Clinical trial NCT02142803 (phase 1, status: active, not recruiting)
Conditions: adult glioblastoma, endometrial clear cell adenocarcinoma, endometrial serous adenocarcinoma, ovarian clear cell cystadenocarcinoma, ovarian endometrioid adenocarcinoma, ovarian mucinous cystadenocarcinoma, ovarian serous cystadenocarcinoma, recurrent fallopian tube carcinoma, recurrent ovarian carcinoma, recurrent primary peritoneal carcinoma, recurrent uterine corpus cancer, solid neoplasm, stage iiia fallopian tube cancer ajcc v7, stage iiia ovarian cancer ajcc v6 and v7, stage iiia primary peritoneal cancer ajcc v7, stage iiib fallopian tube cancer ajcc v7, stage iiib ovarian cancer ajcc v6 and v7, stage iiib primary peritoneal cancer ajcc v7, stage iiic fallopian tube cancer ajcc v7, stage iiic ovarian cancer ajcc v6 and v7, stage iiic primary peritoneal cancer ajcc v7, stage iv fallopian tube cancer ajcc v6 and v7, stage iv ovarian cancer ajcc v6 and v7, stage iv primary peritoneal cancer ajcc v7
ICD codes: C22.0, C4A.9, C7B.1, C4A.0, C4A.31, C4A.51, C4A.8, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, K65.1, K66.0, N99.4, N73.6, R88.0, Z49.32, Z49.02, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, K65.1, K66.0, N99.4, N73.6, R88.0, Z49.32, Z49.02, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, K65.1, K66.0, N99.4, N73.6, R88.0, Z49.32, Z49.02, C57.00, C57.01, C57.02, D28.2, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, K65.1, K66.0, N99.4, N73.6, R88.0, Z49.32, Z49.02
Drugs: sapanisertib
SMILES: CC(C)N1N=C(C2=C(N)N=CN=C12)C1=CC=C2OC(N)=NC2=C1
Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have a histologically/cytologically confirmed diagnosis of recurrent
             glioblastoma or an advanced solid tumor in which bevacizumab has shown benefit in
             specific disease population and for which standard or curative measures do not exist
             or are no longer effective

          -  Measurable or evaluable disease as assessed by Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1 for non-GBM tumors and by Response Assessment in Neuro-Oncology
             (RANO) criteria for GBM

          -  For stage 1 (all patients) and dose expansion (stage 2) endometrial and ovarian cancer
             cohorts, participants are allowed following unlimited prior therapy; for stage 2 GBM
             participants, no more than 2 prior relapses are allowed; for these patients, relapse
             is defined as progression following initial therapy (i.e. radiation +/- chemo if that
             was used as initial therapy) or a subsequent therapy; the intent therefore is that GBM
             patients enrolling onto stage 2 had no more than 3 prior therapies (initial and
             treatment for 2 relapses); if the patient had a surgical resection for relapsed
             disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient
             undergoes another surgical resection, this is considered to constitute 1 relapse

               -  NOTE: for participants who had prior therapy for a low-grade glioma, the surgical
                  diagnosis of glioblastoma will be considered the first relapse; therefore, these
                  participants may have had more than 3 prior therapies

          -  Patients must have recovered from clinically significant toxicity of prior therapy to
             grade =< 1 or pre-treatment baseline; the following intervals from previous treatments
             are required prior to day 1 of study therapy:

               -  12 weeks from the completion of radiation for recurrent GBM unless there is
                  surgical diagnosis of recurrence or a new lesion that was not previously radiated

               -  6 weeks from a nitrosourea chemotherapy

               -  3 weeks from a non-nitrosourea chemotherapy

               -  4 weeks from an investigational agent (not Food and Drug Administration [FDA]
                  approved) (or 5 half lives, whichever is shorter)

               -  2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g.,
                  erlotinib, hydroxychloroquine, etc.) (or 5 half lives, whichever is shorter)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Absolute neutrophil count >= 1,500/uL

          -  Platelets >= 100,000/uL

          -  Hemoglobin >= 9.0 g/dL

          -  Total bilirubin < 1.5 x institutional upper limit of normal with direct bilirubin
             within normal limits except for participants with Gilbert's disease

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal (=< 5 x upper limit of normal [ULN] if
             liver metastases are present)

          -  Creatinine < 1.5 x normal institutional limits OR creatinine clearance >= 50
             mL/min/1.73 m^2 for patients with creatinine level above institutional normal based
             either on Cockroft-Gault estimate or based on urine collection (12 or 24 hour)

          -  Metabolic: fasting serum glucose (=< 130 mg/dL) and fasting triglycerides =< 300 mg/dL

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, the
             duration of study participation and 6 months after completion of MLN 0128 or
             bevacizumab administration; 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 treated or enrolled on this protocol must also
             agree to use adequate contraception prior to the study, for the duration of study
             participation, and 6 months after completion of MLN0128 or bevacizumab administration

          -  Patients must have no concurrent malignancy except curatively treated basal or
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
             bladder; patients with prior malignancies must be disease-free for >= three years
             prior to registration

          -  Solid tumor patients must be off corticosteroids prior to registration; if GBM patient
             is receiving corticosteroids, patient must be on a stable or decreasing dose of
             corticosteroids for at least 5 days prior to baseline magnetic resonance imaging (MRI)
             or computed tomography (CT); if steroids are added or the steroids dose is increased
             between the date of the screening MRI or CT and the start of treatment, a new baseline
             MRI or CT is required

          -  Patients must be able to swallow whole capsules

          -  Ability to understand and the willingness to sign a written informed consent document

          -  For stage 2 GBM participants, a block of paraffin embedded tissue or 30 unstained
             slides at standard 4-5 um thickness from any prior surgery demonstrating GBM pathology
             must be available for submission

          -  Stage 2 endometrial and ovarian cancer patients must have at least one lesion amenable
             to biopsy; this determination will be made by a member of the interventional radiology
             team or surgical associate investigator and an associate investigator; this
             requirement is not necessary for patients in stage 1

          -  Solid tumor patients in stage 2 must have a diagnosis of papillary serous,
             endometrioid or clear cell endometrial carcinoma or, high grade serous, clear cell,
             endometrioid or mucinous ovarian, fallopian or primary peritoneal carcinoma

        Exclusion Criteria:

          -  Concurrent administration of any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MLN0128 or bevacizumab

          -  For all stage 2 participants, no prior treatment with mTOR, PI3 kinase or Akt
             inhibitors; prior treatment with mTOR, PI3 kinase or Akt inhibitors allowed in stage 1
             only

          -  For stage 2 GBM participants, no prior treatment with bevacizumab/vascular endothelial
             growth factor receptor (VEGFR) inhibitors; prior treatment with bevacizumab/VEGFR
             inhibitors is allowed in stage 1 for all participants, as well as stage 2 endometrial
             and ovarian cancer participants

          -  Stage 1 solid tumor and stage 2 endometrial and ovarian cancer participants with known
             central nervous system (CNS) metastatic lesions which are symptomatic and/or growing;
             patients previously treated for these conditions that are asymptomatic in the absence
             of corticosteroid therapy are allowed to enroll; brain metastasis must be stable for 1
             month with verification by imaging (brain MRI completed at screening demonstrating no
             current evidence of progressive brain metastases); CNS imaging will not be mandated
             for asymptomatic patients with no history of CNS metastases

          -  Concurrent use of enzyme-inducing anti-epileptic drugs (EIAED); patients may be on
             non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs;
             patients previously treated with EIAED may be enrolled if they have been off the EIAED
             for 10 days or more prior to the first dose of MLN0128

          -  Subjects taking strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
             and cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) inhibitors and/or
             inducers should be considered with caution; alternative treatments that are less
             likely to affect MLN0128 metabolism, if available, should be considered; if a subject
             requires treatment with 1 or more of the strong CYP3A4 and CYP2C19 inhibitors and/or
             inducers, the principal investigator should be consulted

          -  Concurrent use of herbal supplements and other non-traditional medications; all herbal
             supplements and other non-traditional medications must be stopped before time of
             registration

          -  Concurrent use of anti-coagulants (warfarin, etc.) other than low-molecular weight
             heparin (LMWH); medication must be stopped before time of registration; if patient has
             recently been on anti-coagulants other than LMWH, patient must have international
             normalized ratio (INR) =< 2

          -  Evidence of any significant intracranial hemorrhage, as determined by the treating
             investigator, within 6 weeks from registration or as seen on most recent MRI prior to
             screening/baseline MRI

          -  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

          -  History of any of the following within 6 months prior to start of MLN0128:

          -  Left ventricular ejection fraction (LVEF) =< 55% as determined by multi gated
             acquisition (MUGA) scan or echocardiogram (ECHO)

          -  Heart failure >= New York Heart Association (NYHA) grade 3

          -  Significant ST depression of >= 1.5 mm in 2 or more leads and/or T wave inversions in
             >= 2 leads

          -  Complete left bundle branch block

          -  Right bundle branch block + left anterior hemiblock (bi-fascicular block)

          -  Congenital long QT syndrome

          -  QT interval corrected by Fridericia's formula (QTcF) > 450 msec on screening
             electrocardiogram (ECG)

          -  Requirement of inotropic support (excluding digoxin)

          -  History or presence of clinically significant ventricular or atrial tachyarrhythmias,
             or cardiac arrest

          -  Clinically significant resting bradycardia

          -  Presence of unstable atrial fibrillation (ventricular response > 100 beats per minute)

          -  Patients with stable atrial fibrillation are allowed in the study provided they do not
             meet the other cardiac exclusion criteria

          -  History of arrhythmia requiring an implantable cardiac defibrillator

          -  Angina pectoris =< 12 months prior to starting drug

          -  Acute myocardial infarction =< 12 months prior to starting drug

          -  Any valve disease Common Terminology Criteria for Adverse Events (CTCAE) grade

          -  Ischemic myocardial event including angina requiring therapy and artery
             revascularization procedures

          -  Placement of a pacemaker for control of rhythm

          -  Pulmonary embolism

          -  Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery
             revascularization procedures

          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of oral MLN0128 (e.g., ulcerative diseases, uncontrolled nausea,
             vomiting, diarrhea, malabsorption syndrome, small bowel resection that requires
             nutritional support)

          -  Use of hematopoietic colony-stimulating growth factors (e.g. filgrastim [G-CSF],
             sargramostim [GMCSF], lanimostim [M-CSF]) =< 2 weeks prior to starting study drug;
             erythropoietin, darbepoetin and erythropoietin-biosimilars are allowed for as long as
             they have been initiated at least 2 weeks prior to study enrollment

          -  Pregnant or nursing women; breastfeeding should be discontinued if the mother is
             treated with MLN0128

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible; if an HIV-positive patient has adequate cluster of
             differentiation (CD4) counts (CD4 above the lower limit of institutional normal) and
             is on antiretroviral therapy with newer agents, which are not strong cytochrome (CYP)
             inhibitors, they will be eligible

          -  Uncontrolled high blood pressure (i.e., systolic blood pressure >= 160 mmHg, diastolic
             blood pressure >= 90 mmHg)

          -  Pulmonary hypertension

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

          -  Participants with poorly controlled diabetes mellitus (defined as hemoglobin A1c
             [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

          -  Urine protein should be screened by urinalysis; if protein is 2+ or higher, 24 hour
             urine protein should be obtained and the level should be < 1000 mg for patient
             enrollment

          -  Serious or non-healing wound, ulcer or bone fracture

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months prior to day 1

          -  Invasive procedures defined as follows:

               -  Major surgical procedure, open biopsy or significant traumatic injury within 28
                  days prior to day 1 therapy

               -  Anticipation of need for major surgical procedures during the course of the study

               -  Core biopsy within 7 days prior to day 1 therapy

          -  Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent
             peripheral arterial thrombosis) within 6 months prior to day 1

          -  Evidence of bleeding diathesis or coagulopathy

          -  Patients with known hypersensitivity to Chinese hamster ovary cell products or other
             recombinant human antibodies