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 = 28 days). 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 = 28 days) 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.
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.
