Sapanisertib in Treating Patients With Metastatic or Refractory Pancreatic Neuroendocrine Tumor That Cannot Be Removed by Surgery
Condition: Pancreatic Neuroendocrine Tumor G1; Pancreatic Neuroendocrine Tumor G2; Refractory Pancreatic Neuroendocrine Carcinoma
MeSH terms: Neoplasms; Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Adenoma, Islet Cell; Carcinoma, Islet Cell
Intervention: Sapanisertib
Intervention description: Given PO
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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 somatostatin analogue (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

          -  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

          -  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

        Exclusion Criteria:

          -  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

          -  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