A Phase I/II Study of MLN0128 in Metastatic Anaplastic Thyroid Cancer and Incurably Poorly Differentiated or Radioidodine Refractory Differentiated Thyroid Cancer

This research study is a phase I/II study of MLN0128 in metastatic anaplastic thyroid cancer(ATC) and incurably poorly differentiated or radioidodine refractory differentiated thyroid cancer (DTC).

Due to changes in the manufacturing process which resulted in increased absorption of MLN0128 from capsules, a run-in phase I prior to the phase II of the study was needed.

Phase II 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 FDA (the U.S. Food and Drug Administration) has not approved MLN0128 as a treatment for any disease.

MLN0128 prevents tumor cells from dividing and growing by selectively and potently inhibiting a chemical, mTOR kinase, which regulates cell growth and survival. Patients with anaplastic thyroid cancer have been observed to sometimes carry genetic alterations in their tumor cells which may make the cancer more sensitive to inhibition by MLN0128.

Given the activity with everolimus in RAI refractory thyroid cancer, subjects wth metastatic, incurable differentiated RAI refractory and poorly differentiated thyroid cancer were included.

Patients who fulfill eligibility criteria will be entered into the trial to receive MLN0128.

Eligibility Criteria:
Inclusion Criteria:

* Male or female patients 18 years or older
* Any number of prior chemotherapy or targeted agents including rapamycin analogues allowed
* Newly diagnosed or refractory/metastatic anaplastic thyroid cancer confirmed by histology, incurable by surgery, radiotherapy or chemoradiotherapy alone or in combination
* Must have measurable disease
* ECOG performance status 0-2
* No active intracranial metastases
* Tissue for correlative studies must be available
* Ability to swallow oral medications
* Voluntary written consent must be given before performance of any study related procedure
* Adequate organ function, as specified below, within 21 days:

  * Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL;
  * Hepatic: total bilirubin ≤1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present);
  * Renal: creatinine clearance ≥50 mL/min
  * Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL
  * Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration (ie, if the institutional normal is 50%, subject's LVEF may be as low as 45% to be eligible for the study)
* Female patients who:

  * Are postmenopausal for at least 1 year before the screening visit, OR
  * Are surgically sterile, OR
  * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
* Male patients, even if surgically sterilized (ie, status post-vasectomy), who:

  * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or
  * Agree to completely abstain from heterosexual intercourse
* Treatment with strong CYP2C19, CYP3A4, and CYP2C9 inhibitors and/or inducers must be discontinued

Exclusion Criteria:

* Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period
* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment
* Treatment with any investigational products within 14 days
* Failed to recover from the reversible effects of prior anticancer therapies
* Manifestations of malabsorption due to prior gastrointestinal surgery or disease
* Poorly controlled diabetes mellitus
* History of any of the following within the last 6 months prior to study entry:

  * Ischemic myocardial event
  * Ischemic cerebrovascular event
  * Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia
  * Placement of a pacemaker for control of rhythm
  * New York Heart Association Class III or IV heart failure
  * Pulmonary embolism
* Significant active cardiovascular or pulmonary disease at the time of study entry, including:

  * Uncontrolled high blood pressure
  * Pulmonary hypertension
  * Uncontrolled asthma or O2 saturation \< 90%
  * Significant valvular disease
  * Medically significant (symptomatic) bradycardia
  * History of arrhythmia requiring an implantable cardiac defibrillator
  * Baseline prolongation of the rate-corrected QT interval (QTc)
* Treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids