Anakinra or Denosumab and Everolimus in Advanced Cancer

Study Description

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Brief Summary:

You are being asked to take part in this study because you have advanced cancer that has either gotten worse or is resistant to standard therapy.

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.

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.

Condition or disease	Intervention/treatment	Phase
Advanced Cancers	Drug: Everolimus; Drug: Anakinra; Drug: Denosumab	Phase 1

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	57 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	June 19, 2012
Estimated Primary Completion Date :	June 2020
Estimated Study Completion Date :	June 2021

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Everolimus + Anakinra Dose Escalating Group: Starting doses: Everolimus 5 mg by mouth daily for a 28 day cycle. Anakinra 100 mg subcutaneously daily for a 28 day cycle.	Drug: Everolimus; Starting Dose (Everolimus + Anakinra): Everolimus 5 mg by mouth daily for a 28 day cycle. Starting Dose (Everolimus + Denosumab): Everolimus 10 mg by mouth daily for a 28 day cycle. Expansion Group Starting Dose: Maximum tolerated dose from Dose Escalating Group.; Other Names: Afinitor; RAD001 Drug: Anakinra; Starting dose: 100 mg subcutaneously daily for a 28 day cycle. Expansion Group Starting Dose: Maximum tolerated dose from Dose Escalating Group.; Other Name: Kineret
Experimental: Everolimus + Denosumab Dose Escalating Group; Starting doses: Everolimus 10 mg by mouth daily for a 28 day cycle. Denosumab 120 mg subcutaneously on Day 1 of a 28 day cycle.	Drug: Everolimus; Starting Dose (Everolimus + Anakinra): Everolimus 5 mg by mouth daily for a 28 day cycle. Starting Dose (Everolimus + Denosumab): Everolimus 10 mg by mouth daily for a 28 day cycle. Expansion Group Starting Dose: Maximum tolerated dose from Dose Escalating Group.; Other Names: Afinitor; RAD001 Drug: Denosumab; Starting dose: 120 mg subcutaneously day 1 of a 28 day cycle. Expansion Group Starting Dose: Maximum tolerated dose from Dose Escalating Group.; Other Name: AMG 162

Outcome Measures

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Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) of Anakinra or Denosumab in Combination with Everolimus in Participants with Advanced Cancers [ Time Frame: 8 weeks ]
   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.

Secondary Outcome Measures :

1. Tumor Response of Anakinra or Denosumab in Combination with Everolimus in Participants with Advanced Cancers [ Time Frame: 4 months ]
   Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by RECIST criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA-125 for patients with ovarian cancer), or (4) a partial response according to Choi criteria, i.e., decrease in size by 10% or more, or a decrease in the tumor density, as measured by Hounsfield units (HU), by more than or equal to 15% 49.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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/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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Investigators

Principal Investigator:	Filip Janku, MD, PHD	M.D. Anderson Cancer Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

University of Texas MD Anderson Cancer Center Website 

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT01624766 History of Changes
Other Study ID Numbers:	2011-1043; NCI-2012-01156 ( Registry Identifier: NCI CTRP )
First Posted:	June 21, 2012
Last Update Posted:	March 7, 2018
Last Verified:	March 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by M.D. Anderson Cancer Center:

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

Additional relevant MeSH terms:

Neoplasms; Everolimus; Sirolimus; Denosumab; Interleukin 1 Receptor Antagonist Protein; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors	Physiological Effects of Drugs; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents; Bone Density Conservation Agents; Antirheumatic Agents