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A Phase I Trial of Anakinra (IL-1 Receptor Antagonist) or Denosumab (Anti-RANKL Monoclonal Antibody) in Combination With Everolimus (mTOR Inhibitor) in Patients With Advanced Malignancies


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Advanced Cancers

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Trial Information

A Phase I Trial of Anakinra (IL-1 Receptor Antagonist) or Denosumab (Anti-RANKL Monoclonal Antibody) in Combination With Everolimus (mTOR Inhibitor) in Patients With Advanced Malignancies


Study Groups:

Dose escalation:

If you are found to be eligible to take part in this study, your doctor will decide if you
will receive everolimus with anakinra or everolimus with denosumab. Once it is decided
which combination you will receive, you will be assigned to a dose level based on when you
join the study.

Up to 3 dose levels of everolimus with anakinra will be tested. 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. Up to 6 participants
will be enrolled at each dose level. This will continue until the highest tolerable dose of
everolimus with anakinra is found.

One (1) dose level of everolimus with denosumab will be tested at first. Participants will
receive the highest dose level. This is a dose level that has already been given off-study
in clinical practice, and researchers have experience with it. If intolerable side effects
are seen, up to 4 more lower dose levels may be studied. Each new group of participants
will receive a lower dose than the group before it. Up to 6 participants will be enrolled
at each dose level. This will continue until the highest tolerable dose of everolimus with
denosumab is found.

Dose expansion:

Once the highest tolerable dose of everolimus either with anakinra or denosumab is found, up
to 14 more participants may be enrolled to further study the safety of each combination of
drugs at that dose and the level of effectiveness of the study drugs in a certain tumor
group.

Study Drug Administration:

Each study cycle is 28 days.

You will take everolimus by mouth at the same time every day with or without food, swallowed
whole with a glass of water.

If you receive anakinra, you will receive it by injection under the skin either to the upper
arm, upper thigh, or stomach at the same time every day. The study doctor or nurse will
teach you how to give the injections yourself.

If you receive denosumab, you will receive it by injection under the skin either to the
upper arm, upper thigh, or stomach on Day 1 of each cycle.

Study Visits:

On about Day 15-21 of Cycle 1:

- Your medical history will be recorded, including any cancer symptoms.

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

- Your performance status will be recorded.

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

- Urine may be collected for routine tests if the study doctor thinks it is needed.

Before starting Cycles 2 and beyond:

- Your medical history will be recorded, including any cancer signs and symptoms.

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

- Your performance status will be recorded.

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

- Urine may be collected for routine tests.

Before every odd cycle starting Cycles 3, 5, and beyond:

-Blood (about 1/2 tablespoon) will be drawn to check your immune system.

Every 8 weeks, you will have an x-ray, CT scan, MRI, and/or PET/CT scan to check the status
of the disease. Blood (about 1 tablespoon) will be drawn for tumor marker testing. After
at least 6 months of taking the study drugs, you may have CT, MRI, and/or PET/CT scan and
blood drawn every 12 weeks (every 3 cycles) if the study doctor thinks it is needed.

If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
pregnancy test before starting each study cycle.

If you are receiving the combination of everolimus and denosumab, blood (about 1 tablespoon)
may be drawn more often to check your mineral levels if the study doctor thinks it is
needed.

Length of Dosing:

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.

Follow-up Visit:

You will have a follow-up-visit within 30 days after your last dose of study drugs. You
will be asked about any current health problems you may have and if you have had any side
effects. If your study doctor thinks it is needed, you may have follow-up for a longer
period of time.

This is an investigational study. Everolimus is FDA approved and commercially available to
treat pancreatic cancer that has gotten worse, advanced renal cell carcinoma, and a type of
brain tumor called subependymal giant cell astrocytoma. Anakinra is FDA approved and
commercially available for treatment of rheumatoid arthritis. Denosumab is FDA approved and
commercially available to prevent bone problems in patients with solid tumors that have
spread to the bone. The combination of everolimus either with anakinra or denosumab to
treat advanced cancer is investigational.

Up to 147 patients will take part in this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



1. Patients with advanced or metastatic cancers 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.

2. Patients must be >/= 3 weeks beyond treatment with a cytotoxic chemotherapy regimen,
or therapeutic radiation, or major surgery. Patients may have received palliative
localized radiation immediately before or during treatment provided that radiation is
not delivered to the only site of disease being treated under this protocol. For
biologic/targeted agents patients must be >/= 5 half-lives or >/= 3 weeks form the
last dose (whichever comes first).

3. ECOG performance status
4. Patients must be >/= 18 years of age.

5. Patients must have adequate organ and marrow function defined as: absolute neutrophil
count (ANC) >/= 1,000/mL, platelets >/=75,000/mL; creatinine clearance >/= 35 ml/min;
total bilirubin patients with liver metastasis: total bilirubin Fasting lipid profile: cholesterol Corrected calcium >/= 8.4 mg/dL; phosphorus >/= 2.5 mg/dL for denosumab

6. Oral examination and appropriate preventive dentistry will be performed prior to the
initiation of denosumab therapy.

7. Negative tuberculosis quantiferon test for anakinra arm.

8. Negative serology for histoplasma, blastomycosis, and coccidiomycosis for anakinra
arm.

9. Negative serology for active hepatitis B and C for anakinra arm. Patients with
positive serology for hepatitis B might eligible if they are willing to take
lamivudine preventive therapy.

10. Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 30 days after the last dose.

11. Patients must be able to understand and be willing to sign a written informed consent
document.

Exclusion Criteria:

1. Uncontrolled intercurrent illness, including, but not limited to, uncontrolled
infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support.
Treatment of pre-existing invasive fungal infections must be completed prior to
starting treatment.

2. Patients with an active infection.

3. Pregnant or lactating women.

4. History of hypersensitivity to anakinra.

5. History of hypersensitivity to denosumab.

6. History of hypersensitivity to everolimus.

7. History of hypersensitivity to any component of the formulation.

8. Patients unwilling or unable to sign informed consent document.

9. Patients treated with TNF antagonists.

10. Patients with a history of active systemic fungal infection.

11. Patients with liver disease Child Pugh classification B and C.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

If more than 33% of patients enrolled at any particular dose level develop dose limiting toxicity (DLT), treatment will continue at dose level immediately below. If not more than 33% of patients in cohort develop DLT, this cohort will be considered the MTD.

Outcome Time Frame:

8 weeks

Safety Issue:

Yes

Principal Investigator

Filip Janku, MD, PHD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2011-1043

NCT ID:

NCT01624766

Start Date:

June 2012

Completion Date:

Related Keywords:

  • Advanced Cancers
  • Advanced Cancers
  • Advanced Malignancies
  • Metastatic Cancers
  • Everolimus
  • Afinitor
  • RAD001
  • Anakinra
  • Kineret
  • Denosumab
  • AMG 162
  • Neoplasms

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030