Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Lung Neoplasms

Small Cell Lung Carcinoma

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Small Cell Lung Cancer

William Gmeiner, Ph.D, MBA

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.

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.

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.

TS Overexpression in SCLC: Mechanism and Therapeutic Targeting

TYMS (Thymidylate Synthetase) expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.

miRNA expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.

National Cancer Institute (NCI)

Wake Forest University Health Sciences

All Drugs and Chemicals

Fluorodeoxyglucose F18

Twelve participants with cancer and eight healthy volunteers will be recruited first to undergo whole-body PET/CT imaging to determine the whole body dosimetry of \[18F\]FluorThanatrace.

An additional 30 participants with cancer will undergo a 1-hour dynamic scan upon injection of \[18F\]FluorThanatrace to determine the kinetics of the tracer in tumors to correlate with tissue-based markers of PARP activity and to obtain metabolite information to help determine the best quantification approach for the PET images. When possible these subjects will also undergo 18F-FDG imaging for comparison to tumor metabolism

For the Dosimetry Studies, 10 mCi of \[18F\]FTT will be injected intravenously, and participants will be placed in the following groups to be imaged with PET at the specified time points: 0 minute group--image at 0 and 120 min. after tracer injection; 30 minute group--image at 30 and 150 min. after tracer injection; 60 minute group--image at 60 and 180 min. after tracer injection; and 90 minute group--image at 90 and 210 min. after tracer injection.

For the Kinetic Studies, 10 mCi of \[18F\]FTT will be injected intravenously, and a 60-minute dynamic PET scan will be obtained starting at the time of injection.

[18F]FluorThanatrace

Farrokh L Dehdashti, MD

The purpose of this research study is to determine the feasibility of using positron emission tomography (PET) imaging technology to image cancer with \[18F\]FluorThanatrace (\[18F\]FTT), a new radioactive tracer compound that has been developed that images poly(ADP-ribose) polymerase 1 (PARP-1) activity.

Poly(ADP-ribose) polymerase 1 (PARP1) is a deoxyribonucleic acid (DNA) repair enzyme that enables normal cell survival as well as certain cancers. Pharmaceutical companies have invested heavily in PARP1 inhibitor development because these agents can effectively treat certain cancers as single agents, thus sparing those patients from chemotherapy toxicities. However, clinical trials testing PARP1 inhibitors have demonstrated mixed results due to the inability to measure the degree of PARP1 inhibition in tumors reliably. Accurately measuring tumoral PARP1 activity levels before and after PARP1 inhibitor treatment will: (1) enable identification of patients whose tumors exhibit PARP activity and are therefore good candidates for PARP inhibitor therapy, and (2) confirm that adequate doses of PARP1 inhibitors are being administered to patients, thus improving dose selection for further study in clinical trials. Thus, noninvasive approaches for measuring tumoral PARP1 activity would have commercialization potential in not only supporting development of PARP1 inhibitors but also after Food and Drug Administration (FDA) approval to assess clinical PARP1 inhibitor treatment responses.

Inflammation also contributes to a number of diseases involving the lungs and other organs. Increasing evidence suggests that PARP1 may also play a central role in modulating immune inflammatory responses. Thus, the data from this trial will also be used to develop this approach for studying lung inflammatory responses.

A new radiolabeled compound, \[18F\]FluorThanatrace (\[18F\]FTT), has been generated which can be used to measure PARP1 activity noninvasively and quantitatively using positron emission tomography (PET). Our data in cancer models show that the uptake of our compound is specific for PARP1 activity and correlates with biochemically determined PARP1 activity. Additional preliminary data also suggests that decreased \[18F\]FTT uptake predicts tumor response to PARP inhibition with olaparib, a PARP1 inhibitor currently being evaluated in clinical trials. Therefore, the investigators are conducting this Phase 0 trial to develop \[18F\]FTT for clinical use in cancer patients.

To date, no biomarkers have been developed beyond genetic testing for breast cancer 1 and 2 (BRCA1/2) mutations that can aid in patient selection for treatment with PARP inhibition. Moreover, no technologies are available to monitor the efficacy of PARP inhibition. Our technology provides both a biomarker for patient selection as well as a means of monitoring PARP activity during treatment.

PET Imaging of PARP Activity in Cancer

Positron Emission Tomography (PET) Imaging of Poly(ADP-Ribose) Polymerase (PARP) Activity in Cancer

Washington University School of Medicine

Skin and Connective Tissue Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Nervous System Diseases

Breast Neoplasms

Triple Negative Breast Neoplasms

Pancreatic Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Brain Neoplasms

Pancreatic Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Hypoglycemic Agents

Anti-Infective Agents

Antineoplastic Agents

Lipid Regulating Agents

Herbal and Botanical

Ibuprofen

Metformin

Doxycycline

Mebendazole

Atorvastatin

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Enzyme Inhibitors

Anti-Bacterial Agents

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Anthelmintics

Tubulin Modulators

Antimitotic Agents

Cola

Subjects will take the following treatments and have their data collected from their medical records every 3 months.

* Oral atorvastatin up to 80mg uid, for study duration.
* Oral metformin up to 1000mg uid, increased to bid if tolerated after 2 weeks, for study duration.
* Oral doxycycline 100mg uid, for study duration.
* Oral Mebendazole 100mg uid, for study duration.

While subjects are being treated with the four metabolic drugs, every 3 months they will bring in their medical records and data will be collected to determine the effect of the intervention

Metabolic treatment

Samir Agrawal, MRCP FRCPath

The purpose of this study is to determine the effectiveness of a regimen of selected metabolic treatments for patients with cancer in a real world setting and to conduct exploratory analysis on the relationship between the degree of response and changes in biochemical markers (such as glucose and lipid levels).

\*This study has been designed to collect data prospectively and to retrospectively analyse data on the metabolic treatments within the cancer clinic. The retrospective study is ongoing, while the prospective study has not yet started.\*

This is a real world study since this gives the best opportunity to properly examine the effect of multi-drug regimens in representative populations. Including a standard of care arm is inappropriate, in a population in which that standard of care has already been shown to be ineffective or intolerable.

Patients will be sent to the study clinic directly by their Health Care Professionals ("HCP's") .

The study will consist of a pre-screening visit to determine eligibility for inclusion into the study, an initiation visit and then a follow up visit every three months thereafter. If required, unscheduled visits may take place. Day 0 (baseline) for each patient will be the initiation visit when study treatment is started.

Prior to conducting any study-related procedures, subjects will provide written informed consent, eligibility will be assessed, a medical history and past medical records will be taken and vital signs will be measured. These records will include the stage of their disease, response to previous cancer therapy, their prior and current medications and any specific regimen they are currently on for their cancer. If prior medical records do not contain sufficient information to determine a baseline for the patient, additional blood tests and scans will be undertaken as appropriate.

Patients will be monitored quarterly thereafter when blood tests (e.g. safety parameters, glucose, cholesterol, immune response and cancer markers where applicable) and scans (where applicable) will be taken.

All patients will be on the same drug regimen (see below) at the same doses throughout the study. All patients will be followed up until they choose to leave the study, or death.

Data from all patients recruited to the study will be analysed using an Intention-to-treat (ITT) philosophy, so data will be included in the primary analysis irrespective of whether the dose regimen was followed throughout the study. If appropriate, and numbers allow, analysis will also be conducted on the Per Protocol population, comprising those patients who adhere to the regimen as prescribed.

Survival analysis methods will be used to estimate the Overall survival associated with the study regimen for each type of cancer. These estimates will be interpreted in the light of data obtained from the literature, and from eliciting expert opinion. Bayesian methods may be used where appropriate.

Tumour response, where applicable, will be summarised in tables and graphs. Estimates of response rates will be presented for each cancer type with confidence intervals.

The relationship between changes in biochemistry values (glucose, lipids) and efficacy outcomes (Progression Free Survival (PFS), Overall Survival (OS) and HRQoL) will be investigated graphically, or using other methods as appropriate.

Further exploratory analysis to investigate the effects of other factors such as age , ethnic backgrounds , cancer stage, and response to prior therapy, will also be conducted in order to try and characterise the profile of patients most likely to benefit from the study regimen.

The characteristics of patients on the regimen and those who do not stay on the regimen, for whatever reason, will be summarised to see whether there is any observed bias. If appropriate, methods will be used to adjust for any observed bias, for example using propensity scores. OS can then be assessed adjusted for this to try and mitigate for any possible risk of bias which can occur in uncontrolled studies. Furthermore, by enrolling all eligible patients over a specified time frame, it is hoped that the risk of bias should be further reduced. In addition, a large number of patients are expected to participate in the study.

Study of the Safety, Tolerability and Efficacy of Metabolic Combination Treatments on Cancer

A Non Randomised, Non Blinded Real World Trial of the Safety, Tolerability and Effectiveness of Metabolic Medicines for the Treatment of Cancer Compared Against Matched Controls

Adverse events reported by the subject or their HCP.

• Quarterly assessment of routine laboratory tests

Overall survival for all cancer types and for each cancer type (years and months)

Tumour size for all cancer types and for each cancer type. Units of size vary depending on cancer type.

Tumour spread (metastasized) to other tissues/organs, for all cancer types and for each cancer type. This is measured as either 0 for no spread or 1 for confirmed spread.

Tumour number for all cancer types and for each cancer type

Cancer biomarkers for all cancer types and for each cancer type. Units of measurement vary depending on the cancer type. When biomarkers, either alone or in combination with other biomarkers, are raised above normal they are seen as predictive of cancer of progression. If returned to normal are indicative of treatment response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
TS Overexpression in SCLC: Mechanism and Therapeutic Targeting	NCT03741829	Small Cell Lung...		18 Years -	Wake Forest University Health Sciences
PET Imaging of PARP Activity in Cancer	NCT02469129	Cancer	[18F]FluorThana...	18 Years -	Washington University School of Medicine
Study of the Safety, Tolerability and Efficacy of Metabolic Combination Treatments on Cancer	NCT02201381	Cancer Overall Surviva...	Metabolic treat...	18 Years - 85 Years	Health Clinics Limited
PET Imaging of PARP Activity in Cancer	NCT02469129	Cancer	[18F]FluorThana...	18 Years -	Washington University School of Medicine
TS Overexpression in SCLC: Mechanism and Therapeutic Targeting	NCT03741829	Small Cell Lung...		18 Years -	Wake Forest University Health Sciences
PET Imaging of PARP Activity in Cancer	NCT02469129	Cancer	[18F]FluorThana...	18 Years -	Washington University School of Medicine
Study of the Safety, Tolerability and Efficacy of Metabolic Combination Treatments on Cancer	NCT02201381	Cancer Overall Surviva...	Metabolic treat...	18 Years - 85 Years	Health Clinics Limited
Study of the Safety, Tolerability and Efficacy of Metabolic Combination Treatments on Cancer	NCT02201381	Cancer Overall Surviva...	Metabolic treat...	18 Years - 85 Years	Health Clinics Limited
TS Overexpression in SCLC: Mechanism and Therapeutic Targeting	NCT03741829	Small Cell Lung...		18 Years -	Wake Forest University Health Sciences

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