Inclusion Criteria:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be >/= 18 years of age on day of signing informed consent.
3. Present with a resectable head and neck mucosal melanoma.
4. Be eligible for surgical treatment (without any contraindications).
5. Be eligible for adjuvant radiotherapy.
6. Have measurable disease based on RECIST 1.1.
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
cannot be provided (e.g. inaccessible or subject safety concern) may submit an
archived specimen only upon agreement from the Sponsor.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
9. Demonstrate adequate organ function as defined in table 1, all screening labs should
be performed within 10 days of treatment initiation.
10. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours 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 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects 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 120 days after the last dose of study therapy.
13. Patient affiliated to a social security system or beneficiary of the same. For the cohort B, patients must met the following additional criteria :
14. Not having any contraindication for lenvatinib treatment.
Exclusion Criteria:
1. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
2. Has a metastatic disease.
3. Has a non resectable melanoma.
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (except
topical or inhaled steroids) or any other form of immunosuppressive therapy within 2
weeks prior to the first dose of trial treatment.
5. Has a known history of active TB (Bacillus Tuberculosis)
6. Hypersensitivity to pembrolizumab or any of its excipients.
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to D1 of
study treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse
events due to agents administered more than 4 weeks earlier.
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 4 weeks or 5 half-life times (whatever the shorter) prior to study Day 1 or who
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a
previously administered agent.
- - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
- - Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.
9. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
10. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
11. Has active autoimmune and/or immune mediated inflammatory disease that has required
systemic treatment in the past 2 years (i.e. with use of disease modifying agents,
corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
12. Has known history of, or any evidence of active, non-infectious pneumonitis.
13. Has an active infection requiring systemic therapy.
14. 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.
15. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD L2 agent.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
20. Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
21. Major injuries and/or surgery within the past 4 weeks prior to start of study
treatment with incomplete wound healing. 22. Has a prior history of organ transplant including allogeneic stem cell transplant. 23. Has a LVEF below the institutional (or local laboratory) normal range, as determined
by multigated acquisition (MUGA) or echocardiogram (ECHO)
24. Has an uveal melanoma. For the cohort B, patients must be excluded if one of the following additional
criteria is met :
25. Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite
of an optimized regimen of antihypertensive medication. 26. Electrolyte abnormalities that have not been corrected. 27. Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) Class II, unstable angina, myocardial
infarction or stroke within 12 months of the first dose of study drug, or cardiac
arrhythmia requiring medical treatment at Screening. 28. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree
of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be
considered because of the potential risk of severe hemorrhage associated with tumor
shrinkage/necrosis following lenvatinib therapy. 29. Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine
collection for quantitative assessment indicates that the urine protein is <1 g/24
hours.
30. Subjects who have not recovered adequately from any toxicity from other anti- cancer
treatment regimens and/or complications from major surgery prior to starting therapy.
Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer
for at least 2 weeks following major surgery and until adequate wound healing.
31. The participant has severe hypersensitivity (≥Grade 3) to lenvatinib and/or any of its
excipients.
32. Has presence of a gastrointestinal condition including malabsorption,
gastrointestinal, anastomosis, or any other condition that might affect the absorption
of lenvatinib.
33. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
34. Has clinically significant hemoptysis or significant tumor bleeding within 3 weeks
prior to the first dose of study drug.
35. Prolongation of QTcF interval to >480 ms
