Sirolimus and Auranofin in Treating Patients With Advanced or Recurrent Non-Small Cell Lung Cancer or Small Cell Lung Cancer

A Phase I-II Trial of Combined PKCι and mTOR Inhibition for Patients With Advanced or Recurrent Lung Cancer (NSCLC and SCLC) Without Standard Treatment Options

This phase I/II trial studies the side effects and best dose of auranofin when given together with sirolimus and to see how well it works in treating patients with lung cancer that has spread or other places in the body and cannot be cured or controlled by treatment or has come back after a period of time during which the cancer could not be detected. Auranofin and sirolimus may stop or slow the growth of lung cancer.

Study Overview

• Status: Completed
• Conditions: Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Lung Adenocarcinoma; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer; Extensive Stage Small Cell Lung Carcinoma; Squamous Cell Lung Carcinoma; Recurrent Small Cell Lung Carcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Sirolimus; Drug: Auranofin

Detailed Description

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose of auranofin plus sirolimus after at least one line of platinum based chemotherapy for lung cancer (squamous, ras-mutated adenocarcinoma, or small cell lung cancer) patients with no acceptable standard treatment options. (Phase I) II. To assess the progression-free survival at four months of patients treated with auranofin after at least one line of platinum based chemotherapy for lung cancer (squamous, ras-mutated adenocarcinoma, or small cell lung cancer) patients with no acceptable standard treatment options. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the overall survival in this population in comparison to recent historical controls.

II. To determine the adverse events (AE) profile and safety of the regimen. III. To determine the overall response rate, per Response Evaluation Criteria In Solid Tumors (RECIST) criteria, and duration of tumor response in those patients with measurable disease.

TERTIARY OBJECTIVES:

I. To assess the relationship between molecular correlates and progression-free survival (PFS), overall survival (OS), response and adverse events.

OUTLINE: This is a phase I, dose-escalation study of auranofin followed by a phase II study.

Patients receive auranofin orally (PO) on days 1-28 and sirolimus PO on days 1-28 (days 8-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologic or cytologic confirmation of lung cancer (squamous, ras-mutated adenocarcinoma or small cell lung cancer)
• Patients must have received at least one course of chemotherapy consisting of a platinum doublet and must have no acceptable standard treatment options

• Prior radiation therapy is permitted as long as:

  • Recovered from the toxic effects of radiation treatment before study entry, except for alopecia
• Absolute neutrophil count (ANC) >= 1500 uL
• Platelets (PLT) >= 100,000 uL
• Hemoglobin (Hgb) >= 9 g/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin =< ULN
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN or SGOT (AST) and SGPT (ALT) =< 5 x ULN is acceptable if liver has tumor involvement
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2
• Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
• Ability to provide informed consent
• Life expectancy >= 12 weeks
• Willing to return to Mayo Clinic enrolling institution for follow-up
• Willing to provide tissue samples for correlative research purposes

Exclusion Criteria:

• Any of the following:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
• Symptomatic, untreated, or uncontrolled central nervous system (CNS) metastases or seizure disorder; NOTE: patients with treated CNS metastases without evidence of progression and without uncontrolled symptoms or need for steroids may enroll
• Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded
• Unwilling or unable to, comply with the protocol

• Any of the following prior therapies:

  • Radiation to >= 25% of bone marrow
  • Major surgery (i.e., laparotomy), open biopsy, or significant traumatic injury =< 4 weeks prior to registration; minor surgery =< 2 weeks prior to registration; insertion of a vascular access device is not considered major or minor surgery in this regard

• Any of the following concurrent severe and/or uncontrolled medical conditions:

  • Hypertension, labile hypertension, or history of poor compliance with antihypertensive medication
  • Angina pectoris
  • History of congestive heart failure =< 3 months, unless ejection fraction > 40%
  • Myocardial infarction =< 6 months prior to registration
  • Cardiac arrhythmia
  • Poorly controlled diabetes
  • Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
  • Active or recent history of hemoptysis; if hemoptysis has resolved with measures such as palliative radiation therapy (e.g. 3000 cGy over 10 fractions), arteriographic embolization or endobronchial interventions (e.g. photodynamic therapy, brachytherapy), etc. for > 14 days, patients may be considered for participation in this study
  • >= Grade 2 hypertriglyceridemia
  • >= Grade 2 hypercholesterolemia
  • Any illness that in the opinion of the investigator would compromise the ability of the patient to participate safely in the clinical trial
• Use of St. John's Wort because of its effects on hepatic drug metabolism
• Other active malignancy: EXCEPTIONS: Non-melanoma skin cancer, localized prostate cancer, or carcinoma-in-situ of the cervix; NOTE: If there is a history or prior malignancy, patient must not be receiving other cytotoxic or molecularly targeted therapeutics treatment for their cancer; patients receiving certain hormonal manipulations as part of their treatment may be allowed to continue at the discretion of the Principal Investigator (PI) (e.g. luteinizing hormone-releasing hormone [LHRH] analogs for prostate cancer)
• Unable to discontinue use of potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors/inducers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (auranofin and sirolimus); Patients receive auranofin PO on days 1-28 and sirolimus PO on days 1-28 (days 8-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Other Names: pharmacological studies; Drug: Sirolimus; Given PO; Other Names: AY 22989; RAPA; SILA 9268A; WY-090217; Drug: Auranofin; Given PO; Other Names: Ridaura

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Phase 1 Patients Experiencing a DLT	The number and severity of all adverse events (overall and by dose level) will be tabulated and summarized. A DLT is defined as an adverse event during the first cycle of, at least possibly related to study treatment, and one of the following: Grade 4 Neutropenia, Grade 4 Thrombocytopenia, ≥Grade 3 Anaphylaxis, ≥Grade 3 Proteinuria, ≥Grade 3 Hematuria, ≥Grade 3 Rash acneiform, ≥Grade 3 Diarrhea, ≥Grade 3 Mucositis oral	28 days
Number Phase 1 Patients Experiencing a Grade 3+ AE	Number and severity of all adverse events (overall and by dose level) will be tabulated and summarized.	Up to 5 years
Progression-free Survival Rate	A patient is considered to be a 4-month progression-free survivor, or success, if the patient is 4 months from registration without a documentation of disease progression. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated using the properties of the binomial distribution. Additionally, an estimate and confidence interval for the 4-month progression-free survival rate incorporating censoring may be computed using the method of Kaplan-Meier.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Achieving a Complete Response (CR) or Partial Response (PR) Noted as the Objective Status	The overall response rate will be estimated in the subset of patients with measurable disease by the number of responses in evaluable patients with measurable disease divided by the total number of evaluable patients with measurable disease.	Up to 5 years
Duration of Response	Defined for all evaluable patients with measurable disease who have achieved a response as the date at which the patient's earliest best objective status is first noted to be a CR or PR to the earliest date progression is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier.	Up to 5 years
Overall Survival Time	Overall Survival (OS) is defined as the length of time from study enrollment until death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.	up to 5 years
Progression-free Survival Time	Progression-free survival is defined as the time from study enrollment until disease progression or death from any cause. The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier.	up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Protein Kinase C (PKC) Iota Protein Expression	Will be evaluated at baseline using the baseline tissue specimen and explored in relation to 4-month progression-free survival and subsequently in relation to other clinical outcomes such as tumor response and adverse event incidence using two-way tables and analyzed using Fisher's exact tests.	Baseline to up to 5 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Yanyan Lou, M.D., Ph.D., Mayo Clinic

Publications and helpful links

General Publications

• Rousselle B, Massot A, Privat M, Dondaine L, Trommenschlager A, Bouyer F, Bayardon J, Ghiringhelli F, Bettaieb A, Goze C, Paul C, Malacea-Kabbara R, Bodio E. Conception and Evaluation of Fluorescent Phosphine-Gold Complexes: From Synthesis to in vivo Investigations. ChemMedChem. 2022 Jun 3;17(11):e202100773. doi: 10.1002/cmdc.202100773. Epub 2022 Mar 29.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2014
• Primary Completion (Actual): April 24, 2023
• Study Completion (Actual): April 24, 2023

Study Registration Dates

• First Submitted: November 27, 2012
• First Submitted That Met QC Criteria: November 28, 2012
• First Posted (Estimated): November 29, 2012

Study Record Updates

• Last Update Posted (Estimated): September 5, 2025
• Last Update Submitted That Met QC Criteria: August 19, 2025
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Organic Chemicals; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Macrolides; Lactones; Organometallic Compounds; Aurothioglucose; Organogold Compounds; MTOR Inhibitors; Sirolimus; Auranofin
• Other Study ID Numbers: MC1125 (Mayo Clinic in Arizona); NCI-2012-00518 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 11-001987 (Other Identifier: Mayo Clinic Institutional Review Board); R21CA153000 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No