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

NCT02142803 | Active Not Recruiting Phase 1 Results

• 8 other identifiers: NCI-2014-0111814-0799552P30CA006516U01CA062490U01CA076576UM1CA186709UM1CA186712
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

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.

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 Malignant Uterine Corpus Neoplasm; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Solid Neoplasm; Stage IIIA Fallopian Tube Cancer AJCC v7; Stage IIIA Ovarian Cancer AJCC v6 and 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; Stage IIIA Primary Peritoneal Cancer AJCC v7

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) of Daily Oral MLN0128 When Administered With Bevacizumab

  Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) 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

  28 days

• Most Common Related Toxicities That Led to Dose Hold/Reductions

  Most common related toxicities that led to dose hold/reductions (AEs graded according to NCI CTCAE version 4.0). Safety assessed through summaries of adverse events, changes in selected laboratory test results, changes in vital signs, and TORC1/2 inhibitor MLN0128 and bevacizumab exposure.

  Up to 2 years

Secondary Outcomes (6)

• Progression-free Survival (PFS)

  Up to 2 years

• Objective Response Rate (ORR)

  Up to 2 years

• Overall Survival (OS)

  Up to 4 years

• Number of Participants With Toxicities Leading to Missed Doses or Delays

  Up to 2 years

• Number of Participants Who Had an MLN0128 Dose-Reduction On Study

  Up to 2 years

Other Outcomes (5)

• Cerebrospinal Fluid (CSF) Penetration of TORC1/2 Inhibitor MLN0128, Evaluated Using Plasma and CSF Pharmacokinetic (PK) Parameters of MLN0128

  2-3 hours post-dose day 15 of course 1 and day 1 of course 2

• Markers Associated With Dysregulated Cell Signaling

  Baseline

• Change in Phosphorylated Proteins Within Tumor Biopsies From Patients With Ovarian and Endometrial Cancers

  Baseline to within 7 days after last study drug or within 7 days after decision to end treatment

Study Arms (1)

Treatment (TORC1/2 inhibitor INK128, bevacizumab)

EXPERIMENTAL

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; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Sapanisertib

Interventions

Bevacizumab BIOLOGICAL

Given IV

Also known as: ABP 215, ABP-215, ABP215, Alymsys, Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF Monoclonal Antibody SIBP04, Anti-VEGF rhuMAb, Avastin, Avzivi, Aybintio, BAT 1706, BAT-1706, BAT1706, BAT1706 Biosimilar, Bevacizumab awwb, Bevacizumab Biosimilar ABP 215, Bevacizumab Biosimilar BAT1706, 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 MB02, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar Mvasi, Bevacizumab Biosimilar MYL-1402O, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar QL1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, Bevacizumab Biosimilar Zirabev, Bevacizumab-adcd, Bevacizumab-awwb, Bevacizumab-aybi, Bevacizumab-bvzr, Bevacizumab-equi, Bevacizumab-maly, Bevacizumab-onbe, Bevacizumab-tnjn, BP102, BP102 Biosimilar, CT P16, CT-P16, CTP16, Equidacent, FKB 238, FKB-238, FKB238, 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, MB 02, MB-02, MB02, Mvasi, MYL-1402O, Onbevzi, Oyavas, PF 06439535, PF-06439535, PF06439535, QL1101, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501, SIBP 04, SIBP-04, SIBP04, Vegzelma, Zirabev

Treatment (TORC1/2 inhibitor INK128, bevacizumab)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (TORC1/2 inhibitor INK128, bevacizumab)

Pharmacological Study OTHER

Correlative studies

Treatment (TORC1/2 inhibitor INK128, bevacizumab)

Sapanisertib DRUG

Given PO

Also known as: INK-128, INK128, MLN-0128, MLN0128, TAK-228

Treatment (TORC1/2 inhibitor INK128, bevacizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• weeks from a nitrosourea chemotherapy
• weeks from a non-nitrosourea chemotherapy
• weeks from an investigational agent (not Food and Drug Administration \[FDA\] approved) (or 5 half lives, whichever is shorter)
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Massachusetts General Hospital

Charlestown, Massachusetts, 02129, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

MeSH Terms

Conditions

Glioblastoma; Fallopian Tube Neoplasms; Ovarian Neoplasms

Interventions

Bevacizumab; Immunoglobulin G; Disulfides; sapanisertib

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Fallopian Tube Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals

Results Point of Contact

• Title: Christine Sceppa McCluskey
• Organization: Dana Farber Cancer Institute

christine_sceppa@dfci.harvard.edu

617-632-5394

Study Officials

• Lakshmi Nayak

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2014
• First Posted: May 20, 2014
• Study Start: May 20, 2014
• Primary Completion: December 31, 2020
• Study Completion (Estimated): October 16, 2026
• Last Updated: April 29, 2026
• Results First Posted: October 4, 2023

Record last verified: 2026-02

Locations

US (3)