Nivolumab Plus Ipilimumab in Thyroid Cancer

This research study is a Phase 2 clinical trial. Phase 2 clinical trials test the safety and
effectiveness of an investigational intervention to learn whether the intervention works in
treating a specific disease. "Investigational" means that the intervention is being studied.

The purpose of this study is to evaluate effectiveness (how well the drug/s work) of
nivolumab combined with ipilimumab.

Nivolumab and ipilimumab are types of immunotherapy. Immunotherapy works by encouraging the
body's own immune system to attack cancer cells. Nivolumab has been approved by the US Food
and Drug Administration (FDA) for the treatment of metastatic melanoma (a type of skin
cancer), and specific types of previously treated advanced lung and kidney cancers.
Ipilimumab is approved by the FDA for the treatment of metastatic melanoma.

The combination of nivolumab and ipilimumab is now FDA approved as treatment for patients
with metastatic melanoma. However, the use of nivolumab as well as ipilimumab alone or in
combination for the treatment of patients with thyroid cancer is not approved

Inclusion

- Metastatic, RAI refractory, differentiated thyroid cancer (including papillary and
follicular thyroid cancer and their sub-types such as Hurthle cell thyroid cancer as
well as poorly differentiated thyroid cancer), with progression within 13 months prior
to study registration. RAI refractoriness is defined as absence of uptake of RAI on
either a low-dose diagnostic test or a post-treatment RAI scan in measurable lesions
or radiographic progression of disease within 12 months of the last course of RAI
treatment despite the recorded uptake of RAI with that previous therapy or having a
cumulative lifetime administered dose of greater than 600mCi.

- Exploratory cohort: incurable medullary thyroid cancer with prior tyrosine kinase
inhibitor (TKI) failure and progression within 13 months prior to enrollment (10
patients) and anaplastic thyroid cancer (7 patients)

- Any number of lines of prior treatment are allowed

- Any line of prior treatment for patients under 65y, over 65y must have at least one
prior line of TKI treatment

- Age 18 years or older

- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

- Participants must have normal organ and marrow function as defined below:

- Screening laboratory values must meet the following criteria and should be obtained
within 21 days prior to randomization/registration

- WBC ≥ 2000/μL

- Neutrophils ≥ 1500/μL

- Platelets ≥ 100 x103/μL

- Hemoglobin > 9.0 g/dL

- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using
the Cockcroft-Gault formula below):

- Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in
mg/dL

- Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in
mg/dL

- AST/ALT ≤ 3 x ULN

- Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)

- Ability to understand and the willingness to sign a written informed consent document.

- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30
days plus the time required for nivolumab to undergo five half-lives) after the last
dose of investigational drug

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 iu/l or equivalent units of hcg) within 24 hours of the first
dose of the study drug

- Women of childbearing potential" is defined as any female who has experienced menarche
and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 31
weeks after the last dose of investigational product Women who are not of childbearing
potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men
do not require contraception

Exclusion

- Patients should be excluded if they have an active, known or suspected autoimmune
disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger

- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease.

- As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with a predisposition to hepatoxicity should be used with caution
in patients treated with nivolumab-containing regimen.

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Patients who are receiving any other investigational agents.

- Patients with activebrain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.