This is an, open-label, protocol designed to evaluate the activity of targeted therapy in
anaplastic/undifferentiated thyroid cancer. Arm A will evaluate ATC/UTC with mutations or
rearrangements detected in the ALK gene.
There is no effective treatment for anaplastic thyroid cancer in the locally recurrent or
metastatic setting. Ceritinib will be administered to the patient until disease progression
by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial
for any other reason.
The primary focus of this arm of the protocol is identifying ceritinib's activity in
anaplastic or undifferentiated thyroid cancer patients. Those patients with mutations
identified in their ALK gene by sequencing their tumor samples, or with the established ALK
abnormalities will be treated with ALK-inhibitors. These include the Ventana assay and Vysis
FISH probe, and patients with tumors positive by this assay will also be considered eligible
for therapy on the trial.
Therapeutic Portion:
ARM A: ALK Abnormality IND Ceritinib 750 mg orally daily on Day 1 Continue q4 weeks x 2
cycles
Primary Endpoint: The development of progression; new recurrence or distant metastasis, as
well as enlargement of an existing metastasis on radiographic imaging.
Secondary Endpoints:
1. Overall response rate for patients treated with ceritinib as part of the study.
2. Death of study participant due to any cause.
This is an, open-label, protocol designed to evaluate the activity of targeted therapy in
anaplastic/undifferentiated thyroid cancer. Arm A will evaluate ATC/UTC with mutations or
rearrangements detected in the ALK gene.
There is no effective treatment for anaplastic thyroid cancer in the locally recurrent or
metastatic setting. Ceritinib will be administered to the patient until disease progression
by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial
for any other reason.
The primary focus of this arm of the protocol is identifying ceritinib's activity in
anaplastic or undifferentiated thyroid cancer patients. Those patients with mutations
identified in their ALK gene by sequencing their tumor samples, or with the established ALK
abnormalities will be treated with ALK-inhibitors. These include the Ventana assay and Vysis
FISH probe, and patients with tumors positive by this assay will also be considered eligible
for therapy on the trial.
The goal of this multi-center, multi-arm trial is to measure the impact of treating
metastatic anaplastic thyroid cancer patients with targeted therapy selected for these
patients due the presence of a genetic mutation or other aberration. This trial will serve as
a framework by which new biomarker-drug combinations can be identified and added as new arms.
Therapeutic Portion:
ARM A: ALK Abnormality IND Ceritinib 750 mg orally daily on Day 1 Continue q4 weeks x 2
cycles
Primary Endpoint: The development of progression; new recurrence or distant metastasis, as
well as enlargement of an existing metastasis on radiographic imaging. CT scans of the neck,
chest, abdomen and pelvis will be performed at baseline and every two cycles (cycles are 28
days long) according to standard of care. Other imaging of these areas such as PET/MRI will
be allowed if CT cannot be performed. MRI of the brain will be performed at baseline and as
clinically indicated. Wherever it can be safely given, radiographic contrast agents should be
given for the imaging studies.
Secondary Endpoints:
1. Overall response rate for patients treated with ceritinib as part of the study.
2. Death of study participant due to any cause.
Inclusion Criteria:
1. Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or
undifferentiated thyroid cancer that demonstrates mutation in the ALK gene as assessed
by sequencing of the tumor specimen for Arm A. Other ALK abnormalities as detected by
the approved FISH test (Abbott Molecular Inc), using Vysis breakapart probes (defined
as 15% or more positive tumor cells); or the Ventana IHC test will also be seen as
evidence of ALK abnormality and meeting eligibility requirement.
2. Patients will not have any other curative therapeutic option, such as radiation or
surgery.
3. WHO performance status 0-2.
4. Age greater then or equal to 18 years.
5. Patients must have recovered from all toxicities related to prior anticancer therapies
to ≤ Grade 2 (CTCAE v 4.03), provided that any concomitant medication is given prior
to initiation of treatment with ceritinib. Exception to this criterion: patients with
any grade of alopecia are allowed to enter the treatment.
6. Adequate organ function: the following laboratory criteria have been met:
- Absolute neutrophil count (ANC) greater then or equal to 1.5 x 109/L
- Hemoglobin (Hgb) ≥ 8 g/dL
- Platelets greater then or equal to 75 x 109/L
- Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients
with Gilbert's syndrome who may be included if total bilirubin ≤ 3.0 x ULN and
direct bilirubin ≤ 1.5 x ULN
- Aspartate transaminase (AST) < 2.0 x ULN, except for patients with liver
metastasis, who are only included if AST < 3 x ULN; alanine transaminase (ALT) <
2.0 x ULN, except for patients with liver metastasis, who are only included if
ALT < 3 x ULN
- Calculated or measured creatinine clearance (CrCL) less then or equal to 30
mL/min
7. Patient must have the following laboratory values or have the following laboratory
values corrected with supplements to be within normal limits at screening:
- Potassium ≥ LLN
- Magnesium ≥ LLN
- Phosphorus ≥ LLN
- Total calcium (corrected for serum albumin) ≥ LLN
8. Written informed consent for the protocol must be obtained prior to any screening
procedures.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other procedures.
Exclusion Criteria:
- Patients eligible must not meet any of the following criteria:
1. Patients with known hypersensitivity to any of the excipients of ceritinib
(microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide
and magnesium stearate).
2. Patients with symptomatic CNS metastases who are neurologically unstable or have
required increasing doses of steroids within the 1 week prior to study entry to
manage CNS symptoms.
3. Prior therapy with ceritinib.
4. Presence or history of a malignant disease other than thyroid cancer that has
been diagnosed and/or required therapy within the past year and is undergoing
active anticancer treatment. Exceptions to this exclusion include the following:
completely resected basal cell and squamous cell skin cancers, and completely
resected carcinoma in situ of any type.
5. Patients with known history of extensive disseminated bilateral interstitial
fibrosis or interstitial lung disease, including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis,
and clinically significant radiation pneumonitis (i.e. affecting activities of
daily living or requiring therapeutic intervention).
6. Patient has clinically significant, uncontrolled heart disease and/or recent
cardiac event (within 6 months), such as:
- unstable angina within 6 months prior to screening;
- myocardial infarction within 6 months prior to screening;
- history of documented congestive heart failure (New York Heart Association
functional classification III-IV);
- uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160
mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without
antihypertensive medication
- initiation or adjustment of antihypertensive medication(s) is allowed prior
to screening;
- ventricular arrhythmias; supraventricular and nodal arrhythmias not
controlled with medication;
- other cardiac arrhythmia not controlled with medication;
- corrected QTc > 450 msec using Fridericia correction on the screening ECG
7. Impaired GI function or GI disease that may alter absorption of ceritinib or
inability to swallow up to five ceritinib capsules daily.
8. Ongoing GI adverse events > grade 2 (e.g. nausea, vomiting, or diarrhea) at the
start of the study.
9. Receiving medications that meet one of the following criteria and that cannot be
discontinued at least 1 week prior to the start of treatment with ceritinib and
for the duration of participation (see Appendix 1 Tables):
- Medication with a known risk of prolonging the QT interval or inducing
Torsades de Pointes (please refer to
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm)
- Strong inhibitors or strong inducers of CYP3A4/5 (please refer to
http://medicine.iupui.edu/flockhart/table.htm or
http://www.druginteractioninfo.org)
- Medications with a low therapeutic index that are primarily metabolized by
CYP3A4/5, CYP2C8 and/or CYP2C9 (please refer to
http://medicine.iupui.edu/flockhart/table.htm or
http://www.druginteractioninfo.org)
- Therapeutic doses of warfarin sodium (Coumadin) or any other
coumadin-derived anti-coagulant. Anticoagulants not derived from warfarin
are allowed (eg, dabigatran, rivaroxaban, apixaban).
- Unstable or increasing doses of corticosteroids
- enzyme-inducing anticonvulsive agents
- herbal supplements
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of
a female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test.
11. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of
contraception during dosing and agree to continue for 3 months after the last
dose of study treatment. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception.
- Female sterilization (have had surgical bilateral oophorectomy with or
without hysterectomy) or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level
assessment.
- Male sterilization (at least 6 months prior to screening) with the
appropriate post-vasectomy documentation of the absence of sperm in the
ejaculate. For female subjects on the study the vasectomized male partner
should be the sole partner for that subject.
- Combination of any two of the following (a+b or a+c or b+c):
1. Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy
(failure rate < 1%), for example hormone vaginal ring or transdermal
hormone contraception.
2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository.
In case of use of oral contraception, women should have been stable on the same
pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
ligation at least six weeks prior to screening. In the case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment is she considered not of child bearing
potential.
12. Sexually active males unless they agree to use a condom during intercourse while
taking drug and agree to continue for 3 months after the last dose of study
treatment. Male patients for 3 months should not father a child in this period. A
condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid.
