MLN0128 and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
Adult Solid Neoplasm
Study Type
Study Phase
Phase 1
Study Design
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: Laboratory Biomarker Analysis Type: Other
Name: TORC1/2 Inhibitor INK128 Type: Drug
Name: Ziv-Aflibercept Type: Biological
Overall Status
This phase I trial studies the side effects and best dose of TORC1/2 inhibitor MLN0128 (MLN0128) and ziv-aflibercept in treating patients with solid tumors that have come back and have spread to another place in the body or cannot be removed by surgery. MLN0128 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ziv-aflibercept may stop the growth of solid tumors by blocking the growth of new blood vessels necessary for tumor growth. Giving MLN0128 with ziv-aflibercept may kill more tumor cells.
Detailed Description

I. To evaluate safety and tolerability, determine maximum tolerated dose (MTD) and recommend a phase II dose of the combination of MLN0128 with ziv-aflibercept in patients with advanced cancers refractory to standard therapy.


I. To give early indication of efficacy by evaluation of tumor size. II. To evaluate v-akt murine thymoma viral oncogene homolog 1 (Akt)/mechanistic target of rapamycin (serine/threonine kinase) (mTOR) signaling and adaptive responses; testing phosphorylation levels of biomarkers such as, but not limited to, vascular endothelial growth factor (VEGF)1 and 2, AKT and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) following treatment with MLN0128 and ziv-aflibercept in peripheral blood mononuclear cells (PBMCs) and biopsy samples during expansion cohort.

III. To determine change in blood flow parameter of angiogenesis by assessment with dynamic contrast enhanced-computed tomography (DCE-CT) during expansion cohort.

OUTLINE: This is a dose-escalation study.

Patients receive TORC1/2 inhibitor MLN0128 orally (PO) once daily (QD) on days 1-28 and ziv-aflibercept intravenously (IV) over 60 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 4 weeks.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

- Patients with advanced or metastatic cancer that is refractory to standard therapy or relapsed after standard therapy; patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective

- Patients enrolled in the expansion cohort must have biopsiable disease; there will be preferential enrollment of patients with pancreatic neuroendocrine tumors or ovarian cancer during the dose expansion cohort

- Patients must be >= 4 weeks beyond treatment of any chemotherapy, other investigational therapy, hormonal, biological, targeted agents or radiotherapy, and must have recovered to =< grade 1 toxicity or previous baseline for each toxicity; exception: patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< 1.5 x institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal

- Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min for patients with creatinine levels above institutional normal

- Fasting serum glucose =< 130 mg/dL

- Fasting triglycerides =< 300 mg/dL

- Patients must have evaluable or measureable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

- Women of child-bearing potential MUST have a negative serum or urine pregnancy test within 7 days unless prior hysterectomy or menopause (defined as 12 consecutive months without menstrual activity); patients should not become pregnant or breastfeed while on this study; 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 and for the duration of study participation; 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; male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

- Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, or

- Agree to completely abstain from heterosexual intercourse

- Patients must agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse

- Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration (i.e., if the institutional normal is 50%, subject's LVEF may be as low as 45% to be eligible for the study)

- Ability to understand and the willingness to sign a written informed consent document

- Ability to swallow oral medications

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN0128 or ziv-aflibercept

- Uncontrolled intercurrent illness including active infection

- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MLN0128 and ziv-aflibercept

- Patients with human immunodeficiency virus (HIV) will not be denied an opportunity to participate in this clinical trial, if they have adequate cluster of differentiation (CD)4 counts (> 250 CD4+ T lymphocytes/uL) and would be able to be maintained on an antiretroviral combination without pronounced effects on cytochrome (CYP)3A4, 2C9, or 2C19

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days or manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease that may alter the absorption of MLN0128

- New York Heart Association class III or greater congestive heart failure within last 6 months or uncontrolled hyperlipidemia (cholesterol > 300 mg/dl; triglyceride 2.5 X upper limit of normal [ULN] despite lipid lowering agent) within last 3 months

- Uncontrolled diabetes (fasting serum glucose > 130 mg/dl) despite best medical management or poorly controlled diabetes mellitus defined as hemoglobin (Hb)A1c > 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

- History of uncontrolled hypertension, defined as blood pressure > 150/95 mmHg, or systolic blood pressure > 180 mmHg when diastolic blood pressure < 90 mmHg, on at least 2 repeated determinations on separate days within 3 months prior to study enrollment

- Urine protein should be screened by dipstick or urine analysis; for proteinuria > 1+ or urine protein: creatinine ratio > 1.0, 24-hour urine protein should be obtained and the level should be < 2000 mg for patient enrollment

- Patients receiving any medications or substances that are strong inhibitors or strong inducers of CYP3A4, 2C9, or 2C19 enzymes are ineligible; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

- Patients on anticoagulant therapy with unstable dose of warfarin and/or having an out-of-therapeutic range international normalized ratio (INR) (> 3) within the 4 weeks prior to drug administration

- Evidence of clinically significant bleeding diathesis or underlying coagulopathy, non-healing wound

- History of any of the following within the last 6 months prior to study entry:

- Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures

- Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery revascularization procedures

- Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)

- Placement of a pacemaker for control of rhythm

- Pulmonary embolism

- Significant active cardiovascular or pulmonary disease at the time of study entry, including:

- Uncontrolled high blood pressure (i.e., systolic blood pressure > 150 mm Hg, diastolic blood pressure > 95 mm Hg)

- Pulmonary hypertension

- Uncontrolled asthma or oxygen (O2) saturation < 90% by pulse oximetry on room air

- Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement

- Medically significant (symptomatic) bradycardia

- History of arrhythmia requiring an implantable cardiac defibrillator

- Baseline prolongation of the rate-corrected QT interval (QTc) (e.g. repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)

- Psychiatric illness/social situations that would limit compliance with study requirements

- Have initiated treatment with bisphosphonates less than 30 days prior to the first administration of MLN0128; concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 30 days prior to the first administration of MLN0128
M D Anderson Cancer Center
Houston, Texas, United States
Status: Recruiting
Contact: Aung Naing - 713-563-0803 -
Start Date
June 2014
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Record processing date processed this data on July 28, 2015 page