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Study of Safety and Tolerability of Nivolumab Treatment Alone or in Combination With Relatlimab or Ipilimumab in Head and Neck Cancer

Primary Purpose

Head and Neck Squamous Cell Carcinoma (HNSCC)

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Nivolumab
Relatlimab
Ipilimumab
Sponsored by
Robert Ferris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Head and Neck Squamous Cell Carcinoma (HNSCC) focused on measuring anti-PD1 antibody, anti-CTLA4 antibody, anti-LAG3 antibody, tumor infiltrating lymphocyte (TIL)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Males and females, ages ≥18 years
  2. Histologically or cytologically confirmed Squamous Cell Carcinoma, previously untreated stage III, or IVA HNC by AJCC 8th edition staging system. Newly diagnosed, never treated HNC cancer but could have had a surgically treated primary > 5 years previous without radiotherapy or chemotherapy. For HPV positive oropharyngeal cancer, patients with T3 or T4 primary and/or one ipsilateral lymph node greater than 3 cm, multiple ipsilateral lymph nodes, bilateral lymph nodes, or contralateral lymph node will be included. Patients must undergo CT or MRI to rule out the presence of distant metastases.
  3. Accessible tumor for pretreatment (baseline) open/incisional biopsy to provide adequate correlative specimen.
  4. Have LAG-3 and PD-L1 results for stratification.
  5. LVEF assessment with documented LVEF ≥50% by either TTE or MUGA (TTE preferred test) within 28 days prior to first study drug administration
  6. Women of child-bearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. All WOCBP MUST have a negative pregnancy test within 7 days prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. All WOCBP must agree to use appropriate contraception to prevent pregnancy for the duration of treatment with study treatments, plus 24 weeks after the last dose of study treatment (i.e., 30 days [duration of ovulatory cycle] plus approximately 5 half-lives).
  7. All males must agree to use appropriate contraception for the duration of treatment with study treatments plus 33 weeks after the last dose of study treatment (i.e., 90 days [duration of sperm turnover] plus approximately 5 half-lives). In addition, male participants must be willing to refrain from sperm donation during this time. In addition, men enrolled on this study must be informed of the risks to any sexual partner of childbearing potential and should practice an effective method of birth control
  8. Azoospermic males are exempt from contraceptive requirements unless the potential exists for fetal toxicity due to study drug being present in seminal fluid, even if the participant has undergone a successful vasectomy or if the partner is pregnant. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section.
  9. Primary tumors of the oral cavity, oropharynx, hypopharynx, or larynx will be included.
  10. Eligible for surgical resection.
  11. Age ≥ 18 years
  12. ECOG performance status 0-1.
  13. Have signed written informed consent

Exclusion Criteria:

  1. Prior radiation, chemotherapy, oncology vaccine or immunotherapy.
  2. Prior severe infusion reaction to a monoclonal antibody.
  3. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are less than or equal to 1 x ULN. If TnT or TnI levels are > 1 to 2 × ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the BMS Medical Monitor or designee. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment.
  4. Evidence of distant metastasis.
  5. Prior history of HNC treated < 5 years previously.
  6. Prior history of myocarditis, regardless of etiology
  7. Prior treatment with LAG-3 targeted agents.
  8. A known history of Hepatitis B or C
  9. Patients with active/history of autoimmune disease. "Active" refers to any condition currently requiring therapy. Examples of autoimmune disease include systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis
  10. Psychiatric illness or other social issues limiting compliance
  11. If second primary tumor is found at the time of EUA, the subject will be excluded from study participation.

Sites / Locations

  • UPMC Hillman Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Nivolumab + Relatlimab

Nivolumab + Ipilimumab

Nivolumab

Arm Description

Nivolumab 480mg IV + Relatlimab 160mg IV D1 - optional Nivolumab 480 mg IV + Relatlimab 160mg IV D28 (D28 at clinician discretion i.e. surgery postponed)

Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg D1 then Nivolumab 3 mg /kg D14 and then optional Nivolumab 3 mg/kg D28 (D28 at clinician discretion i.e., surgery postponed)

Nivolumab 480 mg IV D1 and then optional Nivo 480 mg IV D28 (D28 clinician discretion i.e. surgery postponed)

Outcomes

Primary Outcome Measures

Adverse Events related to treatment of nivolumab in combination with relatlimab
Number of participants experiencing adverse events related to treatment with nivolumab in combination with relatlimab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Adverse Events related to treatment of nivolumab in combination with ipilimumab
Number of participants experiencing adverse events related to treatment with nivolumab in combination with ipilimumab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Adverse Events related to treatment of nivolumab
Number of participants experiencing adverse events related to treatment with nivolumab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Secondary Outcome Measures

Radiographic response
Change in tumor volume of target lesion. Difference in tumor volume (using imaging measurements) will be calculated per milometer of size to indicate either growth or shrinkage of the target lesion. A decrease in tumor volume is associated with a positive response to study treatment.
Levels of tumor infiltrating lymphocyte (TIL) subsets
Levels of tumor infiltrating lymphocyte (TIL) subsets in peripheral blood. Tumor-infiltrating lymphocytes are white blood cells that have left the bloodstream and migrated towards a tumor. The presence of lymphocytes in tumors is often associated with better post-surgical clinical outcomes and after immunotherapy.
Levels of peripheral blood lymphocytes (PBL)
Levels of peripheral blood lymphocytes (PBL) in blood. PBL levels may be useful in predicting response to chemotherapy.
Effector CD4+ cells
Presence of CD4+ cells in tumor tissue at the time of biopsy and resection specimen collection. CD4 T-cell can play a role in the development of tumor immunity.
Effector CD8+ cells
Presence and level of CD8+ T cells in peripheral blood. CD8-positive T cells are a critical subpopulation of MHC class I-restricted T cell and are mediators of adaptive immunity. They include cytotoxic T cells, which are important for killing cancerous cells.

Full Information

First Posted
September 3, 2019
Last Updated
July 2, 2023
Sponsor
Robert Ferris
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT04080804
Brief Title
Study of Safety and Tolerability of Nivolumab Treatment Alone or in Combination With Relatlimab or Ipilimumab in Head and Neck Cancer
Official Title
A Phase II Neoadjuvant Study of the Safety and Tolerability of Anti-PD1 (Nivolumab) Administered Alone or in Combination With Anti-LAG3 (Relatlimab) or Anti-CTLA4 (Ipilimumab) in Resectable Head and Neck Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 8, 2020 (Actual)
Primary Completion Date
May 31, 2025 (Anticipated)
Study Completion Date
July 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Robert Ferris
Collaborators
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The aim of this study is to potentiate adaptive immunity to enhance the anti-tumor activity of anti-PD1 antibody by the addition of anti-CTLA4 antibody or anti-LAG3 antibody (relatlimab) given in subjects with resectable locally advanced HNSCC prior to surgical resection.
Detailed Description
Immunotherapeutic agents have been well tolerated in the recurrent/metastatic patient population. Studies have shown that delay of surgical resection for 3-4 weeks after diagnosis is acceptable. Overall survival for locally advanced head and neck squamous cell carcinoma are poor with the current treatment modalities available. Previously untreated, locally advanced (AJCC 8th edition stage III-IVa) HPV+ and HPV- head and neck squamous cell carcinoma patients who are candidates for surgical resection, as deemed by the multidisciplinary team will be included in this trial. Patients with histories of autoimmune disease or with current or previous histories of immune modulating agents will be excluded from participation. Relatlimab will be given IV at a dose of 160 mg IV on D1 (and on D28 if surgery is postponed at the discretion of the investigator). Nivolumab will be given IV at a dose of 480 mg on D1 (and on D28 if surgery is postponed at the discretion of the investigator) when given alone or with relatlimab. Nivolumab will be given at dose of 3 mg/kg IV every 2 weeks on D1 and D14 (and on D28 if the operating room time is not yet available, and the 4-week CT scan demonstrates at least stable disease ) when given with Ipilimumab. Ipilimumab will be given at a dose of 1 mg/kg IV once only on D1. Patients will undergo biopsy and CT scan prior to treatment initiation. 4 weeks (± 1 week) after, patient will undergo surgical resection. CT scan will be repeated prior to surgery (from 1-72 hours prior to surgery).The patients will be monitored from time of biopsy until 6 months postoperatively.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Head and Neck Squamous Cell Carcinoma (HNSCC)
Keywords
anti-PD1 antibody, anti-CTLA4 antibody, anti-LAG3 antibody, tumor infiltrating lymphocyte (TIL)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Stage II-IVa locally advanced (LA) resectable HNSCC; stratified by HPV, LAG-3 and PD-L1 status
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nivolumab + Relatlimab
Arm Type
Experimental
Arm Description
Nivolumab 480mg IV + Relatlimab 160mg IV D1 - optional Nivolumab 480 mg IV + Relatlimab 160mg IV D28 (D28 at clinician discretion i.e. surgery postponed)
Arm Title
Nivolumab + Ipilimumab
Arm Type
Experimental
Arm Description
Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg D1 then Nivolumab 3 mg /kg D14 and then optional Nivolumab 3 mg/kg D28 (D28 at clinician discretion i.e., surgery postponed)
Arm Title
Nivolumab
Arm Type
Experimental
Arm Description
Nivolumab 480 mg IV D1 and then optional Nivo 480 mg IV D28 (D28 clinician discretion i.e. surgery postponed)
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
anti-PD-1 antibody, OPDIVO®
Intervention Description
A fully human anti-programmed death 1 (PD-1) monoclonal antibody checkpoint inhibitor, that blocks a signal that prevents activated T cells from attacking the cancer cells.
Intervention Type
Drug
Intervention Name(s)
Relatlimab
Other Intervention Name(s)
anti-LAG3 antibody, BMS-986016
Intervention Description
A monoclonal antibody with anti-Lymphocyte-activation gene 3 (LAG-3) (immune checkpoint receptor protein found on the cell surface) activity.
Intervention Type
Drug
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
anti-CTLA4 antibody, Yervoy ®
Intervention Description
A monoclonal anitibody that targets CTLA-4, a protein receptor, that down regulates the immune system.
Primary Outcome Measure Information:
Title
Adverse Events related to treatment of nivolumab in combination with relatlimab
Description
Number of participants experiencing adverse events related to treatment with nivolumab in combination with relatlimab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Time Frame
Up to 4 months
Title
Adverse Events related to treatment of nivolumab in combination with ipilimumab
Description
Number of participants experiencing adverse events related to treatment with nivolumab in combination with ipilimumab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Time Frame
Up to 4 months
Title
Adverse Events related to treatment of nivolumab
Description
Number of participants experiencing adverse events related to treatment with nivolumab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Time Frame
Up to 4 months
Secondary Outcome Measure Information:
Title
Radiographic response
Description
Change in tumor volume of target lesion. Difference in tumor volume (using imaging measurements) will be calculated per milometer of size to indicate either growth or shrinkage of the target lesion. A decrease in tumor volume is associated with a positive response to study treatment.
Time Frame
Up to 2 months (prior to treatment and day of surgery)
Title
Levels of tumor infiltrating lymphocyte (TIL) subsets
Description
Levels of tumor infiltrating lymphocyte (TIL) subsets in peripheral blood. Tumor-infiltrating lymphocytes are white blood cells that have left the bloodstream and migrated towards a tumor. The presence of lymphocytes in tumors is often associated with better post-surgical clinical outcomes and after immunotherapy.
Time Frame
Up to 6 months (prior to the first day of treatment, on Days 1 and 28 of treatment, day of surgery, 1, 3, 6 months post surgery)
Title
Levels of peripheral blood lymphocytes (PBL)
Description
Levels of peripheral blood lymphocytes (PBL) in blood. PBL levels may be useful in predicting response to chemotherapy.
Time Frame
Up to 6 months (prior to the first day of treatment, on Days 1 and 28 of treatment, day of surgery, 1, 3, 6 months post surgery)
Title
Effector CD4+ cells
Description
Presence of CD4+ cells in tumor tissue at the time of biopsy and resection specimen collection. CD4 T-cell can play a role in the development of tumor immunity.
Time Frame
Up to 6 months (prior to the first day of treatment, on Days 1 and 28 of treatment, day of surgery, 1, 3, 6 months post surgery)
Title
Effector CD8+ cells
Description
Presence and level of CD8+ T cells in peripheral blood. CD8-positive T cells are a critical subpopulation of MHC class I-restricted T cell and are mediators of adaptive immunity. They include cytotoxic T cells, which are important for killing cancerous cells.
Time Frame
Up to 6 months (prior to the first day of treatment, on Days 1 and 28 of treatment, day of surgery, 1, 3, 6 months post surgery)
Other Pre-specified Outcome Measures:
Title
Tumor mutational burden
Description
A measurement of mutations carried by tumor cells. It is a predictive biomarker being studied to evaluate its association with response to the study therapy, which may help to plan the best treatment. Tumors that have a high number of mutations appear to be more likely to respond to certain types of immunotherapy.
Time Frame
Up to 2 months (prior to treatment and day of surgery)
Title
Gene expression signature
Description
A single or combined group of genes in a cell with a uniquely characteristic pattern of gene expression that occurs as a result of cancer or other altered or unaltered pathogenic. Gene signature can serve as a prognostic biomarker for the associated disease.
Time Frame
Up to 2 months (prior to treatment and day of surgery)
Title
Single cell RNAseq pathways
Description
Cellular pathways that examine the sequence information from individual cells with optimized next generation sequencing (NGS) technologies, providing a higher resolution of cellular differences and a better understanding of the function of an individual cell in the context of its microenvironment.
Time Frame
Up to 2 months (prior to treatment and day of surgery)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and females, ages ≥18 years Histologically or cytologically confirmed Squamous Cell Carcinoma, previously untreated stage III, or IVA HNC by AJCC 8th edition staging system. Newly diagnosed, never treated HNC cancer but could have had a surgically treated primary > 5 years previous without radiotherapy or chemotherapy. For HPV positive oropharyngeal cancer, patients with T3 or T4 primary and/or one ipsilateral lymph node greater than 3 cm, multiple ipsilateral lymph nodes, bilateral lymph nodes, or contralateral lymph node will be included. Patients must undergo CT or MRI to rule out the presence of distant metastases. Accessible tumor for pretreatment (baseline) open/incisional biopsy to provide adequate correlative specimen. Have LAG-3 and PD-L1 results for stratification. LVEF assessment with documented LVEF ≥50% by either TTE or MUGA (TTE preferred test) within 28 days prior to first study drug administration Women of child-bearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. All WOCBP MUST have a negative pregnancy test within 7 days prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. All WOCBP must agree to use appropriate contraception to prevent pregnancy for the duration of treatment with study treatments, plus 24 weeks after the last dose of study treatment (i.e., 30 days [duration of ovulatory cycle] plus approximately 5 half-lives). All males must agree to use appropriate contraception for the duration of treatment with study treatments plus 33 weeks after the last dose of study treatment (i.e., 90 days [duration of sperm turnover] plus approximately 5 half-lives). In addition, male participants must be willing to refrain from sperm donation during this time. In addition, men enrolled on this study must be informed of the risks to any sexual partner of childbearing potential and should practice an effective method of birth control Azoospermic males are exempt from contraceptive requirements unless the potential exists for fetal toxicity due to study drug being present in seminal fluid, even if the participant has undergone a successful vasectomy or if the partner is pregnant. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section. Primary tumors of the oral cavity, oropharynx, hypopharynx, or larynx will be included. Eligible for surgical resection. Age ≥ 18 years ECOG performance status 0-1. Have signed written informed consent Exclusion Criteria: Prior radiation, chemotherapy, oncology vaccine or immunotherapy. Prior severe infusion reaction to a monoclonal antibody. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are less than or equal to 1 x ULN. If TnT or TnI levels are > 1 to 2 × ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the BMS Medical Monitor or designee. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment. Evidence of distant metastasis. Prior history of HNC treated < 5 years previously. Prior history of myocarditis, regardless of etiology Prior treatment with LAG-3 targeted agents. A known history of Hepatitis B or C Patients with active/history of autoimmune disease. "Active" refers to any condition currently requiring therapy. Examples of autoimmune disease include systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis Psychiatric illness or other social issues limiting compliance If second primary tumor is found at the time of EUA, the subject will be excluded from study participation.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jennifer Ruth, RN, BSN
Phone
412-623-8963
Email
ruthj2@upmc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Rosemarie Angelo, RN, BSN
Phone
412-623-7039
Email
angelor3@upmc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Ferris, MD, PhD
Organizational Affiliation
UPMC Hillman Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UPMC Hillman Cancer Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jennifer Ruth, RN, BSN
Phone
412-623-8963
Email
ruthj2@upmc.edu
First Name & Middle Initial & Last Name & Degree
Rosemarie Angelo, RN, BSN
Phone
412-623-7039
Email
angelor3@upmc.edu
First Name & Middle Initial & Last Name & Degree
Robert L Ferris, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No

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Study of Safety and Tolerability of Nivolumab Treatment Alone or in Combination With Relatlimab or Ipilimumab in Head and Neck Cancer

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