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 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
Conditions
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.
Detailed description
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.
Interventions
Given IV
Correlative studies
Correlative studies
Given PO
Sponsors
Study design
Eligibility
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) of Daily Oral MLN0128 When Administered With Bevacizumab | 28 days | 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 |
| Most Common Related Toxicities That Led to Dose Hold/Reductions | Up to 2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 2 years | 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 |
| Objective Response Rate (ORR) | Up to 2 years | 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 |
| Overall Survival (OS) | Up to 4 years | Overall Survival (OS) listed for all patients by dose level. |
| Number of Participants With Toxicities Leading to Missed Doses or Delays | Up to 2 years | Number of Participants with Toxicities Leading to Missed Doses or Delays |
| Number of Participants Who Had an MLN0128 Dose-Reduction On Study | Up to 2 years | Number of patients who had to have their MLN0128 dose reduced while on study. |
| Number of Patients That Discontinue Study Drugs Due to Treatment Related Toxicity | Up to 2 years | Number of patients that discontinue study drugs due to treatment related toxicity; percentage will be summarized. |
Countries
United States
Contacts
Dana-Farber Cancer Institute
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 3 mg/day MLN0128 | 3 |
| Dose Level 2 4 mg/day MLN0128 | 3 |
| Dose Level 3 (MTD) 5 mg/day MLN0128 | 43 |
| Total | 49 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level 3 (MTD) | Total |
|---|---|---|---|---|
| Age, Continuous | 56 years | 42 years | 59 years | 59 years |
| Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | 0 units on a scale | 0 units on a scale | 1 units on a scale | 1 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 41 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 39 Participants | 44 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 35 Participants | 38 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 8 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 2 / 3 | 36 / 43 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 43 / 43 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 19 / 43 |
Outcome results
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) of Daily Oral MLN0128 When Administered With Bevacizumab | 5 mg/day |
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
Population: AEs on the study are reported by dose level.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Lymphopenia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Constipation | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Hyperglycemia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Nausea | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Altered mental status | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Colon obstruction | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Diarrhea | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Fatigue | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypercholesterolemia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypokalemia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypophosphatemia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Oral mucositis | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Pruritus | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Rash | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Thrombocytopenia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Vomiting | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Abdominal pain | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Acute kidney injury | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Anorexia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Dehydration | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Diarrhea | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Fatigue | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Fever | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Hypertriglyceridemia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Lymphopenia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Oral mucositis | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Pruritis | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Pulmonary emboli | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Rash | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Thrombocytopenia | 0 participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Vomiting | 1 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Pruritus | 1 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Lymphopenia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Lymphopenia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Pulmonary emboli | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Constipation | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Acute kidney injury | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Fatigue | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Thrombocytopenia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Nausea | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Vomiting | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Pruritis | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Altered mental status | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Anorexia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Fever | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Colon obstruction | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Oral mucositis | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Hyperglycemia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Diarrhea | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Oral mucositis | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Vomiting | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Fatigue | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Rash | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Hypertriglyceridemia | 1 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypercholesterolemia | 1 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Dehydration | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Abdominal pain | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypokalemia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Thrombocytopenia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Rash | 1 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypophosphatemia | 0 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Diarrhea | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Fatigue | 8 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Oral mucositis | 5 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Lymphopenia | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Pruritus | 3 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Nausea | 3 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Rash | 10 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Rash | 11 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Thrombocytopenia | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Oral mucositis | 4 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Abdominal pain | 2 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Vomiting | 0 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Acute kidney injury | 2 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Anorexia | 2 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Hyperglycemia | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Constipation | 2 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Pruritis | 6 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Dehydration | 3 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Diarrhea | 5 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Vomiting | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Fever | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Lymphopenia | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Pulmonary emboli | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Altered mental status | 2 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Colon obstruction | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Diarrhea | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Thrombocytopenia | 6 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Fatigue | 3 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypercholesterolemia | 2 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 1/2 Hypertriglyceridemia | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypokalemia | 2 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Most Common Related Toxicities That Led to Dose Hold/Reductions | Grade 3 Hypophosphatemia | 1 participants |
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Number of Participants Who Had an MLN0128 Dose-Reduction On Study | 0 Participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Number of Participants Who Had an MLN0128 Dose-Reduction On Study | 2 Participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Number of Participants Who Had an MLN0128 Dose-Reduction On Study | 24 Participants |
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Number of Participants With Toxicities Leading to Missed Doses or Delays | 1 participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Number of Participants With Toxicities Leading to Missed Doses or Delays | 1 participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Number of Participants With Toxicities Leading to Missed Doses or Delays | 33 participants |
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Number of Patients That Discontinue Study Drugs Due to Treatment Related Toxicity | 0 Participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Number of Patients That Discontinue Study Drugs Due to Treatment Related Toxicity | 0 Participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Number of Patients That Discontinue Study Drugs Due to Treatment Related Toxicity | 10 Participants |
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
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Objective Response Rate (ORR) | Progressive Disease | 2 Participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Objective Response Rate (ORR) | Stable Disease | 0 Participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Objective Response Rate (ORR) | Complete Response | 1 Participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Objective Response Rate (ORR) | Partial Response | 0 Participants |
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Objective Response Rate (ORR) | Unevaluable | 0 Participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Objective Response Rate (ORR) | Stable Disease | 2 Participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Objective Response Rate (ORR) | Partial Response | 0 Participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Objective Response Rate (ORR) | Progressive Disease | 1 Participants |
| Dose Level 2 - 4 mg MLN0128 Daily | Objective Response Rate (ORR) | Unevaluable | 0 Participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Objective Response Rate (ORR) | Unevaluable | 8 Participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Objective Response Rate (ORR) | Progressive Disease | 7 Participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Objective Response Rate (ORR) | Stable Disease | 20 Participants |
| Dose Level 3 - 5 mg MLN0128 Daily | Objective Response Rate (ORR) | Partial Response | 8 Participants |
Overall Survival (OS)
Overall Survival (OS) listed for all patients by dose level.
Time frame: Up to 4 years
Population: * Given the limited sample sizes for Dose Levels 1 \& 2 (3 \& 2 patients respectively), the #s presented here may not be statistically valid.~* Censoring \& Final OS #s: 1 patient treated at Dose Level 2 and 6 patients treated at Dose Level 3 were censored from OS analysis for withdrawal of consent or lost to follow-up, and were not followed for survival to their death.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Overall Survival (OS) | 7.9 months |
| Dose Level 2 - 4 mg MLN0128 Daily | Overall Survival (OS) | 11.6 months |
| Dose Level 3 - 5 mg MLN0128 Daily | Overall Survival (OS) | 9.3 months |
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
Population: * Given the limited sample sizes for Dose Levels 1 \& 2 (3 patients each), the #s presented here may not be statistically valid.~* Censoring \& Final PFS #s: 9 patients treated @ Dose Level 3 were censored from PFS analysis for initiation of new therapy or withdrawal of consent. 2 additional patients treated at Dose Level 3 were censored from PFS analysis because they never had a useable scan on study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Dose Escalation to Estimate MTD/RP2D | Progression-free Survival (PFS) | 1.6 months |
| Dose Level 2 - 4 mg MLN0128 Daily | Progression-free Survival (PFS) | 7.3 months |
| Dose Level 3 - 5 mg MLN0128 Daily | Progression-free Survival (PFS) | 5.4 months |
Cerebrospinal Fluid (CSF) Penetration of TORC1/2 Inhibitor MLN0128, Evaluated Using Plasma and CSF Pharmacokinetic (PK) Parameters of MLN0128
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.
Time frame: 2-3 hours post-dose day 15 of course 1 and day 1 of course 2
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
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
Markers Associated With Dysregulated Cell Signaling
The biomarkers predicting response to mechanistic target of rapamycin (mTOR) inhibitor activity will be resulted by dose level and response status.
Time frame: Baseline
Mutation Analysis of Tissue From Biopsies of Patients With Ovarian and Endometrial Cancers
Time frame: Baseline