Extensive Stage Small Cell Lung Carcinoma, Lung Adenocarcinoma, Recurrent Non-Small Cell Lung Carcinoma, Recurrent Small Cell Lung Carcinoma, Squamous Cell Lung Carcinoma, Stage IIIA Non-Small Cell Lung Cancer, Stage IIIB Non-Small Cell Lung Cancer, Stage IV Non-Small Cell Lung Cancer
Conditions
Brief summary
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.
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.
Interventions
DRUGAuranofin
Given PO
DRUGSirolimus
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Rate | 4 months | 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. |
| Number of Phase 1 Patients Experiencing a DLT | 28 days | 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 |
| Number Phase 1 Patients Experiencing a Grade 3+ AE | Up to 5 years | Number and severity of all adverse events (overall and by dose level) will be tabulated and summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Achieving a Complete Response (CR) or Partial Response (PR) Noted as the Objective Status | Up to 5 years | 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. |
| Duration of Response | Up to 5 years | 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. |
| Overall Survival Time | up to 5 years | 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. |
| Progression-free Survival Time | up to 5 years | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Protein Kinase C (PKC) Iota Protein Expression | Baseline to up to 5 years | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 0 Patients receive 3mg 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. \> \> Auranofin: Given PO \> Sirolimus: Given PO \> Laboratory Biomarker Analysis: Correlative studies \> Pharmacological Study: Correlative studies | 3 |
| Dose Level 1 Patients receive 6mg 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. \> \> Auranofin: Given PO \> Sirolimus: Given PO \> Laboratory Biomarker Analysis: Correlative studies \> Pharmacological Study: Correlative studies | 26 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase I | Complicating disease | 1 | 0 |
| Phase I | Disease progression | 2 | 3 |
| Phase II | Adverse Event | 0 | 3 |
| Phase II | Death | 0 | 1 |
| Phase II | Disease progression | 0 | 18 |
| Phase II | Transition to hospice care | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Level 0 | Dose Level 1 | Total |
|---|---|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 7.8 | 62.38 years STANDARD_DEVIATION 9.3 | 61.52 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 24 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Histologic Type Non-small cell lung cancer | 2 Participants | 17 Participants | 19 Participants |
| Histologic Type Small cell lung cancer | 0 Participants | 9 Participants | 9 Participants |
| Histologic Type Unknown | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 24 Participants | 27 Participants |
| Region of Enrollment United States | 3 participants | 26 participants | 29 participants |
| Sex: Female, Male Female | 2 Participants | 12 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 14 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 3 / 26 |
| other Total, other adverse events | 3 / 3 | 23 / 26 |
| serious Total, serious adverse events | 2 / 3 | 8 / 26 |
Outcome results
Primary
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
Time frame: 28 days
Population: Only phase 1 patients were included in analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 0 | Number of Phase 1 Patients Experiencing a DLT | 0 Participants |
| Dose Level 1 | Number of Phase 1 Patients Experiencing a DLT | 0 Participants |
Primary
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.
Time frame: Up to 5 years
Population: Only phase 1 patients were included in analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 0 | Number Phase 1 Patients Experiencing a Grade 3+ AE | 2 Participants |
| Dose Level 1 | Number Phase 1 Patients Experiencing a Grade 3+ AE | 1 Participants |
Primary
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.
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 0 | Progression-free Survival Rate | 66.7 percentage of participants |
| Dose Level 1 | Progression-free Survival Rate | 28.0 percentage of participants |
Secondary
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.
Time frame: Up to 5 years
Population: Only patients that achieved a CR or PR for a known amount of time were included in analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Level 1 | Duration of Response | 16.25 months |
Secondary
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.
Time frame: Up to 5 years
Population: Only patients with measurable disease were included in analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 0 | Number of Patients Achieving a Complete Response (CR) or Partial Response (PR) Noted as the Objective Status | 1 Participants |
| Dose Level 1 | Number of Patients Achieving a Complete Response (CR) or Partial Response (PR) Noted as the Objective Status | 2 Participants |
Secondary
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.
Time frame: up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 0 | Overall Survival Time | 4.9 months |
| Dose Level 1 | Overall Survival Time | 8.6 months |
Secondary
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.
Time frame: up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 0 | Progression-free Survival Time | 4.9 months |
| Dose Level 1 | Progression-free Survival Time | 2.1 months |
Other Pre-specified
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.
Time frame: Baseline to up to 5 years