α-TEA in Advanced Cancer

Study Overview
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Brief Summary
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The goal of this study is to find the highest dose of α-TEA that can be given to patients safely, to identify potential side effects of α-TEA, and to measure the amount of α-TEA in patients' blood. Additional goals of this study are to monitor the effect on tumors, to check for specific immune cells circulating in the blood, and to see if there are certain features of tumors that make it possible to predict the response to α-TEA.

Detailed Description
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This is a dose-escalation study in which doses ranging from 2.4 mg/kg to 26.8 mg/kg of α-TEA will be tested. The main clinical objectives of this phase I two-stage dose-escalation trial will be to characterize α-TEA related toxicity, determine the maximum tolerated dose, and pharmacokinetics of α-TEA in humans. Tumor response and exploratory immunological monitoring will also be performed. Specifically, we will determine the frequency of circulating peripheral T cell subset populations including CD4+, CD8+ T cells and their activation status (central memory, effector cells) and regulatory T cells (CD4/CD25/Foxp3). Exploratory monitoring to assess tumor apoptosis and serum cytokine levels will also be performed to gain additional insight on the influence of α-TEA on the immune response and tumor. An assessment of the immunoscore in patients with tumor amenable to biopsy will also provide hypothesis-generating data on the influence of α-TEA on the tumor microenvironment.

Official Title
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Phase I Study of Alpha-tocopheryloxyacetic Acid (α-TEA) in Patients With Advanced Cancer

Conditions
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Metastatic Carcinoma, Metastatic Sarcoma, Metastatic Lymphoma

Intervention / Treatment
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* Drug: 2.4 mg/kg α-TEA
* Drug: 4.8 mg/kg α-TEA
* Drug: 8.0 mg/kg α-TEA
* Drug: 9.6 mg/kg α-TEA
* Drug: 12 mg/kg α-TEA
* Drug: 16.8 mg/kg α-TEA
* Drug: 19.2 mg/kg α-TEA
* Drug: 22.3 mg/kg α-TEA
* Drug: 26.8 mg/kg α-TEA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with measurable or evaluable metastatic carcinoma, sarcoma or lymphoma who have malignancy refractory or progressed after therapy and for whom no other standard (non-experimental) therapy exists or who have declined available standard therapy, with potential to induce cure, remission or enhanced survival. Either histologic or cytologic diagnosis is acceptable of the primary cancer, or clinical evidence of metastasis. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Age 18 years or above. Laboratory values (performed within 28 days prior to enrollment) within protocol specified range. Confirmed radiographic and/or serum marker showing cancer progression after at least one systemic therapy for metastatic disease. Ability to give informed consent and comply with the protocol. Patients with a history of psychiatric illness must be judged able to understand the investigational nature of the study and the risks associated with the therapy. No active bleeding. No coagulopathy (INR <1.5, PT <16 seconds, PTT < 38 seconds) at baseline. Anticipated lifespan greater than 12 weeks. Ability to swallow capsules Women of childbearing potential must have a negative pregnancy test and must avoid becoming pregnant while on α-TEA and for 4 weeks after the last dose of α-TEA. Men must avoid fathering a child while on α-TEA and for 4 weeks after the last dose of α-TEA. Exclusion Criteria: Active serious infection that could affect treatment. Coagulopathy or need for anti-coagulation therapy. Malabsorbtion state such as ulcerative colitis, previous surgical resection of > 20% of intestine or stomach. History of or active atrial fibrilliationfibrillation or supraventricular tachycardia Cardiac ejection fraction less than the lower limit of normal on echocardiography Right atrial enlargement on echocardiography Active cardiac ischemia. Patients with a history of ischemia ameliorated with stent placement or coronary artery bypass grafting and who have no evidence of ischemia by exercise or physiological stress testing are eligible. History of or active congestive heart failure Patients with tumor that has invaded vagal nerve, carotid bodies, mediastinal structures, pericardium or myocardium. Abnormal thyroid function, or euthyroid, but are on medication for thyroid disorders Need for chronic high dose maintenance oral steroids. Stable treatment with prednisone ≤ 10 mg daily (or a biologically-equivalent dose of another steroid) is allowed. Patients who require brief courses of steroids to manage allergic reaction to intravenous contrast used in radiographic studies are eligible. Patients requiring steroids for management of CNS metastatic disease are not eligible. Surgery or severe trauma within 4 weeks of study entry (minimally invasive procedures acceptable). Active brain metastatic disease. Patients with brain metastases who have been treated with surgery, gamma-knife radiosurgery or radiation and no radiographic progression for at least 4 weeks and off steroids are eligible. Any medical or psychiatric condition that in the opinion of the PI would preclude compliance with study procedures. Vitamin E supplements QTc greater than 450 msec at baseline (calculated using Bazett's formula), sick-sinus syndrome or other active cardiac disease.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2.4 mg/kg α-TEA<br>Patients will receive oral α-TEA 2.4 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 2.4 mg/kg α-TEA<br>* Patients receive oral α-TEA 2.4 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 4.8 mg/kg α-TEA<br>Patients will receive oral α-TEA 4.8 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 4.8 mg/kg α-TEA<br>* Patients will receive oral α-TEA 4.8 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 8.0 mg/kg α-TEA<br>Patients will receive oral α-TEA 8.0 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 8.0 mg/kg α-TEA<br>* Patients will receive oral α-TEA 8.0 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 9.6 mg/kg α-TEA<br>Patients will receive oral α-TEA 9.6 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 9.6 mg/kg α-TEA<br>* Patients will receive oral α-TEA 9.6 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 12 mg/kg α-TEA<br>Patients will receive oral α-TEA 12 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 12 mg/kg α-TEA<br>* Patients will receive oral α-TEA 12 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 16.8 mg/kg α-TEA<br>Patients will receive oral α-TEA 16.8 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 16.8 mg/kg α-TEA<br>* Patients will receive oral α-TEA 16.8 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 19.2 mg/kg α-TEA<br>Patients will receive oral α-TEA 19.2 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 19.2 mg/kg α-TEA<br>* Patients will receive oral α-TEA 19.2 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 22.3 mg/kg α-TEA<br>Patients will receive oral α-TEA 22.3 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 22.3 mg/kg α-TEA<br>* Patients will receive oral α-TEA 22.3 mg/kg daily for the first 14 days of a 28 day cycle.<br>|
| Experimental: 26.8 mg/kg α-TEA<br>Patients will receive oral α-TEA 26.8 mg/kg daily for the first 14 days of a 28 day cycle. | Drug: 26.8 mg/kg α-TEA<br>* Patients will receive oral α-TEA 26.8 mg/kg daily for the first 14 days of a 28 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events | Patients are seen in clinic 7 times over a 28-day period. Patients will have 6 physical exams and meet with a research nurse 5 times for evaluation of any potential drug-related toxicities. In addition, blood will be drawn 7 times for complete blood counts and metabolic panel to check for hematological toxicities. After 28 days, a review of all safety data will determine whether the dose will be increased for subsequent patients. | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events Possibly Caused by α-TEA | Patients are seen in clinic 7 times over a 28-day period. Patients will have 6 physical exams and meet with a research nurse 5 times for evaluation of any potential drug-related toxicities. In addition, blood will be drawn 7 times for complete blood counts and metabolic panel to check for hematological toxicities. This information will be used to identify toxicities of α-TEA and characterize the safety profile. | 28 days | 
| Blood serum levels of α-TEA | Patients will have 11 blood draws over 28 days for evaluation of pharmacokinetics. High-performance liquid chromatography (HPLC) and mass spectrometry detection (MSD) will be used to determine serum drug levels of α-TEA using blood samples collected just before the first dose of α-TEA and 1, 4, 8, and 24 hours after the first dose. Additional samples will be drawn just before the α-TEA dose on Days 2, 5, 8, 15, 22, and 29. | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic, refractory, progressive