Clinical Trials /

Dasatinib, Temsirolimus, and Cyclophosphamide in Treating Patients With Advanced, Recurrent, or Refractory Solid Tumors

NCT02389309

Description:

This phase I trial studies the side effects and best dose of dasatinib and temsirolimus when given together with cyclophosphamide in treating patients with solid tumors that have spread to other places in the body, have come back, or have not respond to previous treatment. Dasatinib and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving dasatinib and temsirolimus together with cyclophosphamide may be a better treatment for advanced solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dasatinib, Temsirolimus, and Cyclophosphamide in Treating Patients With Advanced, Recurrent, or Refractory Solid Tumors
  • Official Title: A Phase I Trial of Dasatinib (PDGFR and SRC Inhibitor), Temsirolimus, and Cyclophosphamide in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 2014-0692
  • SECONDARY ID: NCI-2015-00524
  • SECONDARY ID: 2014-0692
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02389309

Conditions

  • Advanced Malignant Solid Neoplasm
  • Recurrent Brain Neoplasm
  • Recurrent Malignant Solid Neoplasm
  • Refractory Brain Neoplasm

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (dasatinib, cyclophosphamide, temsirolimus)
DasatinibBMS-354825, SprycelTreatment (dasatinib, cyclophosphamide, temsirolimus)
TemsirolimusCCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog, Rapamycin Analog CCI-779, ToriselTreatment (dasatinib, cyclophosphamide, temsirolimus)

Purpose

This phase I trial studies the side effects and best dose of dasatinib and temsirolimus when given together with cyclophosphamide in treating patients with solid tumors that have spread to other places in the body, have come back, or have not respond to previous treatment. Dasatinib and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving dasatinib and temsirolimus together with cyclophosphamide may be a better treatment for advanced solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of
      combination treatment with dasatinib, cyclophosphamide and temsirolimus.

      II. To define and describe the toxicities of the combination of dasatinib, cyclophosphamide
      and temsirolimus administered on this schedule.

      SECONDARY OBJECTIVES:

      I. To preliminarily define the antitumor activity of the combination of dasatinib,
      cyclophosphamide and temsirolimus within the confines of a phase 1 study.

      II. Preliminary assessment of biological markers and correlates of response.

      OUTLINE: This is a dose-escalation study of dasatinib and temsirolimus.

      Patients receive dasatinib orally (PO) twice daily (BID) on days 1-21, cyclophosphamide PO
      once daily (QD) on days 1-21, and temsirolimus intravenously (IV) over 30-60 minutes on days
      1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease
      progression or unacceptable toxicity. Patients experiencing stable disease or better may
      continue treatment with the approval of the study chair.

      After completion of study treatment, patients are followed up for 4 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (dasatinib, cyclophosphamide, temsirolimus)ExperimentalPatients receive dasatinib PO BID on days 1-21, cyclophosphamide PO QD on days 1-21, and temsirolimus IV over 30-60 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing stable disease or better may continue treatment with the approval of the Study Chair.
  • Cyclophosphamide
  • Dasatinib
  • Temsirolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have had a previous histological verification of a solid tumor at the
             original diagnosis and/or recurrence including brain tumors; for patients with brain
             stem gliomas and optic pathway tumors, the requirement for histological evaluation may
             be waived; the patient's disease must be considered refractory to
             conventional/standard therapy, or a disease for which no conventional therapy exists
             and is progressive

          -  The patient must have a stable clinical (neurologic in case of brain tumors) exam and
             be on a stable dose of steroids for at least 1 week prior to study entry; the patient
             should have a measurable and/or evaluable disease; measurable disease which is defined
             as the presence of at least one lesion that can be accurately measured in two
             dimensions (each measures at least 10 mm) or evaluable disease which is defined as at
             least one lesion that can be accurately measured in at least one dimension (measure at
             least 10 mm)

          -  Karnofsky performance status >= 50 for patients >= 16 years of age and a Lansky
             performance status >= 50 for patients aged < 16 years

          -  Life expectancy: must be >= 12 weeks

          -  Chemotherapy:

               -  Must not have received myelosuppressive chemotherapy within 3 weeks of the study
                  entry (6 weeks if prior nitrosourea); prior treatment with either dasatinib or
                  temsirolimus but not both is allowed; at least 3 weeks must have elapsed from the
                  last dose

          -  Biologic therapy (anti-neoplastic)

               -  Must not have received oral tyrosine kinase inhibitors (other than dasatinib) or
                  other similar agents within 3 weeks of the study entry and all toxicities must
                  have resolved to < grade 2 prior to enrollment

               -  Must not have received bevacizumab or other monoclonal antibody therapy within 4
                  weeks of study the entry

          -  Radiotherapy (XRT): at least 4 weeks for focal XRT or 8 weeks for craniospinal XRT
             must have elapsed prior to study entry

          -  Stem cell transplant (SCT): at least 8 weeks following autologous SCT and 12 weeks for
             allogeneic SCT

          -  Surgery: at least 2 weeks following surgery including brain and spine provided
             post-operative magnetic resonance imaging (MRI) shows no active bleeding

          -  Concomitant medications: the following drugs need to be stopped at the time of
             beginning therapy: patient cannot be on liver enzyme inducing anticonvulsants;
             patients must not have received growth factors to support the number or function of
             white cells or platelets within the past 7 days and pegfilgrastim within the past 14
             days; patients must not be receiving any anti-thrombotic or anti-platelet agents;
             patient cannot be on drugs that cause significant prolonged QT (category I drug)

          -  Absolute neutrophil count (ANC) greater than or equal to 1000/mm^3

          -  Platelets greater than or equal to 75,000/mm^3 (transfusion independent; no
             transfusion for >= 7 days prior to study enrollment)

          -  Hemoglobin greater than 8.0 g/dL (transfusion independent; no transfusion for >= 7
             days prior to study enrollment)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit
             of normal for age (ULN)

          -  Bilirubin =< 1.5 x ULN

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70 ml/min/1.73
             m^2 OR serum creatinine based on age/gender as follows:

               -  Age 1 to < 2 years, 0.6 mg/dL (male) and 0.6 mg/dL (female)

               -  Age > 2 and < 6 years, 0.8 mg/dL(male) and 0.8 mg/dL (female)

               -  Age > 6 and < 10 years, 1.0 mg/dL (male) and 1.0 mg/dL (female)

               -  Age > 10 and < 13 years, 1.2 mg/dL (male) and 1.2 mg/dL (female)

               -  Age > 13 and < 16 years, 1.5 mg/dL (male) and 1.4 mg/dL (female)

               -  Age > 16 years, 1.7 mg/dL (male) and 1.4 mg/dL (female)

          -  All post-menarchal females must have a negative serum beta-human chorionic
             gonadotropin (beta HCG); sexually active patients of childbearing potential must agree
             to use an effective method of contraception during the study and for at least 6 months
             after

          -  Adequate pulmonary function as defined as: no evidence of dyspnea at rest, no exercise
             intolerance, and a pulse oximetry > 94% if there is clinical indication for
             determination

          -  Adequate cardiac function defined as: normal 12 lead electrocardiogram (EKG) with
             corrected QT interval (QTc) < 450 msec, and either shortening fraction of >= 28% by
             echocardiogram and qualitatively normal left ventricular function, or ejection
             fraction of >= 55% by echocardiogram

          -  Patients with seizure disorder may be enrolled if on non-enzyme inducing
             anticonvulsants and well controlled

          -  Serum cholesterol and serum triglyceride levels must be < grade 2

          -  A written informed consent MUST be obtained from the patients and/or their
             parents/legal guardians prior to enrollment indicating their awareness of
             investigational nature of this study

        Exclusion Criteria:

          -  Patients with evidence of recent intratumoral hemorrhage (within 3 months of study
             enrollment), gastrointestinal bleeding, history of coronary artery disease or on
             anticoagulation therapy

          -  Pregnant or breast-feeding women will not be entered on this study

          -  Uncontrolled current illness including, but not limited to, uncontrolled infection,
             need for hemodialysis, need for ventilatory support, psychiatric illness/social
             situations that would limit compliance with study requirements

          -  History of hypersensitivity to any component of the formulation

          -  Patients with known human immunodeficiency virus (HIV) are ineligible for this study

          -  Patients must not have received prior therapy with dasatinib and temsirolimus for any
             indication

          -  Patients with clinically significant cardiovascular disease: history of ischemic or
             hemorrhagic stroke within past 6 months; uncontrolled hypertension, on at least 2
             repeated determinations on separate days within past 3 months; myocardial infarction
             or unstable angina within past 6 months; New York Heart Association grade III or
             greater congestive heart failure, serious cardiac arrhythmia requiring medication,
             unstable angina pectoris within past 6 months; clinically significant peripheral
             vascular disease within past 6 months; pulmonary embolism, deep vein thrombosis (DVT),
             or other thromboembolic event within past 6 months; diagnosed congenital long QT
             syndrome; any history of clinically significant ventricular arrhythmias (such as
             ventricular tachycardia, ventricular fibrillation, or torsades de pointes); prolonged
             QTc interval on pre-entry electrocardiogram (> 450 msec); subjects with hypokalemia or
             hypomagnesemia if it cannot be corrected prior to dasatinib administration

          -  Anticonvulsants: patients on enzyme inducing anticonvulsants (EIAED) will be excluded;
             if patients were previously on EIAEDs that have been discontinued, patients must have
             been off EIAEDs for >= 2 weeks prior to initiation of dasatinib

          -  Anticoagulants/anti-platelets: patients on therapeutic (treatment) dose of
             anticoagulants (e.g. warfarin, low molecular-weight heparin) are not eligible;
             patients are not allowed to take aspirin, clopidogrel, ticlopidine, Aggrenox; patients
             on prophylactic anticoagulation may be enrolled and treated on study as long as their
             platelet count is monitored closely and maintained at > 75,000 while they are
             receiving dasatinib

          -  Inducers and Inhibitors of cytochrome P450 family 3, subfamily A, polypeptide 4
             (CYP3A4): patients required to be on any CYP3A4/5 inhibitors or inducers will be
             excluded (with the exception of dexamethasone, but all efforts should be made to
             reduce the dose of dexamethasone); patients must discontinue drug at least 7 days
             prior to starting dasatinib

          -  Angiotensin-converting enzyme (ACE) inhibitors: patients who are currently receiving
             ACE inhibitors are not eligible

          -  Anti-graft-versus-host disease (GVHD) or agents to prevent organ rejection
             post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents
             to prevent either graft-versus-host disease post bone marrow transplant or organ
             rejection post-transplant are not eligible for this trial

          -  Category I drugs that are generally accepted to have a risk of causing torsades de
             pointes including: (patients must discontinue drug at least 7 days prior to starting
             dasatinib)

               -  Quinidine, procainamide, disopyramide

               -  Amiodarone, sotalol, ibutilide, dofetilide

               -  Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

               -  Cisapride, bepridil, droperidol, arsenic, chloroquine, domperidone, halofantrine,
                  levomethadyl, sparfloxacin, lidoflazine

          -  Other drugs permitted but use with caution include; drugs are not recommended but can
             be used with caution

               -  Antacids: use of H2 blockers and proton pump inhibitors is not recommended;
                  patients who require antacids should use short acting, locally active agents
                  (e.g., Maalox, Mylanta etc.); however, these agents should not be taken within
                  either 2 hours before or 2 hours after the dasatinib dose

               -  Drugs prolong QT interval; erythromycin, clarithromycin, pentamidine,
                  ondansetron, granisetron, and methadone
      
Maximum Eligible Age:20 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) defined as the highest dose level tested at which =< 2/6 patients experience dose limiting toxicities (DLT) graded according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTCAE) version 4.0
Time Frame:Up to day 35
Safety Issue:
Description:AEs will be tabulated by dose, grade, and attribution.

Secondary Outcome Measures

Measure:Best response (complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) using the Response Evaluation Criteria in Solid Tumors from the NCI for assessment of radiographic response
Time Frame:Up to 4 weeks post-treatment
Safety Issue:
Description:Tabulated by dose and disease category (CR, PR, SD, and PD).
Measure:Levels of biological markers measured in tissue, blood, or plasma
Time Frame:Up to 4 weeks post-treatment
Safety Issue:
Description:Correlation of biomarkers between tissue and blood will be assessed. The association among various continuous and discrete variables (including response variable) will be assessed first by the exploratory data analysis graphically and then tested using t-test/analysis of variance or Wilcoxon rank sum test/Kruskal-Wallis test, when appropriate. Correlation among continuous biomarkers will be examined by Pearson or Spearman rank correlation coefficients. The association between discrete variables will be tested by chi-square or Fisher's exact test.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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