatment. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of registration are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7. Subjects with a history of interstitial lung disease and/or pneumonitis.
8. Known HIV-positive.
9. Active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy.
10. Positive hepatitis C serology or active hepatitis B infection. Chronic asymptomatic viral hepatitis is allowed.
11. Women who are pregnant or nursing.
12. Psychiatric illness/social situations that would limit compliance with study requirements.
13. Any ongoing toxicity from prior anti-cancer treatment that, in the judgment of the investigator, may interfere with study treatment. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must resolve to grade 1 (NCI CTCAE version 4) or baseline prior to registration.
14. Anti-cancer treatment including surgery, radiotherapy, chemotherapy, other immunotherapy, or investigational therapy within 14 days of registration.
15. Other illness that in the opinion of the investigator would exclude the patient from participating in this study, including uncontrolled diabetes mellitus, cardiac disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: ALT-803 6 µg/kg + Nivolumab 3 mg/kg; Participants receive ALT-803 6 µg/kg + Nivolumab 3 mg/kg IV per protocol	Biological: ALT-803; ALT-803 administered IV at doses per arm (6, 10, 15, 20 µg/kg); Biological: Nivolumab; Nivolumab administered IV at 3 mg/kg per protocol; Other Names: OPDIVO
Experimental: Cohort 2: ALT-803 10 µg/kg + Nivolumab 3 mg/kg; Participants receive ALT-803 10 µg/kg + Nivolumab 3 mg/kg IV per protocol	Biological: ALT-803; ALT-803 administered IV at doses per arm (6, 10, 15, 20 µg/kg); Biological: Nivolumab; Nivolumab administered IV at 3 mg/kg per protocol; Other Names: OPDIVO
Experimental: Cohort 3: ALT-803 15 µg/kg + Nivolumab 3 mg/kg; Participants receive ALT-803 15 µg/kg + Nivolumab 3 mg/kg IV per protocol	Biological: ALT-803; ALT-803 administered IV at doses per arm (6, 10, 15, 20 µg/kg); Biological: Nivolumab; Nivolumab administered IV at 3 mg/kg per protocol; Other Names: OPDIVO
Experimental: Cohort 4: ALT-803 20 µg/kg + Nivolumab 3 mg/kg (RP2D); Participants receive ALT-803 20 µg/kg + Nivolumab 3 mg/kg IV per protocol	Biological: ALT-803; ALT-803 administered IV at doses per arm (6, 10, 15, 20 µg/kg); Biological: Nivolumab; Nivolumab administered IV at 3 mg/kg per protocol; Other Names: OPDIVO
Experimental: Arm A: RP2D ALT-803 + Nivolumab (Nivo-naïve); Participants receive ALT-803 20 µg/kg + Nivolumab 3 mg/kg IV; Nivolumab-naïve population	Biological: ALT-803; ALT-803 administered IV at doses per arm (6, 10, 15, 20 µg/kg); Biological: Nivolumab; Nivolumab administered IV at 3 mg/kg per protocol; Other Names: OPDIVO
Experimental: Arm B: RP2D ALT-803 + Nivolumab (Nivo-progressor); Participants receive ALT-803 20 µg/kg + Nivolumab 3 mg/kg IV; prior Nivolumab exposure	Biological: ALT-803; ALT-803 administered IV at doses per arm (6, 10, 15, 20 µg/kg); Biological: Nivolumab; Nivolumab administered IV at 3 mg/kg per protocol; Other Names: OPDIVO
No Intervention: Exploratory Arm 1; ALT-803 ± Nivolumab for biomarker analysis only
No Intervention: Exploratory Arm 2; ALT-803 ± Nivolumab for biomarker analysis only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence or Absence of a Dose Limiting Toxicity (DLT) of ALT-803 in Combination With Nivolumab	A continual reassessment method (CRM) design will be used to identify the maximum tolerated dose (MTD) for Phase Ib patients	Cycles 1-4: Weeks 1-6 of each cycle
Objective Response Rate	The phase II portion of the study looks to define the objective response rate (using immune-related RECIST) of ALT-803 added to nivolumab in patients with advanced and unresectable non-small cell lung cancer. Objective response rate will be defined by the best overall response, which is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease, the smallest measurements recorded since the treatment started). The subject's best response assignment will depend on the achievement of both measurement and confirmation criteria.	While on study, at the end of each 6 week cycle; if off study, every 3 months, UP TO 3 YEARS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Time from randomization to disease progression or death.	Up to 6 months
Overall Survival (OS)	Overall Survival (OS) was defined as the time from first dose of study treatment until death from any cause. Participants without a death event at the time of data cutoff were censored at the date of last known survival status.	From first dose until death or last known alive, up to 15 months.
Duration of Response (DoR)	Duration of Response (DoR) was defined as the time from the first documented objective response (CR or PR) until disease progression or death. Participants who had not progressed or died at the time of the data cutoff were censored at the date of last adequate tumor assessment. DoR was evaluated only in participants who achieved an objective response.	Up to 6 months

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: Altor BioScience
• Investigators: Principal Investigator: John Wrangle, MD, Medical University of South Carolina

Publications and helpful links

General Publications

• Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, Miller JS, Farhad M, Anderton K, Lindsey K, Taffaro-Neskey M, Sherman C, Suriano S, Swiderska-Syn M, Sion A, Harris J, Edwards AR, Rytlewski JA, Sanders CM, Yusko EC, Robinson MD, Krieg C, Redmond WL, Egan JO, Rhode PR, Jeng EK, Rock AD, Wong HC, Rubinstein MP. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018 May;19(5):694-704. doi: 10.1016/S1470-2045(18)30148-7. Epub 2018 Apr 5.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2016
• Primary Completion (Actual): February 24, 2023
• Study Completion (Actual): February 24, 2023

Study Registration Dates

• First Submitted: August 7, 2015
• First Submitted That Met QC Criteria: August 12, 2015
• First Posted (Estimated): August 14, 2015

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: January 28, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; ALT-803
• Other Study ID Numbers: 102323