Clinical trial NCT00923949: Pioglitazone to Treat Adults Undergoing Surgery for Non-small Cell Lung Cancer
Official title: Pilot Trial of Pioglitazone in Adults Undergoing Surgical Resection of Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-Small-Cell Lung Cancer
Keywords: NSCLC Stage Ia-IIb
Resectable NSCLC
Non-Small Cell Lung Cancer
NSCLC
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2009-06-18
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

* Pioglitazone is a drug that belongs to the class of antidiabetic agents called thiazolidinediones. It is approved for treatment of type 2 diabetes mellitus.
* Research suggests that the thiazolidinediones may have anticancer activity that can reduce cancer risk or cause tumors to shrink.

Objectives:

-To test how a pioglitazone works as a treatment of Stage IA to IIB Non-Small Cell Lung Cancer (NSCLC) and to look at the effect of the drug on cancer cells.

Eligibility:

-Patients 18 years of age or older who will undergo surgery for Stage IA to IIB non-small cell lung cancer (NSCLC).

Design:

-The study includes a screening visit to determine eligibility, treatment with pioglitazone, a follow-up visit after 2 to 3 weeks of treatment and a post-surgery visit. Procedures include:

1. Medical history, physical examination, blood tests, electrocardiogram
2. Bronchoscopy to obtain cancer cells. This is done before pioglitazone treatment begins and again during lung surgery. Some patients may also require mediastinoscopy or biopsy to collect cells.
3. Treatment with pioglitazone tablets once a day for at least 2 weeks and no more than 6 weeks, depending on when surgery has been scheduled.
4. Positron emission tomography (PET) scan before starting pioglitazone treatment. National Cancer Institute (NCI) patients also have a follow-up PET scan after treatment but before surgery.

Detailed description: Background:

Lung cancer is the leading cause of cancer deaths in the United States (US). Chemoprevention is an active area of investigation for reducing the burden of this disease. However, the choice of chemopreventive targets requires sufficient human data to justify extensive clinical interventions.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand activated nuclear transcription factor that is a key regulator of adipogenic differentiation. PPAR gamma ligands, particularly the thiazolidinedione class of antidiabetic agents exemplified by pioglitazone, are under investigation as chemopreventive agents.

PPAR gamma is expressed in normal lung and in NSCLC. PPAR gamma ligands induce apoptosis in NSCLC cell lines and modulate their differentiation status. Animal carcinogenesis studies, however, show equivocal efficacy in prevention of lung cancer.

Relevant human data are limited to an epidemiologic study showing that lung cancer risk is decreased in diabetics taking thiazolidinediones and a small phase IIa trial of pioglitazone in oral leukoplakia showing an 80% clinical response (partial response (PR)+ complete response (CR)). Further data are needed prior to engaging in a phase II lung chemoprevention trial.

Objectives:

The objectives of this pilot feasibility study are to evaluate the effect of pioglitazone on the expression of multiple biomarkers in NSCLC tumor tissue and in histologically normal and premalignant tissue.

* The primary endpoint will be the effect of pioglitazone on Ki-67, a marker of proliferation, in tumor tissue.
* The secondary objectives are to determine the effects of pioglitazone on multiple biomarkers in tumor, premalignant, and histologically normal bronchial epithelium and in serum:

  * Tumor tissue biomarkers: apoptotic index (AI), cyclin D1, p21/Waf1, PPAR gamma, mucin 1 (MUC1), gelsolin, proline oxidase, 15-hydroxyprostaglandin dehydrogenase (15-PGDH)
  * Premalignant tissue biomarkers: Ki-67, apoptotic index, PPAR gamma
  * Histologically normal tissue biomarkers: Ki-67, PPAR gamma
  * Serum markers affected by pioglitazone; C-reactive protein, CA 15-3
  * Serum tumor markers: carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125)
* Additional secondary objectives are:

  * To evaluate the toxicity and safety of pioglitazone in this patient population,
  * To determine if limited treatment with pioglitazone affects tumor metabolic activity as determined by fludeoxyglucose positron-emission tomography (FDG-PET).

Eligibility:

Adult patients with newly diagnosed histologically confirmed stage Ia-IIb resectable non-small cell lung cancer who are eligible for and scheduled to undergo definitive surgery.

Eastern Cooperative Oncology Group (ECOG) 0-2

Normal organ function

Design:

Open label, multi-center, non-randomized pilot study to evaluate the effect of pioglitazone on the expression of multiple biomarkers in NSCLC tumor tissue and in histologically normal and premalignant tissue obtained from treatment-naive individuals who will receive oral pioglitazone prior to definitive surgery. The primary endpoint is Ki-67 measured in tumor tissue.

Patients will receive pioglitazone 45 mg po qd for a minimum of 2 weeks or a maximum of 6 weeks, with duration of treatment determined by standard of care and scheduling of surgery.

The study will consist of a screening visit, baseline bronchoscopy with tissue acquisition, pioglitazone treatment for 2-6 weeks, a 2-week on-treatment clinic visit, definitive surgical resection with bronchoscopy performed at the time of resection, and a post-surgery visit. Tissue (visually normal and abnormal areas identified during bronchoscopy) and tumor will be obtained at baseline and at the time of surgery. Patients who receive their treatment at NCI will also undergo a follow up FDG-PET scan after a minimum of 2 weeks of pioglitazone treatment.

Up to 25 patients are expected to be enrolled to identify 20 patients with adequate tissue for biomarker analysis.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Adult patients with newly diagnosed stage Ia-IIb resectable non-small cell lung cancer who will be undergoing definitive surgery. If histologic confirmation of lung cancer has not previously been made, the baseline study bronchoscopy, as outlined in section 3.6.2, or computed tomography (CT)-guided biopsy with tissue saved for protocol use may be used to document NSCLC, after obtaining informed consent. Should the bronchoscopy or CT-guided biopsy be negative for non-small cell lung cancer (NSCLC), the patient will be taken off study prior to drug treatment. At National Cancer Institute (NCI), histologic confirmation of the diagnosis will be performed by the NCI Laboratory of Pathology.
  2. Age greater than or equal to 18 years of age.
  3. Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2.
  4. Patients must have the capacity and willingness to sign a written informed consent and demonstrate willingness to comply with an oral regimen.
  5. The time between initial diagnosis and the scheduled surgery date allow for the subject to receive a minimum of 2 weeks or a maximum of 6 weeks treatment with pioglitazone. The maximum time between enrollment on this trial and surgery will be 6-weeks and there will be no delay between the end of pioglitazone treatment and surgery.
  6. Patients must have normal organ and marrow function as defined below:
* absolute neutrophil count greater than or equal to 1,500/mL
* hemoglobin greater than 10 g/dL
* platelets greater than or equal to 100,000/mL
* Bilirubin less than 1.8 mg/dL
* aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than 1.5 times upper limits of institutional normal
* creatinine less than 1.5 times upper limit of institutional normal

  7. Patients must agree to swallow oral tablets.

  8. Patients who will agree to undergo two bronchoscopies as detailed in section 3.6.2 (before treatment and at the time of surgery).
* For those patients who are undergoing mediastinoscopy as part of their standard-of-care, the pre-treatment bronchoscopy may be performed during the mediastinoscopy. If the patient remains eligible for definitive surgical resection after the mediastinoscopy, the patient may begin pioglitazone treatment on this protocol.

  9. Females are eligible to participate in the study if
* She is of non-childbearing potential as defined by having had a hysterectomy, a bilateral oophorectomy, a bilateral tubal ligation, or having been post-menopausal for greater than or equal to 1 year.
* She is of childbearing potential and has a negative pregnancy test within 2 weeks of the starting the study drug and agrees to the use of non-hormonal methods of birth control, e.g., barrier methods, for the duration of the study due to possible drug interactions.

EXCLUSION CRITERIA:

1. Pregnant or lactating women.
2. Patients who are undergoing chemotherapy, treatment with biologic agents, or radiation therapy. Prior chemotherapy, biologic agent treatment, or radiation therapy, greater than 1 year ago, is allowed.
3. Patients with greater than or equal to class II New York Heart Association (NYHA) congestive heart failure or history of congestive heart failure.
4. Patients with greater than or equal to grade 2 (moderate) edema.
5. Patients with diabetes mellitus being treated with insulin or any pharmacologic therapy.
6. Patients taking gemfibrozil or rifampin, due to drug interactions with pioglitazone.
7. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active liver disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Primary outcomes:
measure: Number of Participants With a Change in Ki-67 Due to the Effect of Pioglitazone in Tumor Tissue
timeFrame: 58 days
Secondary outcomes:
measure: Number of Participants With Effects of Pioglitazone on Multiple Biomarkers in Tumor
timeFrame: 58 days
measure: Number of Participants With Adverse Events
timeFrame: 58 days
measure: Number of Participants With Metabolic Activity Determined by Fludeoxyglucose Positron-emission Tomography (FDG-PET)
timeFrame: 58 days
measure: Number of Participants With Effects of Pioglitazone on Premalignant Tissue Biomarkers
timeFrame: 58 days
measure: Number of Participants With Effects of Pioglitazone on Histologically Normal Tissue Biomarkers
timeFrame: 58 days
measure: Number of Participants With Effects of Pioglitazone on Serum Tumor Markers
timeFrame: 58 days
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: New York
country: United States
facility: New York University
state: New York
Study officials:
affiliation: National Cancer Institute (NCI)
name: Giuseppe Giaccone, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.
citation: Elstner E, Muller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8806-11. doi: 10.1073/pnas.95.15.8806.
citation: Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM. Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med. 1998 Sep;4(9):1046-52. doi: 10.1038/2030.