| Eligibility |
Inclusion Criteria:
- Cohort A Only: Confirmation in a CLIA certified laboratory that one of the patient's
thyroid tumors (primary tumor, recurrent tumor, or metastases) does not possess a
BRAFV600- mutation (non-V600- BRAF mutations, including BRAF translocations, may be
included in this cohort).
- Cohort A Only: Evidence of progressive disease (e.g. presence of new or growing
lesion(s) on radiologic imaging and/or new or worsening tumor-related symptoms) within
14 months of study enrollment
- Cohort B Only: Confirmation in a CLIA certified laboratory that one of the patient's
thyroid tumors (primary tumor, recurrent tumor, or metastases) possesses a BRAFV600-
mutation (e.g. V600E, V600K, V600D).
- Cohort B Only: Patients must have documented progression (evidence of tumor growth or
appearance of new tumor) on prior BRAF directed therapy (e.g. (but not limited to)
vemurafenib, dabrafenib) and must have tolerated this therapy without > Grade 3
toxicity on their most recent evaluation (excluding Grade 4 asymptomatic laboratory
abnormalities).
- Patients must have pathologically or cytologically confirmed differentiated thyroid
cancer of follicular origin (including papillary thyroid carcinoma, follicular thyroid
carcinoma, hurthle cell carcinomas, poorly differentiated thyroid carcinoma and their
respective variants).
- Patients must have RECIST v1.1 measurable disease.
- Patients must have recurrent or metastatic disease not amenable to curative surgery or
radiation.
- Age > 18 years.
- ECOG performance status of 0 or 1.
- Patients must have no recent treatment for thyroid cancer as defined as:
- No prior RAI therapy is allowed <6 months prior to initiation of therapy on this
protocol. A diagnostic study using <10 mCi of RAI is not considered RAI therapy
- No external beam radiation therapy <4weeks prior to initiation of therapy on this
protocol.
- No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed
<4 weeks prior to the initiation of therapy on this protocol (an exception to
this are patients on dabrafenib who will be enrolling into Cohort B). Dabrafenib
may be continued prior to and through trial enrollment into the start of the
study therapy when PDR001 will be added to dabrafenib
- RAI-refractory disease on structural imaging, defined as one of the following:
- Total lifetime dose of radioiodine > 600 mCi
- A tumor that is not radioiodine-avid on a diagnostic radioiodine scan performed
prior to enrollment in the current study.
- A radioiodine-avid metastatic lesion which remained stable in size or progressed
despite radioiodine treatment 6 months or more prior to study entry in the study.
There are no size limitations for the index lesions used to satisfy this entry
criterion
- The presence of at least one fluorodeoxyglucose (FDG) avid lesion.
- Patients must be able to swallow and retain orally-administered pills without any
clinically significant gastrointestinal abnormalities that may alter absorption, such
as malabsorption syndrome or major resection of the stomach or bowels.
- Patients must have tissue from the primary tumor or metastases available for
correlative studies. Either a paraffin block or at least 20 unstained slides are
acceptable (30 unstained slides would be ideal). (If less than twenty unstained slides
are available and a paraffin bloc is not available, the patient may be able to
participate at the discretion of the investigator).
- Patients must agree to undergo two research biopsies of (a) malignant lesion(s). Tumor
tissue obtained prior to study consent or treatment as part of standard of care can
also be submitted in lieu of performance of the first pre-treatment biopsy if the
Principal Investigator deems it to be of sufficient quantity/quality/timeliness.
Patients may be exempt from biopsy if 1) the investigator or person performing the
biopsy judges that no tumor is accessible for biopsy, 2) the investigator or person
performing the biopsy feels that the biopsy poses too great of a risk to the patient,
or 3) the patient cannot be safely removed from anti-coagulation therapy (if the
anti-coagulation therapy needs to be temporarily held for the biopsy procedure). If
the only tumor accessible for biopsy is also the only lesion that can be used for
RECIST v1.1 response evaluation, then the patient may be exempt from biopsy. If the
investigator deems a second research biopsy to be high risk after a patient has
completed the first research biopsy, the patient may be exempt from the second biopsy.
- Screening laboratory values must meet the following criteria:
- WBC = 2000/µl
- Neutrophils = 1500/µl
- Platelets = 100 x 10^3/µl
- Hemoglobin > 9.0 g/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)
- 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
- Left ventricular ejection fraction = institutional lower limit of normal by
transthoracic echocardiogram (ECHO) performed within 1 month of study drug initiation.
Exclusion Criteria:
- Cohort A Only:
- Patients with the following ophthalmological finding/conditions:
- Intraocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intraocular
pressure).
- Current or past history of central serous retinopathy or retinal vein occlusion.
- Cohort A Only: Prior therapy with a MEK 1/2 targeted drug (with the exception of
patients who received this therapy for a defined period of time to enhance radioiodine
activity).
- Symptomatic metastatic brain or leptomeningeal tumors (asymptomatic or treated
metastatic brain or leptomeningeal tumors are allowed).
- Prior therapy directed at the PD1/PD-L1 axis.
- Any of the following cardiovascular risks:
- A QT interval corrected for heart rate using the Bazett's formula QTcB = 480
msec.
- Clinically significant uncontrolled arrhythmias (Exception: patients with
controlled atrial fibrillation for >30 days prior to enrollment are eligible).
- Acute coronary syndromes (including myocardial infarction and unstable angina),
coronary angioplasty, or stenting within 6 months of enrollment.
- = Class II congestive heart failure as defined by the New York Heart Association
(NYHA) functional classification system.
- Treatment-refractory hypertension defined as a blood pressure of systolic >140
mmHg and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive
therapy.
- Prior malignancy if treated within 2 years of trial drug initiation (with the
exception of non-melanoma skin cancers). Patients may be included if they have
completed therapy for a prior malignancy >2 years prior to drug initiation and are
currently NED.
- Use of any live vaccines against infectious diseases within 4 weeks of initiation of
study treatment.
- Systemic chronic steroid therapy (= 10mg/day prednisone or equivalent) or any
immunosuppressive therapy (including but not limited to methotrexate, azathioprine,
and TNF-alpha blockers) 7 days prior to planned first date of study treatment (note:
topical, inhaled, nasal, intra-articular and ophthalmic steroids are allowed).
- Active, known or suspected autoimmune disease or documented history of autoimmune
disease with the exception of vitiligo, controlled type I diabetes mellitus on stable
insulin, autoimmune thyroid disease or psoriasis not requiring systemic treatment.
- Allogenic bone marrow or solid organ transplant.
- History of severe hypersensitivity reactions to monoclonal antibodies or any other
study drug components which in the opinion of the investigator may pose an increased
risk of serious infusion reaction.
- Known history of current interstitial lung disease or non-infectious pneumonitis.
- Patients with active hepatitis B infection (HBV surface antigen positive).
- Subject is known to be positive for Human Immunodeficiency Virus (HIV) or active
Hepatitis C Virus (HCV). Testing for HIV or Hepatitis C prior to initiation of the
study drug is not required. If a patient has a known history of treated HCV, then a
viral load is required to confirm clearance of infection.
- Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test
within 72 hours prior to initiating study treatment.
- Women of child-bearing potential (as defined in Appendix 18.3), unless they are using
highly effective methods of contraception during dosing and for 150-days after
stopping treatment with PDR001. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of
the patient). 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), total 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). The vasectomized male
partner should be the sole partner for that patient
- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception. NOTE: 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 (i.e. age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy), total
hysterectomy, or tubal ligation at least six weeks ago. 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.
- Sexually active males unless they use a condom during intercourse while on treatment
and for 150 days after stopping treatment with PDR001 and should not father a child in
this period. A condom is required to be used by vasectomized men as well during
intercourse to prevent delivery of the drug via semen.
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