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Personalized Immunotherapy in Patients With Recurrent /Metastatic SCCHN That Have Progressed on Prior Immunotherapy

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.
 
ClinicalTrials.gov Identifier: NCT04326257
Recruitment Status : Recruiting
First Posted : March 30, 2020
Last Update Posted : July 17, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Dan Zandberg, University of Pittsburgh

Brief Summary:
In this Phase II trial of personalized immunotherapy in R/M HNSCC, gene expression of LAG3 and CTLA4 by RNA seq will be determined to select the appropriate agent (Ipilimumab or Relatlimab) to add to Nivolumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) who have failed prior immunotherapy with anti-PD-1 or PD-L1 mAb therapy. The agent, either Ipilimumab or Relatlimab will be chosen based on the highest relevant immune gene expression (CTLA4 or LAG-3) as long as the minimum difference required is met.

Condition or disease Intervention/treatment Phase
Squamous Cell Carcinoma of the Head and Neck Drug: Nivolumab+Relatlimab Drug: Nivolumab+Ipilimumab Phase 2

Detailed Description:

In this Phase II non-randomized trial, n=40 eligible patients will have tumor tissue (core or excisional/incisional) for gene expression of LAG3 and CTLA4 via RNA seq per OmniSeq Immune Report Card to determine which drug (either Relatlimab or Ipilimumab) will be added to Nivolumab for treatment. The patient will then receive the prescribed therapy continuously for up to 24 cycles (1 cycle = 4 weeks of treatment). The drug to be added to Nivolumab will be based on which relevant gene has the highest expression as long as the minimum difference required is met. If the minimum difference is not met than a patient will be randomized to either Nivolumab plus Relatlimab or Nivolumab plus Ipilimumab.

The patient will then receive the prescribed therapy continuously for up to 24 cycles (1 cycle = 4 weeks of treatment) with repeat imaging prior to every 3rd cycle until progression of disease. Response, evaluated by RECIST 1.1, with modifications to allow for continued therapy until progressive disease is confirmed if the patient is clinically stable, will be used in the trial. If the patient has confirmed progression the patient may be eligible to undergo a second biopsy and second treatment on trial. If these criteria are met the patient will then be treated with this new combination with repeat imaging prior to every 3rd cycle as per initial treatment, until progression of disease.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: In this open-label, 2 parallel arms trial, RNA seq analysis via the Omniseq immune report card will be used to determine which drug (Relatlimab or Ipilimumab) will be added to Nivolumab for treatment.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Personalized Immunotherapy in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck That Have Progressed on Prior Immunotherapy
Actual Study Start Date : June 5, 2020
Estimated Primary Completion Date : March 1, 2022
Estimated Study Completion Date : March 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Nivolumab+Relatlimab

Nivolumab will be dosed 480mg IV q 4 weeks and Relatlimab 160mg IV q 4

One cycle is defined as 4 weeks of treatment and both drugs are given on the same day.

Patients will receive the prescribed therapy continuously for up to 24 cycles until progression of disease or adverse event(s) requiring treatment discontinuation.

Drug: Nivolumab+Relatlimab
IV administration of both Nivolumab and Relatlimab
Other Names:
  • Nivolumab: OPDIVO/ BMS-936558/ MDX1106/ ONO-4538;
  • Relatlimab: BMS-986016

Experimental: Nivolumab+Ipilimumab

Nivolumab will be dosed at 3mg/kg IV q 2 weeks and Ipilimumab 1mg/kg IV q 6 weeks.

Patients will receive four doses of Ipilimumab and the last dosage of Nivolumab 3mg/kg IV q 2 weeks will be given at the time of the 4th dose of Ipilimumab, followed 2 weeks later by Nivolumab 480 mg IV q 4 weeks. A cycle of therapy will be defined as 4 weeks of treatment. The patient will receive the prescribed therapy continuously for up to 24 cycles until progression of disease or adverse event(s) requiring treatment discontinuation.

Drug: Nivolumab+Ipilimumab
IV administration of both Nivolumab and Ipilimumab
Other Names:
  • Nivolumab: OPDIVO/ BMS-936558/ MDX1106/ ONO-4538
  • Ipilimumab: YERVOY/ BMS-734016/ MDX-010




Primary Outcome Measures :
  1. Probability of Objective Response (OR) [ Time Frame: From start of treatment, up to 36 months ]
    The estimated probability of response to therapy in patients who have progressed on prior immunotherapy. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Complete Response (CR) is disappearance of all target and non-target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.


Secondary Outcome Measures :
  1. Disease Control Rate (DCR) [ Time Frame: From start of treatment, up to 36 months ]
    The estimated Disease Control Rate (DCR) in patients who have progressed on prior immunotherapy. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Complete Response (CR) is disappearance of all target and non-target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; Stable Disease (SD) is neither sufficient decrease (target lesions) to qualify as a PR or sufficient increase to qualify as PD. Incomplete Response/Stable Disease (SD) is the persistence of one or more non-target lesions.

  2. Progression-free Survival (PFS) [ Time Frame: From start of treatment up to 36 months ]
    The length of time from the start of treatment that patients live with disease that does not progress per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in patients who have progressed on prior immunotherapy. Per RECIST, Progressive Disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions compared to baseline sum of target lesions, or any new lesions.It also includes the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

  3. Overall Survival (OS) [ Time Frame: From start of treatment, up to 36 months ]
    The length of time from the start of treatment that patients remain alive, in patients who have progressed on prior immunotherapy.

  4. Adverse Events per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [ Time Frame: From start of treatment, up to 36 months ]
    Adverse Events possibly, probably or definitely related to study treatment per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 experienced by all patients.



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:

  1. Recurrent and/or Metastatic squamous cell carcinoma of the head and neck that is not amenable to therapy with curative intent. Patients who refuse salvage surgery or radiation for recurrence are potentially eligible.
  2. Failure of prior immunotherapy as defined as:

    1. Progression of disease on anti-PD-1 mAb or anti-PD-L1 mAb treatment in the R/M setting. The anti-PD-1/PDL1 antibody treatment must be the most recent preceding therapy prior to enrollment with progression of disease on anti-PD-1/PD-L1 antibody defined according to iRECIST criteria (Seymour et al, Lancet Oncology 2017; 18: e14352).
    2. Both patients that have received platinum based chemotherapy prior or have not yet received platinum based chemotherapy are eligible.
  3. ECOG performance status of 0-1
  4. Have at least one measurable area of disease (Target Lesion) based on RECIST 1.1.
  5. Provide adequate tissue (core or incisional/excisional biopsy) prior to starting study for analysis for gene expression of LAG3 and CTLA4 per OmniSeq Immune Report Card. FNA is not adequate. Archival tissue can only be used if it was obtained in the recurrent/metastatic setting and there has been no subsequent cancer treatment after that tissue was obtained.
  6. Life expectancy of at least 12 weeks based on investigator estimate.
  7. Age ≥ 18 years old
  8. LVEF assessment with documented LVEF ≥50% by either TTE or MUGA (TTE preferred test) within 6 months from first study drug administration
  9. Patients must have normal organ and marrow function as defined below:

    • absolute neutrophil count ≥1,500/mcL
    • platelets ≥100,000/mcL
    • total bilirubin ≤ institutional upper limit of normal (ULN)
    • AST(SGOT)/ALT(SGPT) ≤2.5 x institutional ULN
    • creatinine ≤ institutional ULN

    OR

    - glomerular filtration rate ≥40 mL/min/1.73 m2 for patients with creatinine levels. (GFR) above institutional normal.

  10. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 1 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  11. Female subjects of childbearing potential should be willing to use 1 methods of birth control or abstain from heterosexual activity for the course of the study through 5 months after the last dose of study medication. Women of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  12. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy.
  13. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  1. SCC of salivary gland origin or cutaneous SCC of the head and neck. HNSCC of unknown origin ARE eligible.
  2. Patients who received Ipilimumab or Relatlimab in the recurrent/metastatic setting will be excluded.
  3. Is currently participating in or has participated in a study of an investigational agent or used an investigational device within 2 weeks of the first dose of treatment.
  4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (equivalent of >10 mg of prednisone) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  5. Has had a prior monoclonal antibody, chemotherapy, or targeted small molecule therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier (alopecia is an exception). Note: Subjects with ≤ Grade 2 neuropathy, ototoxicity, hypothyroidism or hyperthyroidism, are an exception to this criterion and qualify for the study.
  6. History of other malignancy within 3 years with the exception of prior HNSCC, adequately treated basal cell or squamous cell skin cancer, or carcinoma of the cervix.
  7. Has an active autoimmune disease requiring systemic immunosuppressive treatment within the past 3 months. Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic therapy or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
  8. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

    1. Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent;
    2. Uncontrolled angina within the 3 months prior to consent;
    3. Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled atrial fibrillation);
    4. QTc prolongation > 480 msec;
    5. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled deep venous thrombosis, etc.);
    6. Cardiovascular disease-related requirement for daily supplemental oxygen
    7. History of two or more MIs OR two or more coronary revascularization procedures
    8. Subjects with history of myocarditis, regardless of etiology.
  9. A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
  10. Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after endocrinopathy).
  11. 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 ≤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 based on the discretion of the PI. 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, based on the discretion of the PI.
  12. Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis.
  13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  15. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 24 weeks after the last dose of trial treatment.
  16. Has a history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  17. Has active Hepatitis B or Hepatitis C
  18. Has a history of a solid organ transplant.

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): NCT04326257


Contacts
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Contact: Samantha Demko, BSN 412-647-9015 albesl@upmc.edu
Contact: Rosemarie Angelo, BSN 412-623-7039 angelor3@upmc.edu

Locations
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United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Samantha Demko, BSN    412-647-9015    albesl@upmc.edu   
Contact: Rosemarie Angelo, BSN    412-623-7039    angelor3@upmc.edu   
Principal Investigator: Dan P Zandberg, MD, PhD         
Sponsors and Collaborators
Dan Zandberg
Bristol-Myers Squibb
Investigators
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Principal Investigator: Dan P Zandberg, MD UPMC Hillman Cancer Center
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Responsible Party: Dan Zandberg, Director, Head and Neck and Thyroid Cancer Disease Sections and Co-Director, UPMC Hillman Cancer Center Head and Neck Cancer Research Program, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04326257    
Other Study ID Numbers: HCC 18-156
First Posted: March 30, 2020    Key Record Dates
Last Update Posted: July 17, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Dan Zandberg, University of Pittsburgh:
nivolumab
Relatlimab
Ipilimumab
immunotherapy
anti-PD-1
anti-PD-L1
RECIST 1.1
recurrent cancer
metastatic cancer
tumor microenvironment analysis
LAG-3
CTLA-4
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents