| Eligibility |
Inclusion Criteria:
- Written informed consent obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations.
- Age = 18 years at time of study entry.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Body weight >30kg.
- Confirmed differentiated thyroid cancer (papillary, follicular, poorly differentiated
and Hürtle cell), medullary thyroid cancer and anaplastic thyroid cancer.
- Available tumor and blood samples for translational research
- Patients should meet one of the following criteria:
1. Cohort 1: Patients with locally advanced or metastatic differentiated thyroid
cancer (including the subtypes of papillary, follicular, poorly differentiated
and Hürthle cell carcinoma) after disease progression on systemic therapy with
MKIs. Patients could be recruited in the study after progression on Lenvatinib
(regardless prior lines) or progression on at least two prior MKIs which may or
not include Lenvatinib. No prior therapy with immune check point inhibitors is
allowed. Patients with intolerable toxicity to MKIs that meet the prior inclusion
criteria and experience disease progression by RECIST v1.1 after stopping therapy
may be included.
2. Cohort 2: Patients with locally advanced or metastatic medullary thyroid cancer
after progression on systemic therapy with MKIs. Patients could be recruited in
the study after progression to Vandetanib (regardless prior lines) or progression
to at least two prior MKIs that may or not include Vandetanib. No prior therapy
with immune check point inhibitors is allowed. Patients with intolerable toxicity
to MKIs that meet the prior inclusion criteria and experience disease progression
by RECIST v1.1 after stopping therapy may be included.
3. Cohort 3: Patients with locally advanced or metastatic anaplastic thyroid cancer
regardless of prior therapy. No prior therapy with immune check point inhibitors
is allowed.
- No limitation of number of prior therapies.
- Life expectancy >3 months
- Adequate normal organ and marrow function as defined below: a) Haemoglobin =9.0 g/dL.
b) Absolute neutrophil count (ANC) > 1500 per mm3. c) Platelet count =100,000 per mm3.
d) Serum bilirubin =1.5 x institutional upper limit of normal (ULN). This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology), who will be allowed only in consultation with their physician. e)
AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal. f) Measured
creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40mL/min by the
Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for
determination of creatinine clearance.
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre- menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply: a) Women <50 years of age would be considered
post-menopausal if they have been amenorrheic for 12 months or more following
cessation of exogenous hormonal treatments and if they have luteinizing hormone and
follicle-stimulating hormone levels in the post-menopausal range for the institution
or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). b) Women
=50 years of age would be considered post-menopausal if they have been amenorrheic for
12 months or more following cessation of all exogenous hormonal treatments, had
radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced
menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral
oophorectomy, bilateral salpingectomy or hysterectomy).
- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
Exclusion Criteria:
- Participation in another clinical study with an investigational product during the
last 21 days.
- Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
- Any previous treatment with a PD1, PD-L1 or CTLA-4 inhibitor, including durvalumab and
tremelimumab.
- Any previous treatment with immunotherapy, including combinations of immunotherapy and
other anticancer or targeted agents.
- Mean QT interval corrected for heart rate (QTc) =470 ms calculated from 3
electrocardiograms (ECGs) using Fridericia's Correction.
- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
criterion: a) Intranasal, inhaled, topical steroids, or local steroid injections
(e.g., intra articular injection). b) Systemic corticosteroids at physiologic doses
not to exceed 10 mg/day of prednisone or its equivalent. c) Steroids as premedication
for hypersensitivity reactions (e.g., CT scan premedication).
- Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria: a) Patients with Grade =2 neuropathy will be evaluated on a case-by-case
basis after consultation with the Study Physician. b) Patients with irreversible
toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be
included only after consultation with the Study Physician.
- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.
- History of allogenic organ transplantation.
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion: a) Patients with vitiligo or alopecia. b) Patients with hypothyroidism
(e.g., following Hashimoto syndrome) stable on hormone replacement. c) Any chronic
skin condition that does not require systemic therapy. d) Patients without active
disease in the last 5 years may be included but only after consultation with the study
physician. e) Patients with celiac disease controlled by diet alone.
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.
- History of another primary malignancy except for: a) Malignancy treated with curative
intent and with no known active disease =5 years before the first dose of IP and of
low potential risk for recurrence. b) Adequately treated non-melanoma skin cancer or
lentigomaligna without evidence of disease. c) Adequately treated carcinoma in situ
without evidence of disease.
- History of active primary immunodeficiency.
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
- Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ highly effective birth control
from screening to 90 days after the last dose of durvalumab monotherapy and 180 days
for combined treatment with durvalumab and tremelimumab.
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
- Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
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