A Trial of Dasatinib (PDGFR and SRC Inhibitor), Temsirolimus and Cyclophosphamide in Patients With Advanced Solid Tumors

Condition(s) targeted: Solid Tumors

Intervention: Dasatinib (Drug); Cyclophosphamide (Drug); Temsirolimus (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Wafik Zaky, MBBCH, Principal Investigator, Affiliation: M.D. Anderson Cancer Center

Overall contact:
Wafik Zaky, MBBCH, Phone: 713-792-6620

The goal of this clinical research study is to find the highest tolerable dose of the combination of dasatinib, cyclophosphamide, and temsirolimus that can be given to patients with advanced solid tumors. The safety of this drug combination will be studied. As secondary aim the study will evaluate treatment response to this combination and biological markers.

Official title: A Phase I Trial of Dasatinib (PDGFR and SRC Inhibitor), Temsirolimus and Cyclophosphamide in Patients With Advanced Solid Tumors

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Maximum Tolerated Dose (MTD) of Dasatinib, Cyclophosphamide and Temsirolimus

Detailed description: Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a dose level of temsirolimus and dasatinib based on when you join this study. Up to 2 dose levels of both drugs will be tested. Up to 6 participants will be enrolled in each group. The first group of participants will receive the lowest dose level of both drugs. If no intolerable side effects are seen, the next group will receive a higher dose level of temsirolimus. If no intolerable side effects are seen in this second group, the third group will receive the higher dose level of temsirolimus and a higher dose level of dasatinib. All participants will receive the same dose level of cyclophosphamide. Study Drug Administration: Every study cycle will be 28 days. You will take tablets of dasatinib 2 times each day on Days 1-21 of each cycle while you are on study, with or without food. Each dose should be taken about 12 hours apart. The tablets should be swallowed whole, not crushed or broken. If you are unable to swallow the tablets whole, they can be placed and allowed to dissolve in 1 ounce of lemonade, apple juice, or orange juice (note that any juice must be preservative-free). You will receive detailed instructions about how to prepare the liquid form of dasatinib. You will take tablets of cyclophosphamide by mouth 1 time each day on Days 1-21 of each cycle when you take the second dose of dasatinib. You will receive temsirolimus by vein over about 30-60 minutes on Days 1, 8, and 15 of each cycle. Study Visits: Every week during the study, blood (about 2-3 teaspoons) will be drawn for routine tests. Every week during Cycle 1, you will also have a physical exam and urine will be collected for routine tests. On Day 1 of Cycles 2 and beyond:

- You will have a physical exam.

- You will have an EKG.

- Urine and blood will be collected for routine tests.

On Day 15 of Cycles 2 and beyond, you will have a physical exam and blood will be collected for routine tests. Every 2 cycles:

- You will have an MRI or CT scan to check the status of the disease.

- You will have an ECHO, if the study doctor thinks it is needed.

- If the study doctor thinks it is needed, you will have a spinal tap to compare to the

earlier samples taken. If the study tests show abnormal results, you may need to have some of them performed more frequently. Length of Treatment: You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on the study will be over after the end-of-treatment visit. End-of-Treatment Visit: About 4 weeks after you stop receiving the study drugs:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests.

- You will have an MRI or CT scan to check the status of the disease.

- If the study doctor thinks it is needed, you will have a spinal tap.

This is an investigational study. Dasatinib is FDA-approved and commercially available for the treatment of various types of leukemia. Cyclophosphamide is FDA-approved and commercially available for the treatment of several types of cancer, including brain cancer and many types of blood cancers. Temsirolimus is FDA-approved and commercially available for the treatment of kidney cancer. The use of these drugs in combination against solid tumors is investigational. The study doctor can explain how the study drugs are designed to work. Up to 36 participants will be enrolled in this study. All will take part at MD Anderson.

Minimum age: 12 Months. Maximum age: 20 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Age: Patients must be >/= 12 months and < 21 years of age at the time of study enrollment. 2. Diagnostic 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. 3. Disease Evaluation: 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 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). 4. Performance Status: Karnofsky performance status >/= 50 for patients >/= 16 years of age and a Lansky performance status >/= 50 for patients aged < 16 years. 5. Life Expectancy: Must be >/= 12 weeks. 6. a. 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. b. Biologic therapy (anti-neoplastic) i. 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. ii. Must not have received Bevacizumab or other monoclonal antibody therapy within 4 weeks of study the entry. 7. Radiotherapy (XRT): At least 4 weeks for focal XRT or 8 weeks for craniospinal XRT must have elapsed prior to study entry. 8. Stem cell transplant (SCT): At least 8 weeks following autologous SCT and 12 weeks for allogeneic SCT. 9. Surgery: At least 2 weeks following surgery including brain and spine provided post-operative MRI shows no active bleeding. 10. Concomitant Medications: The following drugs need to be stopped at the time of beginning therapy: Patient cannot be on 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 prolonged QT. 11. Adequate Bone Marrow Function Defined As: 1) Absolute neutrophil count (ANC) greater than or equal to 1000/mm3, 2) Platelets greater than or equal to 75,000/mm3 (transfusion independent; no transfusion for >/= 7 days prior to study enrollment), 3) Hemoglobin greater than 8. 0 g/dL (transfusion independent; no transfusion for >/= 7 days prior to study enrollment). 12. Adequate Liver Function Defined As: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 70ml/min/1. 73 m2 OR Serum creatinine based on age/gender as follows: Age 1 to < 2 years, Maximum Serum Creatinine Male 0. 6 mg/dL/Female 0. 6 mg/dL; > 2 and < 6 years, Male 0. 8/ Female 0. 8; > 6 and < 10 years, Male 1. 0/ Female 1. 0; > 10 and < 13 years, Male 1. 2/ Female1. 2; > 13 and < 16 years, Male 1. 5/ Female 1. 4; > 16 years, Male 1. 7/ Female 1. 4. 14. Reproductive Function: 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. 15. 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. 16. Adequate cardiac function defined as: Normal 12 lead electrocardiogram (EKG) with corrected QTc <450 msec, and either shortening fraction of >/= 28% by echocardiogram and qualitatively normal left ventricular function, or ejection fraction of >/= 55% by echocardiogram or multigated acquisition (MUGA). 17. Central Nervous Function Defined As; Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled. 18. Lipid Function: Serum cholesterol and serum triglyceride levels must be < Grade 2. 19. 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: 1. Patients with evidence of intratumoral hemorrhage, gastrointestinal bleeding, history of coronary artery disease or on anticoagulation therapy. 2. Pregnancy or breast-feeding: Pregnant or breast-feeding women will not be entered on this study due to the risk of fetal or teratogenic effects. 3. 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. 4. History of hypersensitivity to any component of the formulation. 5. Patients with known human immunodeficiency virus (HIV) are ineligible for this study. 6. Patients must not have received prior therapy with dasatinib and temsirolimus for any indication. 7. 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. 8. Patients on the following medication will be excluded: a. 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. b. 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. 9. Exclusion #8 continued: c. Inducers and Inhibitors of Cytochrome P450 3A4 (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. d. Angiotensin-converting enzyme (ACE) inhibitors: Patients who are currently receiving ACE inhibitors are not eligible due to the development of angioneurotic edema-type reactions in some subjects who received concurrent treatment with temsirolimus + ACE inhibitors. e. 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. 10. Exclusion #8 continued: f. 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) 1. quinidine, procainamide, disopyramide 2. amiodarone, sotalol, ibutilide, dofetilide 3. chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 4. cisapride, bepridil, droperidol, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, sparfloxacin, lidoflazine Other drugs permitted but use with caution include; 11. Exclusion #8 continued: g. Drugs are not recommended but can be used with caution; 1. Antacids: Use of H2 blockers and proton pump inhibitors is not recommended because systemic antacids (H2 inhibitors, proton pump inhibitors) decrease dasatinib absorption. 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. 2. Drugs prolong QT interval; erythromycin, clarithromycin, pentamidine, ondansetron, granisetron, and methadone.

Wafik Zaky, MBBCH, Phone: 713-792-6620

University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States; Not yet recruiting

University of Texas MD Anderson Cancer Center Website

Starting date: June 2015
Last updated: May 7, 2015