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Combined PKCiota and mTOR Inhibition for Treatment of Advanced Squamous Lung Cancer

Phase 1
18 Years
Not Enrolling
Recurrent Non-small Cell Lung Cancer, Squamous Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Combined PKCiota and mTOR Inhibition for Treatment of Advanced Squamous Lung Cancer

PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) of ATM (gold sodium
thiomalate) plus sirolimus. SECONDARY OBJECTIVES: I. To describe the adverse event
profile associated with this treatment combination. II. To preliminarily evaluate the
response rate, time to progression, progression-free survival and overall survival of
patients treated with this treatment combination. TERTIARY OBJECTIVES: I. To evaluate
tumor biomarkers of protein kinase C (PKCĪ¹) and mammalian Target Of Rapamycin (mTOR)
signaling activity as predictors of response to ATM/sirolimus therapy. II. To evaluate the
use of surrogate biomarkers of PKCĪ¹ and mTOR inhibition in peripheral blood lymphocytes
(PBLs) to monitor response to ATM/sirolimus therapy. OUTLINE: This is a dose-escalation
study. Patients receive sirolimus orally (PO) once daily (QD) on days 1-28 and gold
sodium thiomalate intramuscularly (IM) on days 1, 8, 15, and 22. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity. After completion of
study treatment, patients are followed up for 3 months.

Inclusion Criteria:

- Cohort I (Dose Escalation) only: must have histologic proof of an advanced, solid
tumor that is now unresectable

- Cohort II (MTD) only

- Patients must have platinum-refractory NSCLC (platinum-refractory defined as either
disease progression either during or within 6 months of completion of first-line
platinum-based chemotherapy)

- Must have measurable disease

- Must have received at least one prior approved chemotherapeutic regimen unless there
is no known, approved therapeutic regimen for their malignancy

- Must have evidence of disease progression within the preceding 6 months -
Absolute neutrophil count (ANC) >= 1500/uL

- Platelets (PLT) >= 100,000/uL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- (Serum glutamic oxaloacetic transaminase [SGOT]) aspartate aminotransferase (AST) /
(serum glutamic pyruvic transaminase [SGPT]) alanine transaminase (ALT) =< 3 x ULN or
(SGOT) AST / (SGPT) ALT =< 5 x ULN if liver involvement

- Creatinine =< 1.5 x ULN

- Fasting blood glucose =< 126 mg/dL

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2

- Ability to provide informed consent

- Willingness to return to Mayo Clinic in Florida for follow-up

- Life expectancy >= 84 days (3 months)

- Willing to provide blood and tissue samples for correlative research purposes; Note:
the goals of this study include assessment of the biologic effects of the agent being
tested and are, therefore, contingent upon availability of the biologic specimens

- Women of childbearing potential only: negative (serum) pregnancy test done =< 7 days
prior to registration

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Any of the following prior therapies:

- Chemotherapy =< 28 days prior to registration

- Mitomycin C/nitrosoureas =< 42 days prior to registration

- Immunotherapy =< 28 days prior to registration

- Biologic therapy =< 28 days prior to registration

- Radiation therapy =< 28 days prior to registration

- Radiation to > 25% of bone marrow

- Bevacizumab =< 28 days prior to registration

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment

- New York Heart Association classification III or IV

- Known central nervous system (CNS) metastases or seizure disorder; patients with
known brain metastases that have been successfully treated and stable for >= 6 months
without requirement for corticosteroids and without seizure activity will be eligible

- Patients with known diabetes mellitus unless well-controlled (fasting blood sugar
[FBS] =< 126mg/dL and hemoglobin [Hb]A1C =< 7.0)

- Receiving therapeutic anticoagulation with warfarin; NOTE: prophylactic
anticoagulation (i.e., low dose warfarin) of venous or arterial access devices is
allowed, provided that International Normalized Ratio (INR) < 1.5; therapeutic
anti-coagulation with low molecular weight heparin is allowed at time of registration

- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown: - Pregnant women - Nursing women - Men or women of childbearing potential
who are unwilling to employ adequate contraception - Other concurrent
chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered
investigational (utilized for a non-Food and Drug Administration [FDA] approved
indication and in the context of a research investigation)

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be human immunodeficiency virus (HIV) positive

- Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm

- Cohort II Only: other active malignancy =< 5 years prior to registration; EXCEPTIONS:
non-melanotic skin 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); concurrent endocrine
therapy for breast cancer will not be permitted

- History of myocardial infarction =< 168 days (6 months) or congestive heart failure
requiring use of ongoing maintenance therapy for life threatening ventricular

- Known allergy to ATM (Aurothiomalate [gold sodium thiomalate]) or other gold

- >= Grade 2 hypertriglyceridemia

- >= Grade 2 hypercholesterolemia

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximally tolerated dose (MTD) of ATM plus sirolimus

Outcome Description:

MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Michael Menefee

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic in Florida


United States: Federal Government

Study ID:




Start Date:

June 2011

Completion Date:

Related Keywords:

  • Recurrent Non-Small Cell Lung Cancer
  • Squamous Cell Lung Cancer
  • Stage IIIA Non-Small Cell Lung Cancer
  • Stage IIIB Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms