Clinical trial NCT02824042: Thorough ECG (Electrocardiogram) and Drug Interaction Study With Anetumab Ravtansine and Itraconazole
Official title: An Open Label, Phase I Study to Assess the Effect of Itraconazole (CYP3A4 and P-gp Inhibitor) on the Pharmacokinetics of Anetumab Ravtansine and to Assess the ECG Effects, Safety and Immunogenicity of Anetumab Ravtansine Given as a Single Agent and Together With Itraconazole in Subjects With Mesothelin-expressing Advanced Solid Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Medical Oncology
Keywords: Phase 1
Solid tumors
Mesothelin
Itraconazole
PK DDI
ECG thorough QTC
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2016-07-06
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Characterize the safety, tolerability, ECG effects, pharmacokinetics and immunogenicity of anetumab ravtansine given as single agent and after inhibition of CYP3A4 and P-gp by concomitant administration of itraconazole in subjects with mesothelin-expressing advanced solid cancers


Eligibility criteria: Inclusion Criteria:

* Subjects must have histologically confirmed, locally advanced or metastatic solid cancers of the following histological types:

  1. predominantly epithelial (≥50% tumor component) pleural or peritoneal mesothelioma
  2. epithelial ovarian cancer (fallopian tube and primary peritoneal cancers are eligible)
  3. adenocarcinoma of the pancreas,
  4. triple-negative adenocarcinoma of the breast
  5. non-small-cell adenocarcinoma of the lung
  6. gastric cancer (including gastro-esophageal junction)
  7. colon cancer
  8. cholangiocarcinoma
  9. Thymic carcinoma
* Subjects must have no standard therapy available, or have actively refused standard therapy
* Subjects must provide samples of archival tumor tissue collected and submitted anytime during the study
* Subjects must have a life expectancy of at least 12 weeks
* Subjects must have ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1
* Subjects must have adequate bone marrow, renal and hepatic function and coagulation
* Subjects must have normal or clinically insignificant ECG at screening
* Women of reproductive potential must have a negative serum pregnancy test obtained within 3 days before the start of anetumab ravtansine
* Women of childbearing potential and fertile men must agree to use adequate contraception when sexually active. This applies from the time period between signing of the informed consent until at least 6 months after the last administration of the last study drug. Male patients with a female partner of childbearing potential must use a condom and ensure that an additional form of contraception is also used during treatment and until 6 months after last study drug administration.

Exclusion Criteria:

* Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except cervical carcinoma in situ, treated basal cell carcinoma, superficial noninvasive bladder tumors or any previous cancer curatively treated ≥ 3 years before the start of anetumab ravtansine
* New or progressive brain or meningeal or spinal metastases
* Corneal epitheliopathy or any eye disorder that may predispose the subjects to drug-induced corneal epitheliopathy, or may interfere with diagnosis of treatment-emergent corneal epitheliopathy at the ophthalmologist's or the investigator's discretion
* History or current evidence of

  * biliary cirrhosis
  * malignant biliary obstruction unless the bile flow to the gastrointestinal tract is maintained by a fully operational biliary stent
  * CTCAE (Common Terminology Criteria for Adverse Events) Grade ≥2 bleeding disorder within 4 weeks before the start of anetumab ravtansine
  * uncontrolled cardiovascular disease or uncontrolled hypertension
  * Long QT Syndrome
  * HIV infection
  * Hepatitis B or C infection
* Had a major surgery or significant trauma within 4 weeks before the start of anetumab ravtansine
* Had solid organ or bone marrow transplantation
* Have LVEF (left ventricular ejection fraction) \<50% at screening
* Have QTc \>450 ms or heart rate ≥100 bpm or ≤45 bpm at screening
* Poor CYP2D6 metabolizers based on the screening test for genetic polymorphisms in CYP2D6 metabolizing capacity

Primary outcomes:
measure: PR interval duration
timeFrame: Up to 2 months per patient
measure: QRS interval duration
timeFrame: Up to 2 months per patient
measure: QT interval duration
timeFrame: Up to 2 months per patient
measure: Abnormal T/U waves
timeFrame: Up to 2 months per patient
measure: Heart rate
timeFrame: Up to 2 months per patient
measure: Cycle 1+2 AUC (area under the plasma concentration vs. time curve from zero to infinity after single (first) dose) of BAY94-9343 analytes
timeFrame: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 10h, 24h, 48h, 168h, 336h, 480h and 504h after each dose during first 42 days of the study
measure: Cycle 1+2 AUC(0-tlast) (AUC from time zero to the last data point > LLOQ [lower limit of quantification]) of BAY94-9343 analytes
timeFrame: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 10h, 24h, 48h, 168h, 336h, 480h and 504h after each dose during first 42 days of the study
measure: Cycle 1+2 Cmax (maximum drug concentration in plasma after the first dose administration) of BAY94-9343 analytes
timeFrame: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 10h, 24h, 48h, 168h, 336h, 480h and 504h after each dose during first 42 days of the study
measure: QTcF (QT interval, corrected for heart rate according to Fridericia's formula) interval duration
timeFrame: Up to 2 months per patient
measure: QTcP (QT interval, corrected for heart rate using a population-specific correction) interval duration
timeFrame: Up to 2 months per patient
Secondary outcomes:
measure: Incidence of serious adverse events
timeFrame: Up to 6 months per patient
measure: Incidence of non-serious adverse events
timeFrame: Up to 6 months per patient
measure: Incidence of positive anti-drug antibody titer
timeFrame: Up to 6 months per patient
measure: Incidence of neutralizing antibody titers
timeFrame: Up to 6 months per patient
measure: Cycle 3 Cmax,md (Cmax after multiple-dose administration) of BAY94-9343 analytes
timeFrame: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 168h, 336h and 504h between 43rd and 64th days of the study
measure: Cycle 3 AUC(0-tlast)md (AUC(0-tlast) after multiple-dose administration) of BAY94-9343 analytes
timeFrame: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 168h, 336h and 504h between 43rd and 64th days of the study
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA-Santa Monica Medical Center
state: California
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Dallas
country: United States
facility: Mary Crowley Medical Research Center
state: Texas
city: Blacktown
country: Australia
facility: Blacktown Cancer & Haematology Centre
state: New South Wales
city: Richmond
country: Australia
facility: Epworth HealthCare
state: Victoria
city: Bruxelles - Brussel
country: Belgium
facility: CU Saint-Luc/UZ St-Luc
city: Gent
country: Belgium
facility: UZ Gent
city: Creteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Centre Georges Francois Leclerc Dijon
city: Marseille
country: France
facility: Hôpital de la Timone - Marseille
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut
city: Amsterdam
country: Netherlands
facility: VUmc
city: Nijmegen
country: Netherlands
facility: Universitair Medisch Centrum St. Radboud
city: Barcelona
country: Spain
facility: Ciutat Sanitària i Universitaria de la Vall d'Hebron
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz (Clinica de la Concepcion)
city: Málaga
country: Spain
facility: Hospital Virgen de la Victoria
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References: