Ixabepilone and Temsirolimus in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of ixabepilone and temsirolimus in treating patients with solid tumors that have spread from the primary site to other places in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as ixabepilone, 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. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ixabepilone together with temsirolimus may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) of the combination of ixabepilone and temsirolimus in patients with advanced solid tumors. II. To describe toxicity profiles associated with the combination of ixabepilone and temsirolimus. III. To assess preliminary efficacy of the combination of ixabepilone and temsirolimus. OUTLINE: This is a dose-escalation study. Patients receive ixabepilone intravenously (IV) over 3 hours on day 1 and temsirolimus IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 3 months.

Official Title
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Phase I Study of Ixabepilone and Temsirolimus in Adult Patients With Advanced Solid Tumors

Conditions
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Adult Solid Neoplasm

Intervention / Treatment
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* Drug: Ixabepilone
* Other: Pharmacological Study
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with histologically confirmed solid tumor malignancy that is metastatic or unresectable and for which standard curative measures or other therapy that provide survival benefit do not exist or are no longer effective Patients may not have had more than two systemic therapeutic regimens in the metastatic disease setting with the following exceptions: hormonal therapy (e.g. tamoxifen, aromatase inhibitors, anti-androgen therapy, etc.) Patients with non-measurable, but assessable, disease will be allowed Absolute neutrophil count >= 1500/mcL Hemoglobin >= 9.0 g/dL Platelets >= 100,000/mcL Total bilirubin < 1.5 mg/dL Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) or serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x institutional upper limit of normal (ULN) in the absence of hepatic metastasis; SGPT (ALT) =< 3 x ULN or SGOT (AST) =< 5 x ULN in the presence of hepatic metastasis Creatinine =< 1.5 x ULN International normalized ratio (INR) =< 1.4 for patients not on warfarin (Coumadin) INR range of 2.0-3.0 for patients on therapeutic doses of warfarin (Coumadin) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Ability to provide informed consent Willingness to return to a Mayo Clinic institution for follow up Life expectancy >= 84 days (12 weeks) Women of childbearing potential only: negative serum pregnancy test done =< 7 days prior to registration Exclusion Criteria: Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes or with hemoglobin A1c (HbA1C) > 8, or psychiatric illness/social situations that would limit compliance with study requirements Any of the following prior therapies: Chemotherapy =< 28 days prior to registration Mitomycin C/nitrosoureas =< 42 days prior to registration Immunotherapy =< 28 days prior to registration Biologic therapy =< 28 days prior to registration Radiation therapy =< 28 days prior to registration Radiation to > 25% of bone marrow Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment New York Heart Association classification III or IV Known central nervous system (CNS) metastases or seizure disorder; patients with known brain metastases that have been successfully treated and stable for > 6 months without requirement for corticosteroids and without seizure activity will be eligible Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm History of myocardial infarction =< 168 days (6 months), or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias >= Grade 2 sensory neuropathy >= Grade 2 hypertriglyceridemia >= Grade 2 hypercholesterolemia Patients on medication considered strong cytochrome P450 3A4 (CYP3A4) inducers (efavirenz, nevirapine, carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort) or CYP3A4 inhibitors (indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin) unless the medication can be substituted with another agent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ixabepilone, temsirolimus)<br>Patients receive ixabepilone IV over 3 hours on day 1 and temsirolimus IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Ixabepilone<br>* Given IV<br>* Other names: Ixempra;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of the combination of ixabepilone and temsirolimus, defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) |  | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. | Up to 3 months | 
| Incidence of overall toxicity graded according to Common Toxicity Criteria standard grading | Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. | Up to 3 months | 
| Best response, defined to be the best objective status recorded from the start of the treatment until disease progression/recurrence | Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group). | Up to 3 months | 
| Time until any treatment related toxicity |  | Up to 3 months | 
| Time until treatment related grade 3+ toxicity |  | Up to 3 months | 
| Time until hematologic nadirs (white blood cells, absolute neutrophil count, platelets) |  | Up to 3 months | 
| Time to progression |  | Up to 3 months | 
| Time to treatment failure |  | From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 3 months |