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.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose and recommended phase 2 dose (MTD/RP2D) of daily oral MLN0128 (TORC1/2 inhibitor INK128) when administered with bevacizumab in patients with advanced solid tumors including recurrent glioblastoma (GBM). II. To evaluate the overall safety and tolerability of the combination of MLN0128 and bevacizumab. SECONDARY OBJECTIVES: I. To assess the preliminary anti-tumor activity of the combination of MLN0128 and bevacizumab, as determined by response rate (RR), progression-free survival (PFS) and overall survival (OS). II. To assess tolerability throughout study therapy with MLN0128 and bevacizumab, including beyond the MTD interval with the following measures of cumulative treatment-related toxicities: frequency of toxicities leading to missed doses or delays; percentage of cycles given or not within 7 days of their scheduled times; percentage of actual planned dosage administration; percentage of patients that discontinue study drugs due to treatment related toxicity. TERTIARY OBJECTIVES: I. To assess cerebrospinal fluid (CSF) penetration of MLN0128 in combination with bevacizumab in patients with recurrent GBM by evaluating the plasma and CSF concentrations of MLN0128 in the absence and presence of bevacizumab. II. To perform archival tumor analysis for markers of dysregulated cell signaling that may predict response to mechanistic target of rapamycin (mTOR) inhibitor therapy such as epidermal growth factor receptor (EGFR) (expression by immunohistochemistry \[IHC\] and amplification by fluorescent in situ hybridization \[FISH\]), phosphatase and tensin homolog (PTEN) (expression by IHC and deletion by FISH), phosphorylated (p)-protein kinase B (AKT), p-ribosomal protein S6 kinase (S6K), p-eukaryotic translation initiation factor 4E binding protein 1 (4EBP), p-mTOR and p-mitogen-activated protein kinase 1 (Erk) in patients with recurrent GBM. III. To analyze select phosphorylated proteins (ERK, AKT, mTOR, 4EBP1, glycogen synthase kinase 3-beta \[GSK3beta\], ribosomal protein S6 kinase, 70kDa, polypeptide 2 \[p70S6K\], rS6) from tumor biopsies obtained at baseline and after treatment with MLN0128 from endometrial and ovarian cancer patients enrolled in stage 2. IV. To analyze circulating plasma levels of angiogenic growth factors before, during and after treatment with MLN0128 and bevacizumab V. To perform genetic mutation analysis and proteomic analysis of tissue from biopsies of endometrial and ovarian cancer patients including analysis of Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1) and PTEN. OUTLINE: This is a dose-escalation study of MLN0128. Patients receive TORC1/2 inhibitor MLN0128 orally (PO) once daily (QD) and bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Massachusetts General Hospital
Charlestown, Massachusetts, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
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
Time frame: 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.
Time frame: Up to 2 years
Progression-free Survival (PFS)
Progression is defined as follows: 1. Non-GBM Solid Tumors (Endometrial \& Ovarian Cancers) - using Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline (v.1.1): * Target Lesions: \>/= 20% increase in the sum of the longest diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. * Non-Target Lesions: The appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. 2. GBM - Using the Response Assessment in Neuro-Oncology (RANO) criteria, any of the criteria below qualify for progression: * \>/= 25% increase in sum of the products of perpendicular diameters of enhancing lesions on stable/increasing dose of corticosteroids * Significant increase in T2/FLAIR non-enhancing lesion on stable/increasing dose of corticosteroids * Any new lesion * Clear clinical deterioration not attributable to other cause
Time frame: Up to 2 years
Objective Response Rate (ORR)
Objective Response Rate (ORR), defined as a Complete Response (CR) or Partial Response (PR) utilizing: 1. RECIST criteria v.1.1 (Endometrial \& Ovarian Cancers): * CR: Disappearance of all target \& non-target lesions (+ normalization of tumor marker level) * PR: \>/= 30% decrease in sum of the longest diameters of target lesions (from baseline) \& no new lesions 2. RANO criteria (GBM patients): * CR: * Disappearance of all enhancing measurable \& non-measurable disease (sustained \>/= 4 wks) * No new lesions * No steroids (physiologic replacement doses only) * Stable or improved non-enhancing lesions * Clinically stable or improved * PR: * \>/= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions (sustained \>/= 4 wks) * No progression of non-measurable disease * No new lesions * Steroid \</= dose at time of baseline scan * Stable or improved non-enhancing lesions * Clinically stable or improved
Time frame: Up to 2 years
Overall Survival (OS)
Overall Survival (OS) listed for all patients by dose level.
Time frame: Up to 4 years
Number of Participants With Toxicities Leading to Missed Doses or Delays
Number of Participants with Toxicities Leading to Missed Doses or Delays
Time frame: Up to 2 years
Number of Participants Who Had an MLN0128 Dose-Reduction On Study
Number of patients who had to have their MLN0128 dose reduced while on study.
Time frame: Up to 2 years
Number of Patients That Discontinue Study Drugs Due to Treatment Related Toxicity
Number of patients that discontinue study drugs due to treatment related toxicity; percentage will be summarized.
Time frame: Up to 2 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.