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MLN0128 and Bevacizumab in Treating Patients With Recurrent Glioblastoma or Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: May 16, 2014
Last updated: November 25, 2014
Last verified: June 2014

This phase I trial studies the side effects and best dose of 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. 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 Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Solid Neoplasm
Endometrial Clear Cell Adenocarcinoma
Endometrial Serous Adenocarcinoma
Ovarian Clear Cell Cystadenocarcinoma
Ovarian Endometrioid Adenocarcinoma
Ovarian Mucinous Cystadenocarcinoma
Ovarian Serous Cystadenocarcinoma
Recurrent Adult Brain Neoplasm
Recurrent Fallopian Tube Carcinoma
Recurrent Ovarian Carcinoma
Recurrent Primary Peritoneal Carcinoma
Recurrent Uterine Corpus Carcinoma
Stage IIIA Fallopian Tube Cancer
Stage IIIA Ovarian Cancer
Stage IIIA Primary Peritoneal Cancer
Stage IIIB Fallopian Tube Cancer
Stage IIIB Ovarian Cancer
Stage IIIB Primary Peritoneal Cancer
Stage IIIC Fallopian Tube Cancer
Stage IIIC Ovarian Cancer
Stage IIIC Primary Peritoneal Cancer
Stage IV Fallopian Tube Cancer
Stage IV Ovarian Cancer
Stage IV Primary Peritoneal Cancer
Drug: TORC1/2 Inhibitor INK128
Biological: Bevacizumab
Other: Pharmacological Study
Other: Laboratory Biomarker Analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study of MLN0128 and Bevacizumab in Patients With Recurrent Glioblastoma and Other Solid Tumors

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD/RP2D of 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 ] [ Designated as safety issue: Yes ]
  • Incidence of adverse events, graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    Safety will be assessed through summaries of adverse events, changes in selected laboratory test results, changes in vital signs, and MLN0128 and bevacizumab exposure.

Secondary Outcome Measures:
  • PFS [ Time Frame: From date of first dose to date of progression or death, assessed at 6 months ] [ Designated as safety issue: No ]
    Listed for all patients by dose level.

  • Objective RR, defined as a complete or partial response, as determined by investigator assessment using RECIST or RANO [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • OS [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Listed for all patients by dose level.

  • Frequency of toxicities leading to missed doses or delays [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    Percentage will be summarized.

  • Percentage of courses given or not within 7 days of their scheduled times [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    Percentage will be summarized.

  • Percentage of actual planned dosage administration [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    Percentage will be summarized.

  • Percentage of patients that discontinue study drugs due to treatment related toxicity [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    Percentage will be summarized.

Other Outcome Measures:
  • CSF penetration of 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 ] [ Designated as safety issue: No ]
    Plasma and CSF PK levels of MLN0128 obtained before and after bevacizumab administration will be evaluated and summarized. The ration of plasma to CSF PK levels will also be summarized.

  • Markers associated with dysregulated cell signaling [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The biomarkers predicting response to mTOR inhibitor activity will be resulted by dose level and response status.

  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Mutation analysis of tissue from biopsies of patients with ovarian and endometrial cancers [ Time Frame: Baseline ] [ Designated as safety issue: No ]

Estimated Enrollment: 58
Study Start Date: May 2014
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (MLN0128, bevacizumab)
Patients receive MLN0128 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.
Drug: TORC1/2 Inhibitor INK128
Given PO
Other Names:
  • INK128
  • TORC1/2 Inhibitor INK128
Biological: Bevacizumab
Given IV
Other Names:
  • Avastin
  • rhuMab-VEGF
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies
Other: Laboratory Biomarker Analysis
Correlative studies

  Show Detailed Description


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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/µL
  • Platelets >= 100,000/µL
  • 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 3A4 (CYP3A4) and cytochrome P450 2C19 (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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02142803

United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Lakshmi Nayak    617-632-2166   
Principal Investigator: Lakshmi Nayak         
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Andrew S. Chi    617-724-8770   
Principal Investigator: Andrew S. Chi         
United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Patricia M. LoRusso    313-576-8716   
Principal Investigator: Patricia M. LoRusso         
United States, Ohio
Ohio State University Medical Center Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: John L. Hays    614-685-5840   
Principal Investigator: John L. Hays         
Sponsors and Collaborators
Principal Investigator: Lakshmi Nayak Dana-Farber Cancer Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT02142803     History of Changes
Other Study ID Numbers: NCI-2014-01118, NCI-2014-01118, 14-079, 9552, U01CA062490, U01CA076576, UM1CA186712, P30CA006516, UM1CA186709
Study First Received: May 16, 2014
Last Updated: November 25, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma, Clear Cell
Brain Neoplasms
Carcinoma, Endometrioid
Cystadenocarcinoma, Mucinous
Cystadenocarcinoma, Serous
Fallopian Tube Neoplasms
Ovarian Neoplasms
Peritoneal Neoplasms
Abdominal Neoplasms
Adnexal Diseases
Brain Diseases
Central Nervous System Diseases
Central Nervous System Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Endometrial Neoplasms
Fallopian Tube Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Gonadal Disorders processed this record on November 27, 2014