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EphA2 Gene Targeting Using Neutral Liposomal Small Interfering RNA Delivery (IND# 72924): A Phase I Clinical Trial


Phase 1
18 Years
N/A
Not Enrolling
Both
Advanced Cancers

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Trial Information

EphA2 Gene Targeting Using Neutral Liposomal Small Interfering RNA Delivery (IND# 72924): A Phase I Clinical Trial


Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of siRNA-EphA2-DOPC based on when you join this study. Up to 5 dose levels of
siRNA-EphA2-DOPC will be tested. Up to 6 participants will be enrolled at each dose level.
The first group of participants will receive the lowest dose level. Each new group will
receive a higher dose than the group before it, if no intolerable side effects were seen.
This will continue until the highest tolerable dose of siRNA-EphA2-DOPC is found.

Study Drug Administration:

You will receive siRNA-EphA2-DOPC 2 times a week (Days 1 and 4 of each week) by vein over 30
minutes (+/- 10 minutes).

Cycles in this study are 3 weeks long.

Study Visits:

On Day 1 of Cycle 1, if you have not already had these procedures done within the last week:

- Any updates to your medical history will be recorded, including any drugs you may be
taking and any side effects you may be having.

- You will have a physical exam, including measurement of your vital signs and weight.

- Your performance status will be recorded.

- Blood (about 4-6 teaspoons) will be drawn for routine tests. If you are able to become
pregnant, this blood will also be used for a pregnancy test. Urine will also be
collected for a pregnancy test.

- Blood (about 2 teaspoons each time) will be drawn for pharmacokinetic (PK) testing
before the study drug dose, 1 time during the dose, at the end of the dose, and 6 times
during the 6 hours after the dose. PK testing measures the amount of study drug in the
body at different time points.

On Day 2 of Cycle 1 (24 hours after the first study drug dose), blood (about 2 teaspoons)
will be drawn for PK testing.

On Day 3 or 4 of Cycle 1:

- You will have a core biopsy at the same site(s) that may have been tested at screening
to check the status of the disease. This sample will be compared to the sample
collected at screening.

- Blood (about 4 teaspoons) will be drawn for biomarker testing close to the time of the
tissue biopsy.

- You will have an FDG-PET scan, DCE-MRI scan, and a DWI-MRI to check the status of the
disease and to learn how the drug may be affecting the tumor.

- On Day 4 only, blood (about 2 teaspoons each time) will be drawn for PK testing before
and at the end of the study drug dose.

During Weeks 2 and 3 of Cycle 1:

- Blood (about 2 teaspoons each time) will be drawn for routine tests before each dose of
study drug.

- Blood (about 4 teaspoons each time) will be drawn for biomarker testing after each dose
of study drug.

- You will be asked about any side effects you may be having.

Before Cycle 2, you will have an FDG-PET scan to learn how your cells may be affecting the
tumor.

On Day 1 of Cycle 2:

- You will have a physical exam, including measurement of your vital signs, height, and
weight.

- You will be asked about any drugs you may be taking and about any side effects you may
be having.

- Your performance status will be recorded.

- Blood (about 6 teaspoons) will be drawn for routine tests and biomarker testing.

- You will have an FDG-PET scan, DCE-MRI scan, and a DWI-MRI to check the status of the
disease and to learn how the drugs may be affecting the tumor.

- You will have a CT scan or x-ray to check the status of the disease.

During Weeks 2 and 3 of Cycles 2 and beyond:

- Blood (about 2 teaspoons each time) will be drawn for routine tests before each dose of
study drug.

- You will be asked about any side effects you may be having.

On Day 1 of every even numbered cycle (Cycles 2, 4, 6, and so on):

- You will have a CT scan or x-ray to check the status of the disease.

- Blood (about 4 teaspoons) will be drawn for biomarker testing.

Length of Dosing:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, if study drug dosing is delayed for more than 2 weeks, if
the disease completely responds, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-dosing
visit.

End-of-Dosing Visit:

After you have finished taking the study drug:

- You will have a physical exam, including measurement of your height and weight.

- You will be asked about any drugs you may be taking.

- Your performance status will be recorded.

- Blood (about 4-6 teaspoons) will be drawn for routine tests.

- Blood (about 4 teaspoons) will be drawn for biomarker testing.

- You will have a CT scan, MRI scan, or x-ray to check the status of the disease.

- If the doctor thinks it is needed, you will have an ECG.

This is an investigational study. siRNA-EphA2-DOPC is not FDA approved or commercially
available. It is currently being used for research purposes only.

Up to 30 patients will be enrolled on this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



1. All patients with histologic proof of advanced solid tumors, who are not candidates
for known regimens or protocol treatments of higher efficacy or priority.

2. Subject/patient must be 18 years or older (no dosing or adverse event data are
currently available on the use of EphA2 siRNA-DOPC in patients < 18 years of age).

3. Eastern Cooperative Oncology Group (ECOG) performance status
4. Clinical Laboratory Improvement Act (CLIA) certified Epha2 immunohistochemistry (IHC)
evaluation. IHC staining will be performed on formalin fixed, paraffin-embedded
tissue sections using a monoclonal EphA2 antibody. EphA2 expression will be assessed
through a combination of the % of positive cells and the staining intensity. The % of
positive cells will be rated as follows: 0 points, 0 to 5%; 2 points, 6 to 50%; 3
points, 50%. The staining intensity will be rated as follows: 1 point, weak
intensity; 2 points, moderate intensity; 3 points, strong intensity. Points for
expression and percentage of positive cells will be added, and an overall score will
be assigned. Tumors will then be categorized into four groups: negative (overall
score 0), 5% cells stained, regardless of intensity; weak expression (overall score
1), 1 to 2 points; moderate expression (overall score 2), 3 to 4 points; and strong
expression (overall score 3), 5 to 6 points. An overall score of 3 will be defined as
EphA2 overexpression in tumor cells.

5. Measurable disease is defined as at least one lesion that can be accurately measured
in at least one dimension. At least one lesion greater than 2 cm in short axis is
required to ensure serial biopsy. When imaging (DCE-MRI, DW-MRI and PET-CT imaging)
is being performed for Secondary Objectives (Dose Level III and during the Expansion
Phase) at least one lesion (>/=2 cm) not adjacent to the diaphragm will be required
when measured by conventional techniques, including palpation, plain x-ray, computed
tomography (CT), and magnetic resonance imaging (MRI). A second lesion accessible for
biopsy must also be present. Patients must have at least one 'target lesion' to be
used to assess response on this protocol as defined by RECIST. This may be one of the
lesions mentioned above. Tumors within a previously irradiated field will be
designated as 'non-target' lesions.

6. Resolution of any effects of prior therapy (except alopecia) to NCI CTCAE Version 4
grade
7. Patients must have adequate: Bone marrow function: HGB >/= 9 g/dL, WBC >/= 3,000/mcL,
ANC >/= 1,500/mcL, PLT >/= 100,000/mcL; Hepatic function: Total bilirubin less than
or equal to 1.5, SGOT and SGPT < 2.5 * institutional ULN; Renal function: Creatinine
< 1.5 * ULN or creatinine clearance > 60ml/min according to Cockroft-Gault formula;
Neurologic function: Neuropathy (sensory and motor) coagulation parameters: PT such that international normalized ratio (INR) is < 1.5
(or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times control.

8. Patients should be free of active infection requiring intravenous antibiotics.

9. Any hormonal therapy directed at the malignant tumor must be discontinued at least
one week prior to registration (study enrollment). Continuation of hormone
replacement therapy is permitted. Stable regimens of hormonal therapy i.e. for
prostate cancer (e.g. leuprolide, a GnRH agonist), ovarian or breast cancer are not
exclusionary.

10. Any other prior therapy directed at the malignant tumor, including immunologic
agents, must be discontinued at least three weeks prior to registration (study
enrollment) (6 weeks for nitrosoureas or mitomycin C).

11. Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (i.e., a hormonal contraceptive, intrauterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study and for at least 3 months after completion of EphA2 siRNA-DOPC
therapy.

12. Male subject agrees to use an acceptable method of contraception for the duration of
the study.

13. Patients must voluntarily sign an informed consent indicating that they are aware of
the investigational nature of this study in keeping with the policies of the
hospital.

Exclusion Criteria:

1. Patients may not be receiving any other investigational agents and/or other therapy
for their cancer.

2. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to DOPC, Magnevist, or FDG.

3. Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as a known bleeding disorder, coagulopathy, or tumor involving major
vessels.

4. Patients with history or evidence upon physical examination of central nervous system
(CNS) disease, including primary brain tumor, seizures not controlled with standard
medical therapy, any brain metastases, or history of cerebrovascular accident (CVA,
stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within 6 months
of the first date of treatment on this study.

5. Patients with clinically significant cardiovascular disease; this includes:
Uncontrolled hypertension (greater than 140/90); Myocardial infarction or unstable
angina within 6 months prior to registration; New York Heart Association (NYHA) Grade
II or greater congestive heart failure; Serious cardiac arrhythmia requiring
medication; Grade II or greater peripheral vascular disease; Patients with clinically
significant peripheral artery disease, e.g., those with claudication, within 6 months
of first date of treatment on this study.

6. Patients whose circumstances do not permit completion of the study or the required
follow-up.

7. Patients who are pregnant or nursing. To date, no fetal studies in animals or humans
have been performed with this agent.

8. History of human immunodeficiency virus (HIV) or HIV-positive patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with EphA2 siRNA-DOPC.

9. Patients whose tumor is not accessible for a core biopsy.

10. Exclusion criteria (MRI specific): Patients who are ineligible to undergo an MRI scan
for reasons such as claustrophobia or the presence of implanted devices or metallic
foreign bodies that are not MR compatible. Patients with a known history of allergic
reaction to gadolinium contrast agents. Patients with a history of a GFR of less than
60 or acute renal disease.

11. Exclusion criteria (PET specific): Pregnant or nursing women. Extreme claustrophobia.
Weight near or greater than 350 pounds.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximal Tolerated Dose (MTD)

Outcome Description:

Maximal tolerated dose (MTD) determined using a modified toxicity probability interval (mTPI) design. On Day 1 of Cycle 2, a FDG-PET scan, DCE-MRI scan, and a DWI-MRI done to check status of the disease and to learn how the drugs may be affecting the tumor. CT scan or x-ray to check status of the disease also done on Day 1 of Cycle 2.

Outcome Time Frame:

22 days

Safety Issue:

Yes

Principal Investigator

Robert Coleman, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2011-0216

NCT ID:

NCT01591356

Start Date:

September 2013

Completion Date:

Related Keywords:

  • Advanced Cancers
  • Advanced Cancers
  • Advanced solid tumors
  • siRNA/EphA2
  • Neoplasms

Name

Location

UT MD Andreson Cancer Center Houston, Texas  77030