Anakinra or Denosumab and Everolimus in Advanced Cancer

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase ITreatment18 and over2011-1043
NCI-2012-01156, NCT01624766

Trial Description

Summary

The goal of this clinical research study is to find the highest tolerable dose of the

combination of Afinitor (everolimus) either with Kineret (anakinra) or Xgeva (denosumab)

that can be given to patients with advanced cancer. The safety of these drugs will also be

studied.

Everolimus is designed to stop cells from dividing.

Anakinra is designated to block a protein that is involved in tumor development, new blood

vessels growing, and spread of cancer.

Denosumab is designed to block the activity of a protein, which may prevent bone

complications in cancer that has spread to the bone.

Further Study Information

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.

Eligibility Criteria

Inclusion Criteria:

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 </= 2.

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 </= 2 X ULN (exceptions may apply to benign non-malignant indirect

hyperbilirubinemia such as Gilbert syndrome); ALT (SGPT) and or AST (SGOT) </= 5 X

ULN Exception for patients with liver metastasis: total bilirubin </= 3 x ULN; ALT

(SGPT) </= 8 X ULN; Fasting lipid profile: cholesterol </= 350 mg/dL; triglycerides

</= 400 mg/dL Corrected calcium >/= 8.4 mg/dL; phosphorus >/= 2.5 mg 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.

Exclusion Criteria:

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 </= 2.

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 </= 2 X ULN (exceptions may apply to benign non-malignant indirect

hyperbilirubinemia such as Gilbert syndrome); ALT (SGPT) and or AST (SGOT) </= 5 X

ULN Exception for patients with liver metastasis: total bilirubin </= 3 x ULN; ALT

(SGPT) </= 8 X ULN; Fasting lipid profile: cholesterol </= 350 mg/dL; triglycerides

</= 400 mg/dL Corrected calcium >/= 8.4 mg/dL; phosphorus >/= 2.5 mg 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.

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

M D Anderson Cancer Center

    Trial Sites

    U.S.A.

    Texas
    Houston

    M D Anderson Cancer Center

    Filip Janku
    Principal Investigator

    Link to the current ClinicalTrials.gov record.
    NLM Identifer NCT01624766

    Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.