Clinical Trials /

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

NCT02159989

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
  • Official Title: Phase I Study of MLN0128 (TAK-228) (NSC# 768435) in Combination With Ziv-Aflibercept (NSC# 724770) in Patients With Advanced Cancers

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-01107
  • SECONDARY ID: NCI-2014-01107
  • SECONDARY ID: 2013-0665
  • SECONDARY ID: 9585
  • SECONDARY ID: 9585
  • SECONDARY ID: P30CA016672
  • SECONDARY ID: U01CA062461
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT02159989

Conditions

  • 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

Interventions

DrugSynonymsArms
SapanisertibINK-128, INK128, MLN-0128, MLN0128, TAK-228Treatment (sapanisertib, ziv-aflibercept)
Ziv-AfliberceptAFLIBERCEPT, AVE0005, Eylea, vascular endothelial growth factor trap, VEGF Trap, VEGF Trap R1R2, VEGF-Trap, ZaltrapTreatment (sapanisertib, ziv-aflibercept)

Purpose

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 and have spread to another place in the body or cannot be removed by surgery. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      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. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sapanisertib, ziv-aflibercept)ExperimentalPatients 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. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sapanisertib
  • Ziv-Aflibercept

Eligibility 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

          -  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

          -  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; breastfeeding should be discontinued if
             the mother is treated with MLN0128 (TAK-228) and ziv-aflibercept

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) defined as the highest dose level at which no more than 1 of 6 evaluable patients has had a dose-limiting toxicity,
Time Frame:28 days
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame:Up to 4 weeks after completion of study treatment
Safety Issue:
Description:
Measure:Changes in tumor size
Time Frame:Baseline to up to day 8 of course 1
Safety Issue:
Description: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
Measure:Changes in total expression of AKT, ribosomal protein S6 (S6), phosphatase and tensin homolog (PTEN), and CD31 assessed by reverse phase protein array (expansion cohort)
Time Frame:Baseline to up to day 8 of course 1
Safety Issue:
Description: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.
Measure:Changes in phosphorylated expression of AKT, S6, PTEN, and CD31 assessed by reverse phase protein array (expansion cohort)
Time Frame:Baseline to up to day 8 of course 1
Safety Issue:
Description: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.
Measure:Changes in total expression of AKT, pS6, PTEN, and CD31 assessed by immunohistochemistry (expansion cohort)
Time Frame:Baseline to up to day 8 of course 1
Safety Issue:
Description: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.
Measure:Changes in phosphorylated expression of AKT, pS6, PTEN, and CD31 assessed by immunohistochemistry (expansion cohort)
Time Frame:Baseline to up to day 8 of course 1
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated