| Eligibility |
Inclusion Criteria:
1. Male or female subjects = 18 years of age.
2. Willingness to participate in the research by signing an informed consent form
approved by the research ethics committee.
3. ECOG status 0 or 1 or 2.
4. Measurable disease according to RECIST 1.1, as defined by the investigator.
5. Patients with a histologically confirmed disease (according to the pathologist's
report) that meets one of the following criteria (according to the 2010 WHO
classification):
Poorly differentiated iodine-refractory thyroid tumors in the first line or after
switching to chemotherapy or investigational drugs or anaplastic thyroid cancer in the
first line or after switching to chemotherapy or investigational drugs. The primary
tumor may or may not be removed, but the risk of aerodigestive compression or bleeding
should be excluded.
6. Radioactive iodine resistant disease (RAI), which is defined by one or more of the
following criteria:
- One or more measurable lesions that do not show RAI uptake.
- One or more measurable lesions progressing on RECIST 1.1 = <14 months prior RAI
therapy
- One or more measurable lesions are present after a cumulative dose of RAI> = 600
mCi
- One or more measurable lesions that are F-18 fludeoxyglucose (FDG) -avid (> 5
standardized absorbance value [SUV]) if positron emission tomography (PET) / CT
is performed; these lesions can also be RAI-active
7. Patients with inoperable locally advanced disease or metastases. Patients who do not
want to undergo surgery or radiation are also eligible. Patients with the BRAFV600E
mutation who are unable to take FDA-approved drugs, dabrafenib / trametinib, or
established progression with therapy are eligible for study treatment if documented.
8. Ability to collect samples, including blood and tumors, for translational studies.
9. Weight over 30 kg.
10. Recovery from toxicity associated with any prior treatment to grade = 1, unless
adverse events (AEs) are clinically significant and / or are stable with maintenance
therapy.
11. Ability to swallow pills or have a gastrostomy.
12. Normal organ and bone marrow function as defined below (obtained = <30 days prior to
study entry):
- Hemoglobin = 9.0 g / dL.
- Absolute neutrophil count (ANC)> 1500 per mm.
- Platelet count = 100,000 per mm.
- Serum bilirubin = 1.5 times the upper limit of normal (ULN) if liver metastases
are absent, in which case it should be = 2X ULN. This does not apply to patients
with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia,
which is predominantly unconjugated in the absence of hemolysis or liver
pathology); however, they will only be admitted after consulting their doctor.
- Aspartate transaminase (AST) (SGOT) / alanine aminotransferase (ALT) (SGPT) =
2.5x the institutional upper limit of normal, unless liver metastases are
present, in which case it should be = 3x ULN.
- Measured creatinine clearance (CL)> 40 ml / min or Estimated creatinine
clearance> 40 ml / min using the Cockcroft-Gault formula (Cockcroft and Gault,
1976) or 24-hour urine collection to determine creatinine clearance.
- Albumin> = 2.5 mg / dL (received = <30 days prior to registration)
- International normalized ratio (INR) or prothrombin time (PT) = <1.5 X ULN if the
subject is not receiving anticoagulant therapy while PT or partial thromboplastin
time (PTT) is within the therapeutic range of the intended use of anticoagulants
- Activated partial thromboplastin time (APTT) = <1.5 x ULN if the subject is not
receiving anticoagulant therapy while the PT or PTT is within the therapeutic
range of the intended use of anticoagulants
13. Adequately controlled blood pressure with or without antihypertensive drugs, defined
as blood pressure (BP) <150/90 mm Hg.
14. Female subjects of childbearing age (not surgically sterile or at least 2 years of age
in postmenopausal women) must present a negative pregnancy test at screening and use a
medically accepted double-barrier method of contraception (e.g. spermicide condom +
IUD or cervical caps). In addition, they must agree to continue using this
double-barrier method for the duration of the study and for 4 months after the end of
study participation. Women will be considered postmenopausal if they have had
amenorrhea within 12 months without an alternative medical cause. The following age
requirements apply:
1. Women under 50 are considered to be posttmenopausal if they have had amenorrhea
for 12 months or more after stopping treatment with exogenous hormones, and if
they have postmenpausal levels of luteinizing hormone and follicle-stimulating
hormone or have undergone surgical sterilization (bilateral oophorectomy or
hysterectomy)
2. Women over 50 years of age will be considered postmenopausal if they have had
amenorrhea for 12 months or more after stopping all exogenous hormonal drugs with
the last menstrual period> 1 year ago, had a menopause caused by chemotherapy
with the last menstrual period> 1 year ago, or underwent surgery sterilization
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
15. Men must agree to abstain from intercourse with a female partner or agree to use a
double-barrier method of contraception (for example, a spermicide condom, in addition
to the fact that their female partner is using some form of contraception, such as an
intrauterine device (IUD) or cervical caps), at the time of the study and for 4 months
after the end of participation in the study.
16. Patient willingness and ability to adhere to protocol throughout the study, including
undergoing treatment, and availability for scheduled visits and examinations,
including follow-up.
Exclusion Criteria:
1. The presence of a confirmed BRAF mutation.
2. Concurrent participation in another clinical trial if it is not an observational
(non-interventional) clinical trial or during the follow-up period of an
interventional trial
3. Pretreatment with any immune checkpoint inhibitor therapy (eg anti-CTLA4, -PD-1 or
-PD-L1).
4. Taking any type of low molecular weight kinase inhibitors (including the
investigational kinase inhibitor) for 2 weeks or 5 half-lives of the agent, whichever
is greater.
5. Receiving any type of anti-tumor antibodies (including test antibodies) or systemic
chemotherapy within 2 weeks before starting treatment.
6. Current or previous use of immunosuppressants within 2 weeks prior to the first dose
of study drugs, with the exception of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses that should not exceed 10 mg / day of
prednisone or an equivalent corticosteroid.
7. Active or previously documented autoimmune disease within the past 2 years. Note:
Patients with vitiligo, Graves' disease or psoriasis who do not require systemic
treatment (within the last 2 years) are not excluded.
8. Active or previously documented inflammatory bowel disease (eg Crohn's disease and
ulcerative colitis).
9. History of allogeneic organ transplantation.
10. Subjects diagnosed with immunodeficiency or receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 28 days prior to the first dose of
study treatment.
11. Received radiation therapy for bone metastases within 2 weeks or any other radiation
therapy within 4 weeks prior to enrollment. Subjects with clinically significant
ongoing complications from previous radiation therapy that have not completely
resolved are not eligible for the study (eg, radiation esophagitis or other internal
inflammation).
12. Presence of metastases in the brain or epidural disease of the skull without adequate
treatment with radiation therapy and / or surgery (including radiosurgery). Eligible
patients should be neurologically asymptomatic and not receive corticosteroid
medications during investigational treatment.
13. Concomitant therapy with oral anticoagulants (eg warfarin, direct thrombin and factor
Xa inhibitors) or platelet inhibitors (eg clopidogrel), with the exception of the
following approved anticoagulants:
- Low-dose aspirin for cardioprotection (in accordance with current local
guidelines) and low-dose low molecular weight heparins (LMWH).
- Anticoagulant therapy with therapeutic doses of LMWH in subjects without known
brain metastases who received a dose of LMWH for at least 6 weeks prior to
enrollment and who had no clinically significant hemorrhagic complications from
the anticoagulation regimen or tumor.
14. Subject has an uncontrolled, serious underlying medical condition or recent illness,
including but not limited to the following conditions:
A) Cardiovascular diseases:
- Congestive heart failure, grade 3 or 4 as defined by the New York Heart
Association, unstable angina, and severe cardiac arrhythmias.
- Uncontrolled hypertension, defined as sustained blood pressure> 150 mm Hg.
Systolic or diastolic> 100 mmHg
- Stroke, including transient ischemic attack (TIA), myocardial infarction, other
ischemic events or thromboembolic event, such as deep vein thrombosis (DVT) and
pulmonary embolism) within 6 months prior to inclusion. Subjects with a later
diagnosis of DVT are eligible if they are stable, asymptomatic, and have received
LMWH for at least 6 weeks prior to study treatment.
B) Gastrointestinal disorders (eg malabsorption syndrome or obstruction of the gastric
outlet), including those associated with a high risk of perforation or fistula
formation:
- Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis,
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute
pancreatitis or acute obstruction of the pancreas or bile ducts, or obstruction
of the gastric outlet.
- Abdominal fistula, gastrointestinal perforation, bowel obstruction, or
intra-abdominal abscess within 6 months prior to inclusion. Note: Complete
healing of the intra-abdominal abscess must be confirmed before starting
treatment.
C) Clinically significant vomiting or hemoptysis> 0.5 teaspoon (> 2.5 ml) of red blood
or other significant bleeding in history within 3 months prior to treatment.
D) Interstitial lung lesions or known manifestations of endobronchial disease. F)
Lesions invading the main pulmonary blood vessels.
F) Other clinically significant disorders such as:
- An active infection requiring systemic treatment, infection with human
immunodeficiency virus or disease associated with acquired immunodeficiency
syndrome, or chronic infection with hepatitis B or C.
- Serious non-healing wound / ulcer / bone fracture.
- Moderate or severe liver failure (Child-Pugh B or C).
- The need for hemodialysis or peritoneal dialysis.
- Uncontrolled diabetes mellitus.
- History of solid organ transplantation.
15. Major surgery (such as gastrointestinal surgery and removal or biopsy of brain
metastases) within 8 weeks prior to inclusion. Complete wound healing from major
surgery should occur 4 weeks before the study treatment, and after minor surgery (eg,
simple excision, tooth extraction) at least 10 days before the study treatment.
Patients with clinically significant ongoing complications from prior surgery are not
eligible.
16. Adjusted QT interval calculated by Fridericia formula (QTcf)> 500 ms for 28 days prior
to study treatment.
Note: If a single ECG displays a QTCf with an absolute value> 500 ms, two additional
ECGs at approximately 3 min intervals must be performed within 30 minutes of the
initial ECG, and the average of these three consecutive results will be used to assess
eligibility for study participation.
17. Pregnant (test must be done no later than 7 days before the start of the study) or
lactating mothers.
18. Received any live vaccine = <30 days prior to study initiation.
19. Inability to swallow pills and lack of gastrostomy.
20. Previously identified allergy or hypersensitivity to the components of the
investigational dosage forms.
21. Diagnosis of other malignant neoplasm within 3 years prior to study treatment, with
the exception of superficial skin cancer or localized low-grade tumors that are
considered cured and untreated by systemic therapy.
22. ADDITIONAL EXCLUSION CRITERION FOR COHORT 1 (pembrolizumab + lenvatinib): The presence
of invasion (germination) of the tumor into the major great vessels or the presence of
clinically significant blood clots in the arteries or veins.
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