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

Phase I Study of MLN0128 (TAK-228) (NSC# 768435) in Combination With Ziv-Aflibercept (NSC# 724770) in Patients With Advanced Cancers

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.

Study Overview

• Status: Completed
• Conditions: Advanced Malignant Solid Neoplasm; Refractory Malignant Solid Neoplasm; Recurrent Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm; Ovarian Carcinoma; Pancreatic Neuroendocrine Tumor; Unresectable Solid Neoplasm; Fibrolamellar Carcinoma
• Intervention / Treatment: Drug: Sapanisertib; Biological: Ziv-Aflibercept

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• 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

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

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; Other Names: INK-128; INK128; MLN-0128; MLN0128; TAK-228; Biological: Ziv-Aflibercept; Given IV; Other Names: Eylea; VEGF Trap; Zaltrap; AVE0005; Vascular Endothelial Growth Factor Trap; Aflibercept; VEGF Trap R1R2; VEGF-Trap

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)	DLTs were defined as adverse events per Common Terminology Criteria for Adverse Events version 4.0, related to study agents and fulfilling one of the following criteria: Hematologic; Grade 4 neutropenia for > 7 days; Febrile neutropenia (defined as absolute neutrophil count [ANC] < 1.0 x 109/L and fever ≥ 38.5° C) or grade ≥3 infection with ANC≤1.0 x 109/L.; Platelet count < 25,000/mm for > 7 days Non-hematologic; Any toxicity ≥grade 3 that persists for > 7 days, except:nausea/vomiting, diarrhea and electrolyte imbalances;grade 3 lab abnormalities that are asymptomatic and responsive to supportive measures and that are without clinical consequence; andgrade 3 hyperglycemia or grade 3 diabetes that can be stably controlled.; Delay of treatment > 7 days due to hematologic and > 14 days due to non-hematologic toxicity MTD is the highest dose level at which no more than 1 of 6 evaluable patients had a DLT	DLT was assessed during Cycle 1 (28-day cycle).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1	Tumor response by change in tumor size from baseline assessed by Objective response rate was defined as the percentage of patients who had complete response (CR) or partial response (PR) according to RECIST v1.1.	At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years.
Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1	Tumor response by change in tumor size from baseline assessed by Disease control rate was defined as the percentage of patients who had CR or PR or stable disease (SD) according to RECIST v1.1.	At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Aung Naing, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2014
• Primary Completion (Actual): June 29, 2021
• Study Completion (Actual): January 29, 2024

Study Registration Dates

• First Submitted: June 6, 2014
• First Submitted That Met QC Criteria: June 6, 2014
• First Posted (Estimated): June 10, 2014

Study Record Updates

• Last Update Posted (Actual): October 20, 2025
• Last Update Submitted That Met QC Criteria: September 30, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Genital Diseases, Female; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Adenoma; Pancreatic Neoplasms; Pathological Conditions, Signs and Symptoms; Ovarian Neoplasms; Neoplasm Metastasis; Adenoma, Islet Cell; Fibrolamellar hepatocellular carcinoma; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; aflibercept; sapanisertib
• Other Study ID Numbers: NCI-2014-01107 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA016672 (U.S. NIH Grant/Contract); UM1CA186688 (U.S. NIH Grant/Contract); U01CA062461 (U.S. NIH Grant/Contract); 2013-0665; 9585 (Other Identifier: CTEP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes