Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Gemcitabine

Carboplatin

Cisplatin

Itraconazole

Clotrimazole

Miconazole

Hydroxyitraconazole

Antifungal Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Patients will receive intravenous doses of cisplatin 80 mg/m2 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks for a maximum of 6 cycles + itraconazole 200 mg oral tablet daily, on a 21-day cycle.

Alternatively, Carboplatin may be used instead of Cisplatin, Carbplatin AUC 5 DAY 1 only Dose = AUC x (GFR + 25) IV in 250 mL Normal Saline over 30 minutes

Patients will receive intravenous doses of cisplatin 80 mg/m2 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks for a maximum of 6 cycles.

Alternatively, Carboplatin may be used instead of Cisplatin, Carbplatin AUC 5 DAY 1 only Dose = AUC x (GFR + 25) IV in 250 mL Normal Saline over 30 minutes

itraconazole 200 mg oral tablet daily, on a 21-day cycle.

Itraconazole 200 mg

intravenous doses of cisplatin 80 mg/m2 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks for a maximum of 6 cycles.

Alternatively, Carboplatin may be used instead of Cisplatin, Carbplatin AUC 5 DAY 1 only Dose = AUC x (GFR + 25) IV in 250 mL Normal Saline over 30 minutes

Chemotherapy

Asmaa WH Mohamed, Master

Amr Sh Tawfik, MD

Amr sh Tawfik, MD

Amr Shafik Tawfik, MD

Circulating levels of angiogenic factors have been correlated with aggressive tumor growth, prediction of metastasis and prognosis in a wide range of solid tumors, including non-small cell lung cancer.

Food and Drug Administration (FDA) approved Itraconazole as an anti-angiogenic agent including both Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), and inhibited phosphorylation of the primary angiogenic receptors for these factors in 2007 and also known as an inhibitor of Hedgehog signalling, AKT (protein kinase B)/mechanistic target of rapamycin (mTOR) signaling adding its induction of autophagic cell death function based on cellular and laboratory studies, and allowed its use in phase II trials in prostate, lung and skin cancer.

Itraconazole also interferes directly with mitochondrial Adenosine triphosphate (ATP) production, leading to the activation of the adenosine monophosphate (AMP) -activated protein kinase pathway and subsequent inhibition of mTOR pathway (Head et al., 2015).

Testing Itraconazole on experimental settings was associated also with tumor hypoxia, as proved by induction of tumor-specific expression of Hypoxia-inducible factor 1-alpha (HIF1α), as well as decreased tumor micro-vessel load

Lung cancer is the leading cause of cancer death in the United States

The American Cancer Society estimates lung cancer incidence in the United States for 2018 to be about 234,030 and about 154,050 deaths.

In 2012, GLOBOCAN estimated that 1.8 million people were diagnosed with lung cancer, accounting for about 13% of total cancer diagnoses.

Lung cancer death rates declined 45% from 1990 to 2015 among men and 19% from 2002 to 2015 among women. From 2005 to 2014, the rate of new lung cancer cases dropped by 2.5% per year in men and 1.2% per year in women, These differences reflect historical patterns in tobacco use, where women began smoking in large numbers many years later than men, and were slower to quit .

World Health Organization (WHO) divides lung cancer into 2 major classes based on its biology, therapy, and prognosis: non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

The NSCLC subtype accounts for 87% of lung cancer cases with its most common types to be adenocarcinomas where it is approximately 40% of lung cancers.

Different factors like age, Performance state, co-morbidities, histology, molecular pathology and last but not least; the patient's preferences should be taken into account along the treatment strategy after a multidisciplinary tumor board discussion, to allow adequate and careful evaluation of the available data to reach the most appropriate management plan and treatment modality for each patient individually (Ung et al., 2016).

Platinum doublets Chemotherapy should be considered in all stage IV and inoperable stage III NSCLC patients with epidermal growth factor receptor (EGFR) and Anaplastic lymphoma kinase (ALK) negative disease, without major comorbidities and Performance state 0-2.

Circulating levels of angiogenic factors have been correlated with aggressive tumor growth, prediction of metastasis and prognosis in a wide range of solid tumors, including non-small cell lung cancer.

Food and Drug Administration (FDA) approved Itraconazole as an anti-angiogenic agent including both Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), and inhibited phosphorylation of the primary angiogenic receptors for these factors in 2007 and also known as an inhibitor of Hedgehog signalling, AKT (protein kinase B)/mechanistic target of rapamycin (mTOR) signaling adding its induction of autophagic cell death function based on cellular and laboratory studies, and allowed its use in phase II trials in prostate, lung and skin cancer.

Itraconazole was proved to be among one of the most potent and selective inhibitors of endothelial cell proliferation.

Itraconazole also interferes directly with mitochondrial Adenosine triphosphate (ATP) production, leading to the activation of the adenosine monophosphate (AMP) -activated protein kinase pathway and subsequent inhibition of mTOR pathway (Head et al., 2015).

Testing Itraconazole on experimental settings was associated also with tumor hypoxia, as proved by induction of tumor-specific expression of Hypoxia-inducible factor 1-alpha (HIF1α), as well as decreased tumor micro-vessel load.

Taken together, these data support that Itraconazole may become a promising novel anti-angiogenic agent and In contrast to bevacizumab, Itraconazole is an inexpensive oral agent, currently available in a generic formulation and has been safely administered to thousands of patients as an antifungal drug with an excellent tolerance.

Interventional, Randomized, Controlled, Prospective, Open label, Phase II study.

Itraconazole in Non Small Cell Lung Cancer

The Effect of Itraconazole on the Clinical Outcomes of Patients With Advanced Non Small Cell Lung Cancer Receiving Platinum Based Chemotherapy

According to the sharing protocol of the official affliation

time from treatment initiation to either progression, death from any cause or lost to follow up.

time in months from time of diagnosis to death or date of last contact.

To compare radiological response of patients with advanced lung cancer receiving platinum bases chemotherapy combined with itraconazole to those receiving platinum based chemotherapy only after 3 and 6 cycles of chemotherapy.

Patient's quality of life will be assessed at baseline, after 3 cycles, and at the end of chemotherapy treatment using EORTC modules specific to lung cancer.

Incidence and severity will be evaluated using National Cancer Institute-Common Toxicity Criteria for adverse events (CTCAE V4.03).

Ain Shams University

Doctor

Carcinoma, Basal Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Basal Cell

Oral Itraconazole capsules, 200 mg, twice daily, for 60 days prior to surgery with curative intent.

Renato M Bakos, Ph. D.

Rodrigo P Pereira, M.D.

Renato M Bakos, Ph.D.

Patients with localized basocellular carcinoma of the skin, will receive oral Itraconazole, 200 mg twice daily, for 60 days, prior to curative intent surgery.

Patients with localized basocellular carcinoma of the skin, will receive oral Itraconazole, 200 mg once daily, for 60 days, before surgery with curative intent.

Tumor area regression will be measured through dermatologic evaluation and photographic documentation on baseline and at the end of the 60 day treatment period.

The activity of the Hedgehog pathway will be measured on tissue samples obtained at the time of diagnosis and at the time of curative intent surgery, through the measuring of the Ki67 index.

Use Of Oral Itraconazole In Patients With Locally Limited Basocellular Carcinoma Of Skin.

Evaluation Of The Treatment With Oral Itraconazole In Patients With Basocellular Carcinoma Of Skin, Locally Limited Disease.

tumor area response registered through dermatologic evaluation

Measured through the Ki67 index on pathological specimens at the beginning and at the end of treatment.

Hospital de Clinicas de Porto Alegre

Rare Diseases

Oculocerebral Syndrome With Hypopigmentation

Pharmaceutical Solutions

Rifampin

Trichostatin A

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Subjects will receive a single dose of GSK525762 10 mg on Day 1 followed by 200 mg Itraconazole two times a day (BID) on Day 3. On Day 4 to Day 6 inclusive subjects will receive a single dose of itraconazole 200 mg in the morning. On Day 7 subjects will receive a single dose of GSK525762 5 mg one hour after receiving 200 mg dose of itraconazole. On day 8 and 9 subjects will receive a single dose of 200 mg itraconazole in the morning.

Subjects will receive a single dose of GSK525762 10 mg on day 1 followed by 200 mg Itraconazole BID on day 3. On day 4 to day 6 inclusive subjects will receive a single dose of itraconazole 200 mg in the morning. On day 7 subjects will receive a single dose of GSK525762 5 mg or GSK525762 10 mg one hour after receiving 200 mg dose of itraconazole. On day 8 and 9 subjects will receive a single dose of 200 mg itraconazole in the morning.

Subjects will receive a single dose of GSK525762 10 mg on day 1. From day 3 to 17 inclusive, subjects will receive a single dose of 600 mg rifampicin in fasting conditions. On day 18 subjects will receive single dose of GSK525762 either 20 or 30 mg along with 600 mg dose of rifampicin. On day 19 subjects will receive a single dose of rifampicin 600 mg.

GSK525762 is available as a film-coated, white to slightly colored round, biconvex tablets with no markings. It is available in unit dose strength of 5 mg.

GSK525762 Besylate Tablets

Itraconazole is available as a clear yellow solution with unit dose strength of 10 mg/mL

Rifampicin is available as a red capsule with printed markings and as a 300 mg unit dose strength.

Rifampicin 300 mg

GSK Clinical Trials

This is a Phase I, single center, two-part, randomized, open label, cross-over study. Part 1 of this study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of itraconazole, a known strong inhibitor of Cytochrome P450 3A4 (CYP3A4) and a Para-glycoprotein (Pgp) inhibitor. Part 1 will consist of 2 Cohorts with preliminary PK and safety data obtained from Cohort 1 informing Cohort 2. Part 2 (one Cohort) of the study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of rifampicin, a known potent inducer of CYP3A4. In vitro inhibition data indicate CYP3A4 may be the major route of clearance for GSK525762 and co-administration of drug therapies which modulate CYP3A4 (i.e.CYP3A4 inhibitors and inducers) is likely to alter the exposure of GSK525762 (i.e. increase or decrease exposure, respectively). The data generated from this current study to justify exclusion criteria on concomitant medications which affect CYP3A4 or Pgp and also inform potential dose modification in case of co-administration with medication affecting CYP3A4 activity. All subjects will undergo a screening visit within 28 days of the first dose of study drug followed by one treatment period and a follow-up visit 7-10 days after the last dose of GSK525762. Subjects in Part 1 will participate in the study for up to 45 days and subjects in Part 2 will participate for up to 56 days.

A Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics (PK) of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential

A Single Center, Two Part, Randomized, Open Label Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential

IPD for this study is available via the Clinical Study Data Request site.

An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze platelet counts, red blood cells (RBC) count, white blood cells (WBC) count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze blood urea nitrogen (BUN), creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP) levels, gamma-glutamyltransferase (GGT), total and direct bilirubin, total carbon dioxide, total protein and albumin

Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.

ECGs will be measured in supine position after 5 minutes rest using a standard 12-lead ECG machine that automatically calculates the HR and measures PR, QRS, QT and QTcF intervals.

Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest.

Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest.

An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE.

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up to analyze platelet counts, RBC count, WBC count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze BUN, creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, AST/SGOT, ALT/SGPT, ALP levels, GGT, total and direct bilirubin, total carbon dioxide, total protein and albumin

Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.

On Day 1 and Day 18 ECGs will be measured in supine position after 5 minutes rest at screening, pre-dose, 1 hr, 24 hr and 48 hrs.

GlaxoSmithKline

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Prostatic Neoplasms

Disease Progression

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Itraconazole, 200 mg, by mouth, once daily (200 mg total daily dose)

Itraconazole, 300 mg, by mouth, twice daily (600 mg total daily dose)

Itraconazole 300mg

Michael A Carducci, MD

This research is being done to test an investigational drug, called itraconazole, in the treatment of prostate cancer. Itraconazole is approved by the Food and Drug Administration (FDA) for the treatment of various fungal infections such as fingernail/toenail infections and other more serious fungal infections. The word "investigational" means that itraconazole is not approved for use in people with cancer. However, the FDA is allowing the use of itraconazole in this research study. Itraconazole has been shown to have activity against cancer (including prostate cancer) in the laboratory, but has not been tested against cancer in humans.

The purpose of this study is to find out:

* If itraconazole is safe when given at two different doses
* How itraconazole affects prostate specific antigen (PSA): a blood test that measures substances released by prostate cancer
* Whether itraconazole can delay further prostate cancer growth and spread
* How itraconazole affects other markers of prostate cancer

Itraconazole is an oral, generic, and commercially available antifungal drug with a long safety record when used at doses ranging from 200 to 600 mg daily.

Itraconazole has been shown in cellular and animal models to be a potent angiogenesis inhibitor as well as a Hedgehog pathway antagonist; both pathways are considered important in prostate cancer. Itraconazole has not previously been tested as an antineoplastic agent, but given its well-established safety profile, the gap between further preclinical studies and human clinical trials can be narrowed to accelerate development of this agent as a putative anticancer drug. The investigators hypothesize that itraconazole will prevent PSA progression in a significant proportion of men with metastatic CRPC and that it will have an acceptable safety profile at both doses. Itraconazole may ultimately delay the need for chemotherapy in these men.

A Two-dose Level Clinical Trial of Itraconazole in Patients With Metastatic Prostate Cancer Who Have Had Disease Progression While on Hormonal Therapy

A Randomized Phase II Clinical Trial of Two Dose-levels of Itraconazole in Patients With Metastatic Castration-resistant Prostate Cancer

To Determine the Proportion of Patients With Metastatic CRPC Who do Not Have Prostate Specific Antigen (PSA) Progression After 24 Weeks of Therapy. "PSA progression" is defined as a 25% increase in PSA over baseline \[or nadir (lowest)\] and an increase in absolute PSA level by at least 2 ng/mL, both confirmed by a second value at least 4 weeks later.

Will be reported as the percentage of men with ≥ 50% PSA reduction from baseline.

Memorial Sloan Kettering Cancer Center

Johns Hopkins University

Itraconazole, 200 mg, by mouth, once daily (200 mg total daily dose)

Itraconazole 200 mg: Itraconazole, 200 mg, by mouth, once daily (200 mg total daily dose)

Low Dose

Itraconazole, 300 mg, by mouth, twice daily (600 mg total daily dose)

Itraconazole 300mg: Itraconazole, 300 mg, by mouth, twice daily (600 mg total daily dose)

High Dose

Total

Age, Continuous

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Dr. Michael Carducci

Low Dose Itraconazole

High Dose Itraconazole

Based on how many participants were evaluable for the study primary endpoint

To Determine the Proportion of Patients With Metastatic CRPC Who do Not Have Prostate Specific Antigen (PSA) Progression After 24 Weeks of Therapy With One of Two Dose-levels of Itraconazole: 200 mg or 600 mg Daily.

One subject in the high dose arm was not evaluable on account of subject discontinuing study drug during cycle 1 due to clinical progression.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Itraconazole in Non Small Cell Lung Cancer	NCT03664115	Lung Cancer	Itraconazole 20... Chemotherapy	18 Years -	Ain Shams University
Use Of Oral Itraconazole In Patients With Locally Limited Basocellular Carcinoma Of Skin.	NCT03972748	Basal Cell Carc... Hedgehog Pathwa...	Itraconazole 20...	18 Years -	Hospital de Clinicas de Porto Alegre
A Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics (PK) of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential	NCT02706535	Drug Interactio... Neoplasms	GSK525762 Besyl... Itraconazole 20... Rifampicin 300 ...	18 Years - 70 Years	GlaxoSmithKline
A Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics (PK) of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential	NCT02706535	Drug Interactio... Neoplasms	GSK525762 Besyl... Itraconazole 20... Rifampicin 300 ...	18 Years - 70 Years	GlaxoSmithKline
A Two-dose Level Clinical Trial of Itraconazole in Patients With Metastatic Prostate Cancer Who Have Had Disease Progression While on Hormonal Therapy	NCT00887458	Prostate Cancer	Itraconazole 20... Itraconazole 30...	18 Years -	Johns Hopkins University
A Two-dose Level Clinical Trial of Itraconazole in Patients With Metastatic Prostate Cancer Who Have Had Disease Progression While on Hormonal Therapy	NCT00887458	Prostate Cancer	Itraconazole 20... Itraconazole 30...	18 Years -	Johns Hopkins University

Spots Global Cancer Trial Database for itraconazole 200 mg