Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Liver Failure

Hepatic Insufficiency

Neoplastic Processes

Liver Diseases

Gastrointestinal Diseases

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Dexamethasone acetate

Trabectedin

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Antineoplastic Agents, Alkylating

Alkylating Agents

Control group Trabectedin 1.3 mg/m\^2 i.v.will be administered on Day 1. Dexamethasone will be administered 30 minutes prior to trabectedin.

Hepatic dysfunction group Trabectedin 0.58 mg/m\^2 (or adjusted dose) i.v. will be administered on Day 1. Dexamethasone will be administered 30 minutes prior to trabectedin.

Trabectedin 0.58 or 1.3 mg/m\^2 (or adjusted dose) i.v. will be administered on Day 1.

Dexamethasone will be administered as 20 mg/m\^2, 30 minutes prior to trabectedin.

Janssen Research & Development, LLC C. Clinical Trial

The purpose of this study is to characterize the pharmacokinetics (blood levels) of trabectedin after administration to patients with advanced malignancies and hepatic (liver) dysfunction.

This is an open-label (patients will know the names of study drugs they receive), single-dose, study that will examine the pharmacokinetics (blood levels) and assess survival and safety of trabectedin in patients with advanced malignancies who either have hepatic (liver) dysfunction or do not have hepatic dysfunction (patients enrolled without hepatic dysfunction will be referred to as the control group). Trabectedin is a drug being developed to treat patients with cancer that will be administered intravenously (i.v.) through a catheter (tube) into a central vein. In addition, dexamethasone, a drug used to prevent nausea and vomiting in chemotherapy patients that may have protective effects on the liver, will be administered to patients before the administration of trabectedin. Patients who complete the treatment phase of the study who in the opinion of the investigator would derive an overall clinical benefit from further treatment with trabectedin will have the opportunity to continue treatment with trabectedin in the optional extension phase. The dose and schedule of trabectedin may be modified by the treating physician in the optional extension phase to be more appropriate for the type of malignancy being treated. A single dose of trabectedin (1.3 mg/m2 in patients in the control group and 0.58 mg/m2 in patients with hepatic dysfunction) will be administered by i.v.infusion over a 3-hour period. The dose of trabectedin may be adjusted if necessary for patients with hepatic dysfunction subsequently enrolled in the study. All patients will be administered dexamethasone 20 mg i.v. (or equivalent) approximately 30 minutes before the administration of trabectedin.

A Pharmacokinetic Study of Trabectedin in Patients With Advanced Malignancies and Hepatic Dysfunction

An Open-Label, Multicenter, Pharmacokinetic Study of Trabectedin in Subjects With Advanced Malignancies and Hepatic Dysfunction

PharmaMar

Janssen Research & Development, LLC

Anti-Infective Agents

Rifampin

Sequence 2 Cycle 1: Trabectedin 1.3 mg/m2 i.v. on Day 1 followed by 2 rifampin 300 mg capsules once daily on Days 24-28 followed by Cycle 2 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 of Cycle 2. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.

Sequence 1 Cycle 1: 2 rifampin 300 mg capsules 1x daily for 5 days followed by 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 followed 28 days later by cycle 2 trabectedin 1.3 mg/m2 i.v. on Day 1. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.

Cycle 1: 2 rifampin 300 mg capsules 1x daily for 5 days followed by 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 followed 28 days later by cycle 2 trabectedin 1.3 mg/m2 i.v. on Day 1. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.

Sequence 1

Cycle 1: Trabectedin 1.3 mg/m2 i.v. on Day 1 followed by 2 rifampin 300 mg capsules once daily on Days 24-28 followed by Cycle 2, 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 of Cycle 2. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.

Sequence 2

The purpose of this study is to evaluate the potential effects of rifampin on blood levels of trabectedin after administration to patients with advanced malignancies.

This is an open-label study (patients will know the names of the study drugs they receive), randomized (patients will be assigned 1 of 2 treatment sequences by chance) that is designed to examine the pharmacokinetics (blood levels) and to assess survival and safety of trabectedin when coadministered with rifampin in patients with advanced malignancies. Study drugs include trabectedin and rifampin. Trabectedin is a drug being developed to treat patients with cancer that will be administered intravenously (i.v.) through a catheter (tube) into a central vein over a period of 3 hours once every 28 days with and without rifampin. Rifampin is an antibiotic that may interfere with the action of trabectedin that will be taken orally (by mouth) as capsules. In addition, dexamethasone, a drug used to prevent nausea and vomiting in chemotherapy patients that may have protective effects on the liver, will be administered to patients before the administration of trabectedin. In the study, 3 patients will initially be randomized sequentially to Treatment Sequence 1 or Treatment Sequence 2 to evaluate safety. If the safety and pharmacokinetic data collected from these 3 patients is deemed acceptable, additional patients will be randomized to 1 of 2 treatment sequences. Patients who complete the treatment phase of the study or who are discontinued due to rifampin toxicity, and who in the opinion of the investigator would derive an overall clinical benefit from further treatment with trabectedin, will have the opportunity to continue treatment with trabectedin in the optional extension phase. The dose and schedule of trabectedin may be modified by the treating physician in the optional extension phase to be more appropriate for the type of malignancy being treated. Patients will receive 20 mg of i.v. dexamethasone (or its equivalent) prior to trabectedin administration in all cycles. Patients randomized to Sequence 1 will receive rifampin 600mg 1X daily(6 doses)+trabectedin 1.3 mg/m2 i.v. followed 28 days later by trabectedin 1.3 mg/m2 i.v. Patients randomized to Sequence 2 will receive trabectedin 1.3 mg/m2 i.v. followed 28 days later by rifampin 600mg 1X daily(6 doses)+trabectedin 1.3mg/m2 i.v. Dexamethasone 20 mg i.v., or equivalent will be administered 30 minutes prior to trabectedin administration.

A Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies

An Open-Label, Multicenter Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Subjects With Advanced Malignancies

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Recurrence

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Camurati-Engelmann Disease

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Mitogens

Investigational study drug, administered intravenously every 2 weeks until disease progression or unacceptable toxicity.

PF-03446962 will be administered in 1hr intravenously at a dose of 10 mg/Kg on day 1, then every 2 weeks until the evidence of disease progression or onset of unacceptable toxicity.

PF03446962

Andrea Necchi, MD

Filippo G De Braud, MD

Alessandro M Gianni, MD

Salvage chemotherapy for advanced urothelial cancer (UC) yields suboptimal response rates of 15-40%, a median progression-free survival of 2-4 months and a median overall survival of 6 months. A rationale for targeting angiogenesis in UC is supported by preclinical evidences and early signals of clinical activity of anti-VEGF TKI as demonstrated by our group with the use of pazopanib.

Despite this activity, progression inevitably occurs and mechanisms determining resistance to conventional anti-angiogenic agents are under investigation.

PF-03446962 (Pfizer Inc) is a novel fully human monoclonal antibody (mAb) against ALK1 with dose-dependent antiangiogenic activity as demonstrated in nonclinical studies in a chimera mouse model bearing human tumor xenograft. The investigators suggest that PF-03446962 may increase current results for patients with advanced urothelial cancer failing upfront chemotherapy due to its mechanisms of action. Due to the lack of reliable and reproducible predictors of response as well as of imaging tools to assess tumor response, the trial will provide incorporation of 18FDG-PET/CT and contrast-enhanced ultrasound to stage and evaluate response of urothelial cancers, together with standard imaging modalities (RECIST criteria). Blood and tissue samples will be collected for translational purposes.

This is an open-label, single arm, non randomised, phase II proof-of-concept study of the monoclonal antibody against TGF-beta receptor ALK1 (PF03446962) for patients with urothelial cancer relapsing/progressing after first line chemotherapy.

The study is planned according to Simon's Optimal two-stage design. The primary endpoint is the proportion of patients who are progression-free at 2-months. A 2-month PFS rate of 50% is not promising, while a 70% rate will be promising. In stage 1, 21 evaluable patients will be accrued. If 12 patients at least will be progression-free at 2 months, enrollment will be extended to the 2nd stage for further 24 patients. If, out of the total of 45 patients, 27 at least will be progression-free at 2 months, treatment will be declared worthy for further investigations.

Maximum overall accrual is 45 patients. Type I and type II error rates will be set both at the 10% level.

PF-03446962 in Relapsed or Refractory Urothelial Cancer

Phase II Study of the Fully Human Monoclonal Antibody Against Transforming Growth Factor-beta (TGFβ) Receptor ALK1 (PF-03446962) in Relapsed or Refractory Urothelial Cancer (UC) Failing First-line Treatment.

Progression-free survival (PFS) is defined as the interval from the first dose of study drug to the date of the first documented disease progression or death for any reason, with censoring at the date of last contact for alive patients. A patient who has not progressed or died by the date of the analysis cut-off or when the patient received any further anticancer therapy would have the PFS censored at the time of last adequate tumor assessment before either cut-off date or the commencement of further anticancer therapy date, respectively.

Incidence of adverse events (AEs), defined as any new untoward medical conditions occurrence or worsening of a pre-existing medical condition that does not necessarily have a causal relationship with the study drugs. AEs will be graded according to the NCI-CTC version 4.03 and the relationship of each AEs to study drugs will be assessed by the investigator.

Assessment of response-rate by RECIST v1.1 criteria. RR (%) = CR + PR

Overall Survival (OS) will be calculated as the interval from the date of the first dose of study drug to the date of death for any cause, with censoring at the date of last contact for patients alive. The Kaplan-Meier method will be used to estimate the OS curve (median and 95% confidence interval).

Tissue will be examined in terms of genotyping by high-resolution array comparative genome hybridization (aCGH) and expression of VEGFR, PDGFR, KIT, EGFR, HER2/neu, PTEN on tissue microarrays (TMAs).

Circulating VEGF, soluble VEGFR-1, 2 and -3, soluble c-Kit, IL-6, 8, 12 and HGF will be evaluated by using multiplex ELISA plates.

Circulating tumor cells will be evaluated as a potential response biomarkers.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Principal Investigator

Ketoconazole

Clotrimazole

Miconazole

Antifungal Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Cytochrome P-450 CYP3A Inhibitors

Patients will receive trabectedin+ketoconazole followed by trabectedin alone. Each cycle will be will be separated by 21 days. Patients will receive 6 total consecutive doses of ketoconazole. Dexamethasone or equivalent steroid will be administered before trabectedin in each cycle.

Patients will receive 1 of 2 treatment sequences; Sequence 1: trabectedin+ketoconazole followed by trabectedin alone or Sequence 2: trabectedin alone followed by trabectedin+ketoconazole. Each cycle will be separated by 21 days. Patients will receive 15 total consecutive doses of ketoconazole. Dexamethasone or equivalent steroid will be administered before trabectedin in each cycle.

Patients will receive trabectedin 1.3 mg/m2 when given alone and 0.2mg/m2 when given with ketoconazole, intravenously (into a vein) for 3-hour.

Patients will receive ketoconazole 1 X 200 mg tablet, two times a day, orally (by mouth)

Patients will receive dexamethasone 20 mg or equivalent steroid intravenously, 30 minutes before trabectedin in each cycle.

Dexamethasone or equivalent steroid

The purpose of this study is to evaluate the potential effects of ketoconazole on blood levels of trabectedin after administration to patients with advanced malignancies.

This is an open-label study (patients will know the names of the study drugs they receive), randomized (patients will be assigned 1 of 2 treatment sequences by chance) that is designed to examine the pharmacokinetics (blood levels) of trabectedin when coadministered with ketoconazole in patients with advanced malignancies. Study drugs include trabectedin and ketoconazole. Trabectedin is a drug being developed to treat patients with cancer that will be administered intravenously (IV) through a catheter (tube) into a central vein over a period of 3 hours once every 21 days with and without ketoconazole. Ketoconazole is an antifungal agent taken as tablets orally (by mouth), that may interfere with the metabolism of trabectedin. In addition, dexamethasone or equivalent steroid, a drug used to prevent nausea and vomiting in chemotherapy patients that may have protective effects on the liver, will be administered to patients before the administration of trabectedin in each treatment cycle. This study will consist of 2 parts, Part A and B. In Part A, trabectedin+ketoconazole followed by trabectedin alone will be administered with ketoconazole to 4 patients to evaluate safety. If the safety and PK data collected in Part A is deemed acceptable, enrollment in Part B of the study will begin and patients will receive 1 of 2 treatment sequences of trabectedin and ketoconazole. Patients in Part A and Part B who complete the treatment phase of the study or who are discontinued due to ketoconazole toxicity, and who in the opinion of the investigator would derive an overall clinical benefit from further treatment with trabectedin will have the opportunity to continue treatment with trabectedin in the optional extension phase. The dose and schedule of trabectedin may be modified by the treating physician in the optional extension phase to be more appropriate for the type of malignancy being treated. Patients will receive 20 mg of IV dexamethasone or equivalent steroid prior to trabectedin administration in all cycles. Part A consists of ketoconazole 200mg 2x daily+trabectedin 0.2mg/m2 i.v. followed 21 days later by trabectedin 1.3mg/m2 i.v. Part B consists of Sequence 1 (ketoconazole 200mg 2x daily+trabectedin 0.2mg/m2 i.v.followed 21 days later by trabectedin 1.3mg/m2 i.v.) and Sequence 2 (trabectedin 1.3mg/m2 i.v followed 21 days later by ketoconazole 200mg 2x daily+trabectedin 0.2mg/m2 i.v). Dexamethasone 20mg i.v. or equivalent, will be given 30 minutes before trabectedin in each cycle.

A Study to Assess the Potential Effects of Ketoconazole on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies

An Open-Label, Multicenter Study to Assess the Potential Effects of Ketoconazole on the Pharmacokinetics of Trabectedin in Subjects With Advanced Malignancies

This will be measured when ketoconazole will be administered.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Pharmacokinetic Study of Trabectedin in Patients With Advanced Malignancies and Hepatic Dysfunction	NCT01273493	Neoplasm Metast... Hepatic Insuffi...	Trabectedin Dexamethasone	18 Years - 70 Years	Janssen Research & Development, LLC
A Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies	NCT01273480	Neoplasm Metast...	Sequence 1 Sequence 2 Sequence 1 Sequence 2	18 Years -	Janssen Research & Development, LLC
PF-03446962 in Relapsed or Refractory Urothelial Cancer	NCT01620970	Transitional Ce...	PF03446962	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
A Study to Assess the Potential Effects of Ketoconazole on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies	NCT01267084	Neoplasm Metast...	Trabectedin Ketoconazole Dexamethasone o...	18 Years -	Janssen Research & Development, LLC
PF-03446962 in Relapsed or Refractory Urothelial Cancer	NCT01620970	Transitional Ce...	PF03446962	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
A Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies	NCT01273480	Neoplasm Metast...	Sequence 1 Sequence 2 Sequence 1 Sequence 2	18 Years -	Janssen Research & Development, LLC

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