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Phase I Combination of Pazopanib and Everolimus in PI3KCA Mutation Positive/PTEN Loss Patients With Advanced Solid Tumors Refractory to Standard Therapy


Phase 1
16 Years
N/A
Open (Enrolling)
Both
Advanced Cancers, Solid Tumors

Thank you

Trial Information

Phase I Combination of Pazopanib and Everolimus in PI3KCA Mutation Positive/PTEN Loss Patients With Advanced Solid Tumors Refractory to Standard Therapy


Study Groups:

Dose Escalation:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of the combination of pazopanib and everolimus based on when you joined this study.
Up to 8 dose levels of pazopanib and everolimus 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
pazopanib and everolimus is found.

Expansion:

Once the highest tolerable dose of pazopanib and everolimus is found, up to 14 more
participants may be enrolled to further study the safety of the drugs at that dose and the
efficacy of the drugs in a certain tumor group.

Study Drug Administration:

Each study cycle is 28 days.

Pazopanib and everolimus are taken by mouth on an empty stomach (1 hour before meals or 2
hours after meals).

On Days 1-5 of Cycle 1 only, you will take pazopanib and everolimus together. First take
pazopanib and then take everolimus.

After those first 5 days, you will take pazopanib and everolimus every other day separately.
Starting Day 6 of Cycle 1, pazopanib will be taken every even day (6, 8, 10, and so on) .
Everolimus will be taken every odd day (7, 9, 11, and so on).

Beginning with Cycle 2, you will take pazopanib every even day (2, 4, 6, and on so) and
everolimus every odd day (3, 5, 7, and so on).

Study Visits:

At each study visit, you will be asked what about any drugs or herbal supplements that you
may be taking and if you have had any side effects.

On Day 1 of Cycle 1:

- Your medical history will be recorded if it has been more than 3 days since screening.

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

- Your performance status will be recorded.

- You will have an ECG.

- Blood (about 2 teaspoons) and urine will be collected for routine tests and hepatitis
screening

- Blood (about 2 teaspoons) will be drawn for biomarker testing. Biomarkers are found in
the blood and may be related to your reaction to the study drug.

On Days 8, 15, and 22 of Cycle 1:

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

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

On Day 1 of Cycles 2 and beyond:

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

- Your performance status will be recorded.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

- You will have an ECG.

On Day 15 of Cycle 2:

-Blood (about 2 teaspoons) will be collected for routine tests.

Every 8 weeks:

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

- Blood (about 1 teaspoon) may be drawn for tumor marker testing.

- If you are able to become pregnant, you will have a blood (about ½ teaspoon) or urine
pregnancy test.

PK testing:

At least 6 participants in the expansion part of the study will have blood (about 1 teaspoon
each time) will be drawn for pharmacokinetic (PK) testing. The study staff will tell you if
you will have this testing. PK testing measures the amount of study drug in the body at
different time points.

- On Day 5 of Cycle 1 and Days 1 and 2 of Cycle 2, blood will be drawn before and 8 more
times up to 10 hours after taking the study drugs.

- On Day 2 of Cycle 2, blood will be drawn 1 more time for PK testing after 24 hours of
taking everolimus. If you could not have the 10 hour draw the day before, this will be
drawn at this day.

- On Day 6 of Cycle 1 and Day 3 of Cycle 2, blood will be drawn 1 time for PK testing
after 24 hours of taking pazopanib. If you could not have the 10 hour draw the day
before, this will be drawn at this day.

- Blood will be drawn 1 time at the end-of-dosing visit.

Length of Study:

You may continue taking the study drugs for as long as you are benefitting. You will be
taken off study early if the disease gets worse, intolerable side effects occur, you develop
new health problems, or your doctor thinks that it is no longer in your best interest to
receive the study drug.

End-of-Dosing Visit:

Within 4 weeks after your last dose of study drugs:

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

- Your performance status will be recorded.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

- If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
pregnancy test.

This is an investigational study. Pazopanib is FDA approved and commercially available for
the treatment of advanced renal cancer and certain types of advanced soft tissue sarcoma but
has not been approved for use in other cancer types. Everolimus is FDA approved and
commercially available for the prevention of kidney transplant rejection, to treat advanced
renal cancer, and to treat subependymal giant cell astrocytoma associated with tuberous
sclerosis.

The combination of pazopanib and everolimus to treat advanced cancer is investigational.

Up to 62 patients will be enrolled in this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



1. Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments and must be willing to comply with treatment and follow up.

2. Patients with advanced or metastatic solid tumors that are refractory to standard
therapy, relapsed after standard therapy, or who have no standard therapy available
that improves survival by at least three months.

3. Patients must have been off previous chemotherapy or radiotherapy for two weeks prior
to start of treatment. For biologic/targeted therapies, patients must be >/= five
half-lives or >/= 2 weeks from the last treatment dose, whichever comes first.
Patients may have received palliative localized radiation immediately before (or
during) treatment provided radiation is not delivered to the single target lesion
available.

4. ECOG performance status
5. Abnormal organ function is permitted. However, patients must meet the following
criteria: neutrophil count >/= 1.5 x 10*9/L; platelets >/= 100 x 10*9/L; creatinine
UPC < 1.

6. Women of child-bearing potential MUST have a negative serum or urine HCG test within
14 days of first dose. Sexually active patients must agree to use contraception for
the duration of study participation: women, 2 weeks before the first treatment dose
and for 28 days after the last dose; and men, from the first treatment dose and for
28 days after the last dose of treatment. For the purpose of this protocol women of
child-bearing potential are defined as: a female able to have children that has not
been surgically sterilized or that has not been without menses for 12 consecutive
months.

7. Patients must be >/=16 years of age.

8. Fresh blood samples must be provided for all subjects for biomarker analysis before
treatment with investigational product.

9. Patients must have evaluable disease by RECIST criteria.

10. For the dose expansion cohort patients will have to have any kind of genomic
alteration in either PI3K and/or PTEN of their tumor.

Exclusion Criteria:

1. Central nervous system (CNS) metastases at baseline, with the exception of those
subjects who have previously-treated CNS metastases (surgery +/- radiotherapy,
radiosurgery, or gamma knife) and who meet both of the following criteria: a) are
asymptomatic and b) have no requirement for steroids or enzyme-inducing
anti-convulsants in prior 2 weeks.

2. Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to:Active peptic ulcer disease;
Known intraluminal metastatic lesion/s with risk of bleeding; Inflammatory bowel
disease (e.g. ulcerative colitis, Chrohn's disease),or other gastrointestinal
conditions with increased risk of perforation; History of abdominal fistula,
gastrointestinal perforation, or intra-abdominal abscess within 28 days prior
beginning study treatment.

3. Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to; Malabsorption syndrome; Major
resection of the stomach or small bowel

4. Corrected QT (QTc) > 480 msecs.

5. History of any one or more of the following cardiovascular conditions within the past
6 months:Cerebrovascular accident, Myocardial infarction, Unstable angina , Cardiac
angioplasty or stenting, Coronary artery bypass graft surgery, Class III or IV heart
failure, as defined by the New York Heart Association (NYHA), Untreated pulmonary
embolism (PE) or deep venous thrombosis (DVT). Note: subjects with recent PE or DVT
who have been therapeutically coagulated for at least 6 weeks are eligible.

6. Uncontrolled systemic vascular hypertension (systolic blood pressure >/= 140 mmHg,
diastolic blood pressure >/= 90 mmHg). Note: Initiation or adjustment of
antihypertensive medication(s) is permitted prior to study entry. Following
antihypertensive medication initiation or adjustment, blood pressure (BP) must be
re-assessed three times at approximately 2-minute intervals. At least 24 hours must
have elapsed between anti-hypertensive medication initiation or adjustment and BP
measurement. These three values should be averaged to obtain the mean diastolic BP
and mean systolic BP. The mean SBP/DBP ration must be < 140/90.

7. Major surgery or trauma within 28 days prior to first dose of investigational product
and/or presence of any non-healing wound, fracture, or ulcer (procedures such as
catheter placement not considered to be major surgery).

8. Evidence of active bleeding or bleeding diathesis.

9. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage. Note: Lesions infiltrating major pulmonary
vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor
that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with
contrast is strongly recommended to evaluate such lesions). Large protruding
endobronchial lesions in the main or lobar bronchi are excluded; however,
endobronchial lesions in the segmented bronchi are allowed. Lesions extensively
infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in
the wall of the bronchi are allowed.

10. Recent hemoptysis (>/= ½ teaspoon of red blood within 8 weeks before first dose of
study drug).

11. Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures.

12. Administration of any non-oncologic investigational drug within 30 days or 5 half
lives whichever is longer prior to receiving the first dose of study treatment.

13. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
progressing in severity, except alopecia.

14. Prior malignancy Note: Subjects who have had another malignancy and have been
disease-free for 2 years, and/or subjects with a history of completely resected
non-melanomatous skin carcinoma or successfully treated in situ carcinoma are
eligible.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum Tolerated Dose (MTD) of Pazopanib and Everolimus

Outcome Description:

MTD defined as highest dose studied in which the incidence of Dose Limiting Toxicity (DLT) was less than 33%, with no more than 1 of 6 evaluable participants had a DLT using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Jennifer J. Wheler, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2011-0322

NCT ID:

NCT01430572

Start Date:

October 2011

Completion Date:

Related Keywords:

  • Advanced Cancers
  • Solid Tumors
  • Advanced Cancers
  • Solid Tumors
  • PI3KCA Mutation Positive/PTEN
  • Refractory to standard therapy
  • Relapsed after standard therapy
  • Pazopanib
  • GW786034
  • Everolimus
  • Afinitor
  • RAD001
  • Neoplasms

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030