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TORC1/2 Inhibitor MLN0128 and Bevacizumab in Treating Patients With Recurrent Glioblastoma or Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT02142803
Recruitment Status : Active, not recruiting
First Posted : May 20, 2014
Last Update Posted : June 30, 2022
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of raptor/rictor-mammalian target of rapamycin (mTOR) (TORC1/2) inhibitor MLN0128 when given in combination with bevacizumab in treating patients with glioblastoma, a type of brain tumor, or a solid tumor that has spread and not responded to standard treatment. TORC1/2 inhibitor MLN0128 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the progression of tumors by blocking the growth of new blood vessels necessary for tumor growth.

Condition or disease Intervention/treatment Phase
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 Biological: Bevacizumab Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Sapanisertib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of MLN0128 and Bevacizumab in Patients With Recurrent Glioblastoma and Other Solid Tumors
Actual Study Start Date : May 20, 2014
Actual Primary Completion Date : December 31, 2020

Arm Intervention/treatment
Experimental: Treatment (TORC1/2 inhibitor INK128, bevacizumab)
Patients receive TORC1/2 inhibitor INK128 PO QD on days 1-28 and bevacizumab IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Biological: Bevacizumab
Given IV
Other Names:
  • ABP 215
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF Monoclonal Antibody SIBP04
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab awwb
  • Bevacizumab Biosimilar ABP 215
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar CT-P16
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar GB-222
  • Bevacizumab Biosimilar HD204
  • Bevacizumab Biosimilar HLX04
  • Bevacizumab Biosimilar IBI305
  • Bevacizumab Biosimilar LY01008
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar Mvasi
  • Bevacizumab Biosimilar MYL-1402O
  • Bevacizumab Biosimilar QL 1101
  • Bevacizumab Biosimilar RPH-001
  • Bevacizumab Biosimilar SCT501
  • Bevacizumab Biosimilar Zirabev
  • Bevacizumab-awwb
  • Bevacizumab-bvzr
  • BP102
  • BP102 Biosimilar
  • HD204
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Mvasi
  • MYL-1402O
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF
  • SCT501
  • SIBP 04
  • SIBP-04
  • SIBP04
  • Zirabev

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Sapanisertib
Given PO
Other Names:
  • INK-128
  • INK128
  • MLN-0128
  • MLN0128
  • TAK-228

Primary Outcome Measures :
  1. MTD/RP2D of TORC1/2 inhibitor MLN0128, determined according to incidence of dose-limiting toxicity, as graded using the National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: 28 days ]
  2. Incidence of adverse events, graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 30 days ]
    Safety will be assessed through summaries of adverse events, changes in selected laboratory test results, changes in vital signs, and TORC1/2 inhibitor MLN0128 and bevacizumab exposure.

Secondary Outcome Measures :
  1. PFS [ Time Frame: From date of first dose to date of progression or death, assessed at 6 months ]
    Listed for all patients by dose level.

  2. Objective RR, defined as a complete or partial response, as determined by investigator assessment using RECIST or RANO [ Time Frame: Up to 1 year ]
  3. OS [ Time Frame: Up to 1 year ]
    Listed for all patients by dose level.

  4. Frequency of toxicities leading to missed doses or delays [ Time Frame: Up to 30 days ]
    Percentage will be summarized.

  5. Percentage of courses given or not within 7 days of their scheduled times [ Time Frame: Up to 30 days ]
    Percentage will be summarized.

  6. Percentage of actual planned dosage administration [ Time Frame: Up to 30 days ]
    Percentage will be summarized.

  7. Percentage of patients that discontinue study drugs due to treatment related toxicity [ Time Frame: Up to 30 days ]
    Percentage will be summarized.

Other Outcome Measures:
  1. CSF penetration of TORC1/2 inhibitor MLN0128, evaluated using plasma and CSF pharmacokinetic (PK) parameters of MLN0128 [ Time Frame: 2-3 hours post-dose day 15 of course 1 and day 1 of course 2 ]
    Plasma and CSF PK levels of TORC1/2 inhibitor MLN0128 obtained before and after bevacizumab administration will be evaluated and summarized. The ration of plasma to CSF PK levels will also be summarized.

  2. Markers associated with dysregulated cell signaling [ Time Frame: Baseline ]
    The biomarkers predicting response to mTOR inhibitor activity will be resulted by dose level and response status.

  3. Change in phosphorylated proteins within tumor biopsies from patients with ovarian and endometrial cancers [ Time Frame: Baseline to within 7 days after last study drug or within 7 days after decision to end treatment ]
  4. Change in circulating plasma levels of angiogenic growth factors in patients with ovarian and endometrial cancers [ Time Frame: Baseline to day 1 of last course of treatment ]
  5. Mutation analysis of tissue from biopsies of patients with ovarian and endometrial cancers [ Time Frame: Baseline ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02142803

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United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital
Charlestown, Massachusetts, United States, 02129
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Lakshmi Nayak Dana-Farber Cancer Institute
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02142803    
Other Study ID Numbers: NCI-2014-01118
NCI-2014-01118 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9552 ( Other Identifier: Dana-Farber Cancer Institute )
9552 ( Other Identifier: CTEP )
P30CA006516 ( U.S. NIH Grant/Contract )
U01CA062490 ( U.S. NIH Grant/Contract )
U01CA076576 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
UM1CA186712 ( U.S. NIH Grant/Contract )
First Posted: May 20, 2014    Key Record Dates
Last Update Posted: June 30, 2022
Last Verified: May 2022
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Fallopian Tube Neoplasms
Peritoneal Neoplasms
Cystadenocarcinoma, Serous
Carcinoma, Endometrioid
Adenocarcinoma, Clear Cell
Cystadenocarcinoma, Mucinous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Neuroepithelial
Neuroectodermal Tumors