Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

TS Overexpression in SCLC: Mechanism and Therapeutic Targeting

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03741829
Recruitment Status : Active, not recruiting
First Posted : November 15, 2018
Last Update Posted : March 6, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Wake Forest University Health Sciences

Brief Summary:
The purpose of this research study is to determine the amount of a protein named thymidine synthase that is being made by cancer and to develop laboratory models called PDX (patient derived xenografts) to learn more about SCLC (small cell lung cancer) and to begin testing new treatments.

Condition or disease
Small Cell Lung Cancer

Detailed Description:

Small cell lung cancer (SCLC) is a highly lethal malignancy that is not treatable with targeted therapies and that does not respond long-term to treatment with cytotoxic chemotherapy1. One distinguishing molecular characteristic of SCLC is very high expression levels of thymidylate synthase (TS). TS plays an important role in de novo nucleotide biosynthesis and the very high TS levels expressed in SCLC cells indicate that these cells require the de novo nucleotide biosynthetic pathway to proliferate. Thus, complete TS inhibition could result in highly favorable outcomes in SCLC patients. TS inhibitors have been evaluated in SCLC clinical trials and have anti-tumoral activity when combined with a second chemotherapeutic agent. However, treatment with TS inhibitors has not been shown to surpass other combination chemotherapy regimens. An important point regarding these clinical studies is that TS activity levels were not monitored as an endpoint of drug response, thus it is not known whether TS activity was efficiently inhibited.Investigators predict that complete TS inhibition will result in favorable outcomes.

With support from Wake Innovations, Investigators are developing a novel fluoropyrimidine polymer, CF10, which strongly inhibits TS. CF10 is a second generation fluoropyrimidine polymer. The first generation polymer, F10, showed excellent anti-cancer activity in animal models of acute myeloid leukemia, glioblastoma, and prostate cancer. CF10 is designed to have improved tumor penetration and better in vivo stability than F10. Investigators hypothesize that CF10 will be highly effective for treating SCLC both as a single agent and in combination with TS inhibitors that target alternative sites of the TS enzyme.

After establishing CF10 has activity as a single agent and in combination with folate-based TS inhibitors (e.g. pemetrexed) in SCLC cell lines and xenograft models, Investigators will test CF10 in patient-derived xenograft (PDX) models and in organoids derived from SCLC patient samples. Investigators will develop PDX models of SCLC and SCLC organoids using transbronchial fine needle aspiration (FNA) from SCLC patients at Baptist/WFBCCC collected by co-I's Bellinger, Dotson, and Thomas. Non-malignant cells will be collected using a brush biopsy to enable comparison of malignant and non-malignant tissue from the same patient with regard to mechanistic endpoints.


Layout table for study information
Study Type : Observational
Actual Enrollment : 12 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: TS Overexpression in SCLC: Mechanism and Therapeutic Targeting
Actual Study Start Date : June 14, 2017
Actual Primary Completion Date : January 7, 2019
Estimated Study Completion Date : February 2020

Resource links provided by the National Library of Medicine


Group/Cohort
Samples from transbronchial Biopsy
Samples from participants with SCLC.



Primary Outcome Measures :
  1. TYMS (Thymidylate Synthetase) expression levels [ Time Frame: After biopsy collection, up to 1 year ]
    TYMS (Thymidylate Synthetase) expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.

  2. miRNA expression levels [ Time Frame: After biopsy collection, up to 1 year ]
    miRNA expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.


Other Outcome Measures:
  1. Survival of mice at 60 days implanted with tumor and treated with CF10 [ Time Frame: 60 days ]
  2. Number of samples with PDX model development [ Time Frame: After biopsy collection, up to 1 year ]
  3. Levels of TS activity [ Time Frame: After biopsy collection, up to 1 year ]
  4. Levels of Top1cc [ Time Frame: After biopsy collection, up to 1 year ]
  5. Levels of DNA double strand breaks [ Time Frame: After biopsy collection, up to 1 year ]
  6. Tumor volume [ Time Frame: After biopsy collection, up to 1 year ]
  7. Number of apoptotic cells. [ Time Frame: After biopsy collection, up to 1 year ]

Biospecimen Retention:   Samples With DNA
DNA will be extracted from the PDX tumor and from the blood sample obtained from the same subject/patient. Both samples will undergo DNA sequencing in the Cancer Genomics Shared Resource. The DNA sequences will be compared to differentiate between tumor-specific mutations and germ-line polymorphisms from the same individual. The mutation profile is characteristic of the tumor and will also be used to test for genetic drift as the PDX tumor is propagated.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
  • Women and men of all races and ethnicity who meet the above-described eligibility criteria are eligible for this trial.
  • The study consent form will also be provided in Spanish for Spanish-speaking participants.
Criteria

Inclusion Criteria:

  • Patients undergoing a diagnostic FNA by the following diagnostic modalities utilizing FNA: Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS- TBNA) or conventional transbronchial FNA.
  • Patients must have radiographic evidence for presumed lung cancer or have a previously diagnosed SCLC with clinical evidence of recurrence. Patients undergoing FNA of potential SCLC metastates to lymph nodes are also included (e.g., patients with abnormal mediastinal lymphadenopathy). FNA biopsies from separate locations in the same patient will be considered separate specimens.
  • Age >18 years. Used to define adult age that can independently provide consent.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients whose FNA biopsy is unable to provide classification by pathology or is non-diagnostic.

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): NCT03741829


Locations
Layout table for location information
United States, North Carolina
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
Sponsors and Collaborators
Wake Forest University Health Sciences
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: William Gmeiner, Ph.D, MBA Wake Forest University Health Sciences

Publications:

Layout table for additonal information
Responsible Party: Wake Forest University Health Sciences
ClinicalTrials.gov Identifier: NCT03741829     History of Changes
Other Study ID Numbers: IRB00043264
Pilot Funds 11347 ( Other Grant/Funding Number: Comprehensive Cancer Center of Wake Forest University )
P30CA012197 ( U.S. NIH Grant/Contract )
CCCWFU 62A17 ( Other Identifier: NCI )
First Posted: November 15, 2018    Key Record Dates
Last Update Posted: March 6, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Wake Forest University Health Sciences:
Thymidylate Synthase
Cancer
Cancer Treatments

Additional relevant MeSH terms:
Layout table for MeSH terms
Small Cell Lung Carcinoma
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases