Sapanisertib in Treating Patients With Metastatic or Refractory Pancreatic Neuroendocrine Tumor That Cannot Be Removed by Surgery
Sapanisertib in Treating Patients With Metastatic or Refractory Pancreatic Neuroendocrine Tumor That Cannot Be Removed by Surgery
This phase II trial studies how well sapanisertib works in treating patients with pancreatic
 neuroendocrine tumor that has spread to other places in the body (metastatic), does not
 respond to treatment (refractory), or cannot be surgically removed. Drugs such as
 sapanisertib may stop the growth or shrink tumor cells by blocking some of the enzymes needed
 for cell growth.
PRIMARY OBJECTIVE:

 I. To evaluate overall response rate associated with sapanisertib (MLN0128 [TAK-228]) in
 patients with advanced pancreatic neuroendocrine tumors (PNETs).

 SECONDARY ENDPOINTS:

 I. To evaluate progression-free survival (PFS) associated with MLN0128 (TAK-228) in patients
 with advanced pancreatic neuroendocrine tumors (PNETs).

 II. To measure the safety and tolerability of MLN0128 (TAK-228) in patients with advanced
 PNETs.

 III. To evaluate disease control rate associated with MLN0128 (TAK-228) in patients with
 advanced PNETs.

 IV. To measure duration of response rate associated with MLN0128 (TAK-228) in patients with
 advanced PNETs.

 OUTLINE:

 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 2 years,
 every 6 months for 1 year, and then yearly for 2 years.
Inclusion Criteria:

 -  Patients must have unresectable or metastatic, histologically confirmed low or
 intermediate grade (Klimstra Criteria) pancreatic neuroendocrine tumor (PNET) with
 radiological evidence of disease progression since last treatment

 -  Refractory disease to treatment with an mTOR inhibitor

 -  Patients with 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, are ineligible

 -  Disease that is currently not amenable to surgery, radiation, or combined modality
 therapy with curative intent

 -  Patients must not have poorly differentiated neuroendocrine carcinoma, high-grade
 neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell
 carcinoma

 -  Patients must have measurable disease

 -  Documented radiological evidence for disease progression (measurable or nonmeasurable)
 =< 12 months prior to enrollment

 -  NOTE: If patient has had previous radiation to the marker lesion(s), there must
 be evidence of progression since the radiation; at least one measurable lesion as
 per Response Evaluation Criteria in Solid Tumors (RECIST)

 -  Prior or concurrent therapy with SSA is permitted; a stable dose at least 2 months
 prior to study start and must continue on the stable dose while receiving study
 treatment; SSA is not considered as systemic treatment

 -  Recovered from adverse events to grade 1 or less toxicity according to Common
 Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) due to agents
 administered previously

 -  NOTE: Chemotherapy-induced alopecia and grade 2 neuropathy are acceptable

 -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

 -  Patients must be able to swallow intact capsules

 -  Leukocytes >= 3,000/mm^3 (within less than or equal to 14 days prior to registration)

 -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within less than or equal to 14 days
 prior to registration)

 -  Hemoglobin >= 10 g/dL (within less than or equal to 14 days prior to registration)

 -  Platelets >= 100 x 10^9/L (within less than or equal to 14 days prior to registration)

 -  Total serum bilirubin =< institutional upper limit of normal (ULN) (within less than
 or equal to 14 days prior to registration)

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
 (within less than or equal to 14 days prior to registration)

 -  Serum creatinine =< 1.5 X institutional ULN and creatinine clearance >= 60 ml/min
 (within less than or equal to 14 days prior to registration)

 -  NOTE: Creatinine clearance must be calculated using the Cockcroft-Gault equation

 -  Glycosylated hemoglobin (HbA1c) < 7.0% (within less than or equal to 14 days prior to
 registration)

 -  Fasting serum glucose =< 130 mg/dL (within less than or equal to 14 days prior to
 registration)

 -  Fasting triglycerides =< 300 mg/dL (within less than or equal to 14 days prior to
 registration)

 -  Diabetics are allowed if:

 -  Fasting blood glucose (FBG) =< 130 mg/dL (mmol/L), OR

 -  HbA1c =< 7%

 -  Women must not be pregnant or breast-feeding due to potential harm to the fetus from
 MLN0128 (TAK-228); all females of childbearing potential must have a blood test or
 urine study within 7 days of registration to rule out pregnancy; a female of
 childbearing potential is any woman, regardless of sexual orientation or whether they
 have undergone tubal ligation, who meets the following criteria: 1) has not undergone
 a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal
 for at least 24 consecutive months (i.e., has had menses at any time in the preceding
 24 consecutive months)

 -  Women of child-bearing potential and men must agree to practice 1 highly effective
 method of contraception and 1 additional effective (barrier) method of contraception,
 at the same time, from the time of signing the informed consent through 90 days (for
 female patients) and 120 day (for male patients) after the last dose of study drug, or
 agree to completely abstain from heterosexual intercourse; should a woman become
 pregnant or suspect she is pregnant while she or her partner is participating in this
 study, she should inform her treating physician immediately; men must agree not to
 donate sperm during the course of this study or within 120 days after receiving their
 last dose of study drug

 -  Patient is INELIGIBLE if patient discontinued prior mTOR inhibitor due to toxicity

 -  Patients must NOT have radiotherapy, or major surgery or active drug therapy for pNET
 (SSA permitted) within 4 weeks prior to study treatment start

 -  Patient must NOT have had previous treatment with any PI3K or AKT inhibitor

 -  NO hepatic artery embolization or cryoablation/radiofrequency ablation of hepatic
 metastasis within 2 months of study treatment start

 -  Patients must NOT have previous or concurrent malignancy within 2 years; exceptions
 are made for patients who meet any of the following conditions:

 -  Adequately treated basal cell or squamous cell skin cancer, superficial bladder
 cancer OR

 -  Adequately treated stage I or II cancer currently in complete remission, or any
 other cancer that has been in complete remission for at least 2 years

 -  No more than 3 prior systemic treatment regimens for advanced PNET

 -  Patients with a history of the following within =< 6 months of study entry are NOT
 eligible:

 -  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)

 -  New York Heart Association (NYHA) class III or IV heart failure

 -  Pulmonary embolism

 -  Patients with known significant active cardiovascular or pulmonary disease at the time
 of study entry are INELIGIBLE including:

 -  Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, diastolic
 blood pressure > 95 mm Hg); use of anti-hypertensive agents to control
 hypertension before cycle1 day 1 is allowed

 -  Pulmonary hypertension

 -  Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas
 analysis or pulse oximetry on room air

 -  QT syndrome, or torsades de pointes

 -  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

 -  Patients with known manifestations of malabsorption due to prior gastrointestinal (GI)
 surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128
 (TAK-228) are INELIGIBLE

 -  Patients who have a history of brain metastasis are eligible for the study provided
 that all the following criteria are met:

 -  Brain metastases which have been treated

 -  No evidence of disease progression for >= 3 months before the first dose of study
 drug

 -  No hemorrhage after treatment

 -  Off-treatment with dexamethasone for 4 weeks before administration of the first
 dose of TAK-228

 -  No ongoing requirement for dexamethasone or anti-epileptic drugs

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are INELGIBLE because of the potential for pharmacokinetic interactions with
 MLN0128 (TAK-228)

 -  NO treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, or
 CYP2C19 within 1 week preceding the first dose of study drug

 -  NO patients receiving systemic corticosteroids (either intravenous [IV] or oral
 steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week
 before administration of the first dose of study drug

 -  Patients CANNOT have daily or chronic use of a proton pump inhibitor (PPI) and/or
 having taken a PPI within 7 days before receiving the first dose of study drug

 -  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