Nivolumab with Relatlimab or Ipilimumab for the Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Cancer
This phase II trial investigates how well nivolumab with relatlimab or ipilimumab work in treating patients with head and neck squamous cell cancer that has come back (recurrent) and/or has spread to other places in the body (metastatic) and has progressed on prior immunotherapy. Immunotherapy drugs are drugs that work by trying to get the immune system to attack cancer. Comparing the immune system to a car, there are two ways to make a car go faster. One is to press on the gas pedal and the other is to take the foot of the brake. The immune system has many “gas pedals” and “brakes” in order to help it decide whether to attack or not attack. The drugs nivolumab, relatlimab, and ipilimumab are antibodies (a type of protein) that work by blocking a “brake” (akin to taking the foot off the brake in the car) on the immune system cells which can lead to the immune system attacking the cancer. Each drug blocks a different brake. Nivolumab blocks PD-1, relatlimab blocks LAG-3, and ipilimumab blocks CTLA4. Giving nivolumab together with relatlimab or ipilimumab may cause the tumor to shrink in size.
Inclusion Criteria
- 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 eligible
- Failure of prior immunotherapy as defined as: * Progression of disease on anti-PD-1 monoclonal antibody (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 Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria * Both patients that have received platinum based chemotherapy prior or have not yet received platinum based chemotherapy are eligible
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Have at least one measurable area of disease (target lesion) based on RECIST 1.1
- 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. Fine needle aspiration (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
- Life expectancy of at least 12 weeks based on investigator estimate
- Left ventricular ejection fraction (LVEF) assessment with documented LVEF >= 50% by either transthoracic echocardiogram (TTE) or multigated acquisition scan (MUGA) (TTE preferred test) within 6 months from first study drug administration
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
- Creatinine =< institutional ULN OR glomerular filtration rate >= 40 mL/min/1.73 m^2 for patients with creatinine levels (glomerular filtration rate [GFR]) above institutional normal
- Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 28 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. Pregnancy testing will be repeated on cycle 1 day 1 (C1D1) prior to the first does of study medication
- Female subjects of childbearing potential should be willing to use 1 method of birth control or abstain from heterosexual activity for the course of the study through 24 weeks 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
- 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
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Squamous cell carcinoma (SCC) of salivary gland origin or cutaneous SCC of the head and neck. HNSCC of unknown origin ARE eligible
- Patients who received ipilimumab or relatlimab in the recurrent/metastatic setting will be excluded
- 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
- 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
- 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
- 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
- Has an active autoimmune disease requiring systemic immunosuppressive treatment within the past 3 months. Subjects with vitiligo, Graves 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 Sjogren’s syndrome will not be excluded from the study
- Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: * Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent * Uncontrolled angina within the 3 months prior to consent * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled atrial fibrillation) * Corrected QT interval (QTc) prolongation > 480 msec * 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.) * Cardiovascular disease-related requirement for daily supplemental oxygen * History of two or more MIs OR two or more coronary revascularization procedures * Subjects with history of myocarditis, regardless of etiology
- A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
- Subjects with history of life-threatening toxicity related to prior immune therapy (e.g. 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 (e.g., hormone replacement after endocrinopathy)
- Troponin T (TnT) or I (TnI) > 2 x institutional ULN. Subjects with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are =< 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment based on the discretion of the principal investigator (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
- Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis
- 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
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- 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
- Has a history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has active hepatitis B or hepatitis C
- Has a history of a solid organ transplant
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04326257.
PRIMARY OBJECTIVE:
I. Estimate the probability of objective response to treatment determined by gene expression of LAG3 and CTLA4 per Omniseq Immune Report card in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients who have progressed on prior immunotherapy.
SECONDARY OBJECTIVES:
I. Estimate the disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety of treatment determined by gene expression of LAG3 and CTLA4 per Omniseq Immune Report card for R/M HNSCC patients who have progressed on prior immunotherapy.
II. Estimate the probability of objective response, DCR, PFS, OS and safety of treatment that is randomly assigned instead of determined by gene expression.
III. Estimate the probability of objective response, disease control rate (DCR), PFS, OS and safety of treatment determined by gene expression of LAG3 and CTLA4 per Omniseq Immune Report card for R/M HNSCC patients who have progressed on trial treatment and undergo a second biopsy and second treatment determined by a second gene expression analysis of LAG3 and CTLA4.
EXPLORATORY BIOMARKER OBJECTIVES:
I. Evaluate immune gene expression, immune co-signaling molecule expression by immunohistochemistry (IHC), and immune cell populations over time via paired samples after exposure to combination immunotherapy.
II. Evaluate co-signaling molecule expression by IHC and correlate with gene expression by ribonucleic acid sequencing (RNAseq) as well as the predictive value of co-signaling molecule expression by IHC and the efficacy of the combination selected.
III. Evaluate immune cell populations and other biomarkers in the peripheral blood at baseline and over time.
IV. Evaluate saliva and stool microbiome to determine if any correlation with efficacy of the combination selected.
OUTLINE: Patients whose LAG-3 is at least 15.2 higher than CTLA-4 are assigned to Arm I. Patients whose CTLA-4 is at least 15.2 higher than LAG-3 are assigned to Arm II. Patients with a difference between CTLA4 and LAG3 relative rank score of less than 15.2 are randomized to Arm III or IV.
ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes and relatlimab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive nivolumab IV over 30 minutes on days 1 and 15 for cycles 1-5 and on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes every 42 days for up to 4 doses in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive nivolumab IV over 30 minutes on days 1 and 15 for cycles 1-5 and on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes every 42 days for up to 4 doses in the absence of disease progression or unacceptable toxicity.
ARM IV: Patients receive nivolumab IV over 30 minutes and relatlimab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 3 months for the first year, every 6 months for the second year, then yearly thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Pittsburgh Cancer Institute (UPCI)
Principal InvestigatorDan Paul Zandberg
- Primary IDHCC 18-156
- Secondary IDsNCI-2020-05488
- ClinicalTrials.gov IDNCT04326257