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Everolimus and Anakinra or Denosumab in Treating Participants With Relapsed or Refractory Advanced Cancers

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ClinicalTrials.gov Identifier: NCT01624766
Recruitment Status : Active, not recruiting
First Posted : June 21, 2012
Last Update Posted : September 20, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I trial studies the side effects and best dose of everolimus when given together with anakinra or denosumab in treating participants with cancers that have spread to other places in the body and have come back or aren't responding to treatment. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Anakinra is designated to block a protein that is involved in tumor development, new blood vessels growing, and the spread of cancer. Monoclonal antibodies, such as denosumab, may interfere with the ability of tumor cells to grow and spread. Giving everolimus and anakinra or denosumab may work better in treating participants with advanced cancers.

Condition or disease Intervention/treatment Phase
Advanced Malignant Neoplasm Metastatic Malignant Neoplasm Recurrent Malignant Neoplasm Refractory Malignant Neoplasm Biological: Anakinra Biological: Denosumab Drug: Everolimus Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of anakinra or denosumab in combination with everolimus in patients with advanced cancers who progressed on standard therapy.

SECONDARY OBJECTIVES:

I. Preliminary assessment of antitumor efficacy of anakinra or denosumab in combination with everolimus in patients with advanced cancers.

II. Assessment of the pharmacokinetic (PK) profile of anakinra or denosumab in combination with everolimus.

III. Preliminary assessment of biomarkers.

OUTLINE: This is a dose-escalation study of everolimus. Participants are assigned to 1 of 2 arms.

ARM I: Participants receive everolimus orally (PO) daily and anakinra subcutaneously (SC) daily on days 1-28. Treatment repeats every 28 days in absence of disease progression or unacceptable toxicity.

ARM II: Participants receive everolimus PO daily on days 1-28 and denosumab SC on day 1. Treatment repeats every 28 days in absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 147 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 30, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (everolimus, anakinra)
Participants receive everolimus PO daily and anakinra SC daily on days 1-28. Treatment repeats every 28 days in absence of disease progression or unacceptable toxicity.
Biological: Anakinra
Given SC
Other Names:
  • Kinaret
  • Kineret
  • rIL-1ra
  • rIL1RN

Drug: Everolimus
Given PO
Other Names:
  • 42-O-(2-Hydroxy)ethyl Rapamycin
  • Afinitor
  • Certican
  • RAD 001
  • RAD001
  • Votubia
  • Zortress

Experimental: Arm II (everolimus, denosumab)
Participants receive everolimus PO daily on days 1-28 and denosumab SC on day 1. Treatment repeats every 28 days in absence of disease progression or unacceptable toxicity.
Biological: Denosumab
Given SC
Other Names:
  • AMG 162
  • AMG-162
  • Prolia
  • Xgeva

Drug: Everolimus
Given PO
Other Names:
  • 42-O-(2-Hydroxy)ethyl Rapamycin
  • Afinitor
  • Certican
  • RAD 001
  • RAD001
  • Votubia
  • Zortress




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of everolimus [ Time Frame: At 28 days ]
    If more than 33% of patients enrolled at any particular dose level develop dose limiting toxicity (DLT), the treatment will continue at the dose level immediately below. If not more than 33% of the patients in the cohort develop DLT, this cohort will be considered the MTD. Only DLTs within course 1 (4 weeks) will be counted with respect to the dose-escalation algorithm.

  2. Incidence of adverse events [ Time Frame: Up to 30 days ]
    Describing the toxicity profile, descriptive statistics will be provided on the grade and type of toxicity by dose level.



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

Inclusion Criteria:

  • 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.
  • 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).
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
  • Absolute neutrophil count (ANC) >= 1,000/mL.
  • Platelets >= 75,000/mL.
  • Creatinine clearance >= 35 ml/min.
  • Total bilirubin =< 2 X upper limit of normal (ULN) (exceptions may apply to benign non-malignant indirect hyperbilirubinemia such as Gilbert syndrome). Exception for patients with liver metastasis: total bilirubin =< 3 x ULN.
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 5 X ULN. Exception for patients with liver metastasis: ALT (SGPT) =< 8 X ULN.
  • Fasting lipid profile: cholesterol =< 350 mg/dL.
  • Fasting lipid profile: triglycerides =< 400 mg/dL.
  • Corrected calcium >= 8.4 mg/dL.
  • Phosphorus >= 2.5 mg/dL for denosumab.
  • Oral examination and appropriate preventive dentistry will be performed prior to the initiation of denosumab therapy.
  • Negative tuberculosis quantiferon test for anakinra arm.
  • Negative serology for histoplasma, blastomycosis, and Coccidioidomycosis for anakinra arm.
  • 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.
  • 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.
  • Patients must be able to understand and be willing to sign a written informed consent document.

Exclusion Criteria:

  • 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.
  • Patients with an active infection.
  • Pregnant or lactating women.
  • History of hypersensitivity to anakinra.
  • History of hypersensitivity to denosumab.
  • History of hypersensitivity to everolimus.
  • History of hypersensitivity to any component of the formulation.
  • Patients unwilling or unable to sign informed consent document.
  • Patients treated with TNF antagonists.
  • Patients with a history of active systemic fungal infection.
  • Patients with liver disease Child Pugh classification B and C.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01624766


Locations
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Filip Janku M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01624766     History of Changes
Other Study ID Numbers: 2011-1043
NCI-2018-01842 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2011-1043 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: June 21, 2012    Key Record Dates
Last Update Posted: September 20, 2018
Last Verified: September 2018

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

Additional relevant MeSH terms:
Neoplasms
Neoplasms, Second Primary
Recurrence
Disease Attributes
Pathologic Processes
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