Sapanisertib in Treating Patients with Newly Diagnosed or Refractory / Metastatic Anaplastic Thyroid Cancer
- Any number of prior chemotherapy or targeted agents including rapamycin analogues are allowed
- For the Phase II part of the study, newly diagnosed OR refractory/metastatic anaplastic thyroid cancer confirmed by histology, incurable by surgery, radiotherapy or chemoradiotherapy alone or in combination
- For the Phase I part of the study, eligible patients must have incurable poorly differentiated thyroid cancer; OR anaplastic thyroid cancer; OR radioiodine refractory differentiated thyroid cancer that is refractory to a tyrosine kinase inhibitor (TKI); OR patients who cannot tolerate a TKI are also eligible; histological confirmation of poorly differentiated, undifferentiated or anaplastic histology is required for untreated cases, but is not required for the refractory cases
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension
- Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0-2
- No active intracranial metastases
- Tissue for correlative studies must be available (paraffinized or frozen), but confirmation at screening is not needed; archival tissue may be used instead of a fresh biopsy at baseline if it already exists
- Ability to swallow oral medications and maintain an empty stomach state for 2 hours prior to the MLN0128 dose and for 1 hour following administration
- Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within =< 4 weeks prior to study entry)
- Platelet count >= 100 x 10^9/L (within =< 4 weeks prior to study entry)
- Hemoglobin >= 9 g/dL (within =< 4 weeks prior to study entry)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within =< 4 weeks prior to study entry)
- Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) =< 2.5 x institutional ULN (=< 5 x institutional ULN if liver metastases are present) (within =< 4 weeks prior to study entry)
- Creatinine within normal institutional limits, OR creatinine clearance >= 60 mL/min, based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour), for participants with creatinine levels above institutional normal (within =< 4 weeks prior to study entry)
- Fasting serum glucose (=< 130 mg/dL) (within =< 4 weeks prior to study entry)
- Fasting triglycerides =< 300 mg/dL (within =< 4 weeks prior to study entry)
- 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 (i.e., 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 cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19), cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) inhibitors and/or inducers must be discontinued at least 1 week before administration of the first dose of study drug
- 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 according to this protocol
- Treatment with any investigational products within 14 days before the first dose of study drug
- Failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia
- Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128
- Poorly controlled diabetes mellitus defined as glycated hemoglobin (HbA1c) > 7%; subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/exclusion criteria are met
- History of any of the following within the last 6 months prior to study entry: * Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures * Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery revascularization procedures * Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) * Placement of a pacemaker for control of rhythm * New York Heart Association (NYHA) 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 (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg) * Pulmonary hypertension * Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas (ABG) analysis or pulse oximetry on room air * Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement * Medically significant (symptomatic) bradycardia * History of arrhythmia requiring an implantable cardiac defibrillator * Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)
- Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either intravenous [IV] or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (patients already receiving erythropoietin on a chronic basis for >= 4 weeks are eligible)
- Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study
- Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; for patients with anaplastic thyroid cancer or otherwise particularly aggressive disease (as determined by the investigator), the washout period for chemotherapy/radiotherapy and/or targeted agents will be at the investigator’s discretion
- Presence of active brain metastases or epidural disease * Subjects with brain metastases are eligible if previously treated with whole brain radiation or radiosurgery, and do not require steroid treatment for at least 2 weeks before starting study treatment * Subjects with epidural disease are eligible if previously treated with radiation or surgery, are asymptomatic, and do not require steroid treatment for at least 2 weeks before starting study treatment
- Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
I. To determine the recommended phase II dose (RP2D). (Phase I)
II. To evaluate the proportion progression free at 4 months. (Phase II)
I. To evaluate safety/adverse events.
II. To evaluate response rate (ORR).
III. To evaluate overall survival (OS).
IV. Identification of biomarkers predictive of response to therapy with MLN0128 (sapanisertib).
OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.
Patients receive sapanisertib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 24 months.
Trial Phase Phase I/II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Jochen Hanns-Martin Lorch
- Primary ID 14-223
- Secondary IDs NCI-2015-01607
- Clinicaltrials.gov ID NCT02244463