Sapanisertib And Ziv-Aflibercept In Treating Patients With Recurrent Solid Tumors That Are Metastatic Or Cannot Be Removed By Surgery

Study Overview

Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

This phase I trial studies the side effects and best dose of sapanisertib and ziv-aflibercept in treating patients with solid tumors that have come back (recurrent) and have spread to another place in the body (metastatic) or cannot be removed by surgery (unresectable). Sapanisertib 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 sapanisertib with ziv-aflibercept may kill more tumor cells.

PRIMARY OBJECTIVE: I. To evaluate safety and tolerability, determine maximum tolerated dose (MTD) and recommend a phase II dose of the combination of MLN0128 (TAK-228) (sapanisertib) with ziv-aflibercept in patients with advanced cancers refractory to standard therapy. SECONDARY OBJECTIVES: 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 (TAK-228) and ziv-aflibercept in peripheral blood mononuclear cells (PBMCs) and biopsy samples during expansion cohort. OUTLINE: This is a dose-escalation study. Patients receive sapanisertib orally (PO) once daily (QD) on days 2-4, 9-11, 16-18, and 23-25 and ziv-aflibercept intravenously (IV) over 60 minutes on days 1 and 15. Cycles 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.

Advanced Malignant Solid Neoplasm
Fibrolamellar Carcinoma
Metastatic Malignant Solid Neoplasm
Ovarian Carcinoma
Pancreatic Neuroendocrine Tumor
Recurrent Malignant Solid Neoplasm
Refractory Malignant Solid Neoplasm
Unresectable Solid Neoplasm

DRUG: Sapanisertib
BIOLOGICAL: Ziv-Aflibercept

NCI-2014-01107
NCI-2014-01107 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
2013-0665
9585 (OTHER Identifier) (OTHER: M D Anderson Cancer Center)
9585 (OTHER Identifier) (OTHER: CTEP)
P30CA016672 (U.S. NIH Grant/Contract)
U01CA062461 (U.S. NIH Grant/Contract)
UM1CA186688 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2014-06-06	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-02-27
First Submitted that Met QC Criteria 2014-06-06	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2024-02-28
First Posted (ACTUAL) 2014-06-10	Results First Posted N/A	Last Verified 2024-02

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (sapanisertib, ziv-aflibercept) Patients receive sapanisertib PO QD on days 2-4, 9-11, 16-18, and 23-25 and ziv-aflibercept IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	DRUG: Sapanisertib Given PO BIOLOGICAL: Ziv-Aflibercept Given IV

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (sapanisertib, ziv-aflibercept)

Patients receive sapanisertib PO QD on days 2-4, 9-11, 16-18, and 23-25 and ziv-aflibercept IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

DRUG: Sapanisertib

Given PO

BIOLOGICAL: Ziv-Aflibercept

Given IV

Primary Outcome Measures	Measure Description	Time Frame
Maximum tolerated dose (MTD)	Will be defined as the highest dose level at which no more than 1 of 6 evaluable patients has had a dose-limiting toxicity. Graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (CTCAE version 5.0 beginning April 1, 2018).	28 days
Incidence of toxicity	Will be graded according to NCI CTCAE version 4.0 (CTCAE version 5.0 beginning April 1, 2018). Adverse experiences and laboratory results will be summarized by severity grade.	Up to 4 weeks after completion of study treatment

Secondary Outcome Measures	Measure Description	Time Frame
Tumor response	Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	Up to 4 weeks after completion of study treatment
Changes in tumor size	For each patient, the percent change in tumor size from baseline to best response will be computed. Will construct a waterfall plot of these values. Will compute the Pearson correlation coefficient between the percent change between baseline and cycle 1 day 8 for blood flow and tumor size	Baseline to up to day 8 of cycle 1
Changes in total expression of AKT, ribosomal protein S6 (S6), phosphatase and tensin homolog (PTEN), and CD31	Will be assessed by reverse phase protein array (expansion cohort). For each marker, changes from baseline to cycle 1 day 8 will be assessed using a paired t-test unless the data are clearly not normally distributed in which case the Wilcoxon signed rank test will be used.	Baseline to up to day 8 of cycle 1
Changes in phosphorylated expression of AKT, S6, PTEN, and CD31	Will be assessed by reverse phase protein array (expansion cohort). For each marker, changes from baseline to cycle 1 day 8 will be assessed using a paired t-test unless the data are clearly not normally distributed in which case the Wilcoxon signed rank test will be used.	Baseline to up to day 8 of cycle 1
Changes in total expression of AKT, pS6, PTEN, and CD31	Will be assessed by immunohistochemistry (expansion cohort). For each marker, changes from baseline to cycle 1 day 8 will be assessed using a paired t-test unless the data are clearly not normally distributed in which case the Wilcoxon signed rank test will be used.	Baseline to up to day 8 of cycle 1
Changes in phosphorylated expression of AKT, pS6, PTEN, and CD31	Will be assessed by immunohistochemistry (expansion cohort). For each marker, changes from baseline to cycle 1 day 8 will be assessed using a paired t-test unless the data are clearly not normally distributed in which case the Wilcoxon signed rank test will be used.	Baseline to up to day 8 of cycle 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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
Glycosylated hemoglobin (HbA1c) < 7.0%
Patients must have evaluable or measurable 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 must agree to use 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [e.g.; United Surgical Partners International (USPI), Summary of Product Characteristics (SmPC), etc;]) after the last dose of study drug; or agree to practice true abstinence; 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 highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, or
Agree to completely abstain from heterosexual intercourse
Ability to understand and the willingness to sign a written informed consent document
Ability to swallow oral medications

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 to =< grade 1 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) or ziv-aflibercept
Uncontrolled intercurrent illness including active infection
Pregnant women are excluded from this study because MLN0128 (TAK-228) and ziv-aflibercept are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN0128 (TAK-228) and ziv-aflibercept, breastfeeding should be discontinued if the mother is treated with MLN0128 (TAK-228) and ziv-aflibercept; these potential risks may also apply to other agents used in this study
Patients with known human immunodeficiency virus infection are not to be enrolled in the study
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 (TAK-228)
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 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 (TAK-228); concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 30 days prior to the first administration of MLN0128 (TAK-228)
Patients who are taking proton pump inhibitor (PPI) within 7 days before receiving the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug
Patients with known history of hepatitis B surface antigen-positive, or known history or suspected active hepatitis C infection are not to be enrolled in the study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Aung Naing, M.D. Anderson Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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Clinical Trial Record