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.
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 3mg/kgIV 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.
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.
