Thorough ECG (Electrocardiogram) and Drug Interaction Study With Anetumab Ravtansine and Itraconazole

Medical Oncology Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02824042
• Other study ID #: 18329
• Secondary ID: 2017-001978-42
• Status: Completed
• Phase: Phase 1
• Start date: September 7, 2016
• Est. completion date: August 5, 2019

Study information

• Verified date: July 2020
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: August 5, 2019
• Est. primary completion date: June 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Medical Oncology
• Neoplasms

Intervention

Drug:
• Anetumab ravtansine (BAY94-9343)
Anetumab ravtansine given IV On Day 1 of each 21-day treatment cycle Part 1: Cycle 1 Day 1: 6.5 mg/kg of body weight (BW) Cycle 2 Day 1: 0.6 mg/kg BW Part 2: Cycle 1 Day 1: 6.5 mg/kg BW Cycle 2 Day 1: 6.5 mg/kg BW (planned dose) Continuous treatment: Cycles =3 Day 1: 6.5 mg/kg BW once every 3 weeks (Q3W)
• Itraconazole
Itraconazole 100 mg oral capsules given by mouth Cycle 1 (Day 18): 200 mg twice daily (BID) (Days 19 - 21): 200 mg once daily (QD) Cycle 2 (Days 1-8): 200 mg QD 12 days in total (Part 1 or Part 2)

Locations

Country	Name	City	State
Australia	Blacktown Cancer & Haematology Centre	Blacktown	New South Wales
Australia	Epworth HealthCare	Richmond	Victoria
Belgium	CU Saint-Luc/UZ St-Luc	Bruxelles - Brussel
Belgium	UZ Gent	Gent
France	Hôpital Henri Mondor	Creteil
France	Centre Georges Francois Leclerc Dijon	Dijon
France	Hôpital de la Timone - Marseille	Marseille
Netherlands	Nederlands Kanker Instituut	Amsterdam
Netherlands	VUmc	Amsterdam
Netherlands	Universitair Medisch Centrum St. Radboud	Nijmegen
Spain	Ciutat Sanitària i Universitaria de la Vall d'Hebron	Barcelona
Spain	Fundacion Jimenez Diaz (Clinica de la Concepcion)	Madrid
Spain	Hospital Virgen de la Victoria	Málaga
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Mary Crowley Medical Research Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	UCLA-Santa Monica Medical Center	Santa Monica	California

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  France,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PR interval duration	ECG evaluation	Up to 2 months per patient
Primary	QRS interval duration	ECG evaluation	Up to 2 months per patient
Primary	QT interval duration	ECG evaluation	Up to 2 months per patient
Primary	Abnormal T/U waves	ECG evaluation	Up to 2 months per patient
Primary	Heart rate	ECG evaluation	Up to 2 months per patient
Primary	Cycle 1+2 AUC (area under the plasma concentration vs. time curve from zero to infinity after single (first) dose) of BAY94-9343 analytes		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
Primary	Cycle 1+2 AUC(0-tlast) (AUC from time zero to the last data point > LLOQ [lower limit of quantification]) of BAY94-9343 analytes		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
Primary	Cycle 1+2 Cmax (maximum drug concentration in plasma after the first dose administration) of BAY94-9343 analytes		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
Primary	QTcF (QT interval, corrected for heart rate according to Fridericia's formula) interval duration	ECG evaluation	Up to 2 months per patient
Primary	QTcP (QT interval, corrected for heart rate using a population-specific correction) interval duration	ECG evaluation	Up to 2 months per patient
Secondary	Incidence of serious adverse events		Up to 6 months per patient
Secondary	Incidence of non-serious adverse events		Up to 6 months per patient
Secondary	Incidence of positive anti-drug antibody titer		Up to 6 months per patient
Secondary	Incidence of neutralizing antibody titers		Up to 6 months per patient
Secondary	Cycle 3 Cmax,md (Cmax after multiple-dose administration) of BAY94-9343 analytes		At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 168h, 336h and 504h between 43rd and 64th days of the study
Secondary	Cycle 3 AUC(0-tlast)md (AUC(0-tlast) after multiple-dose administration) of BAY94-9343 analytes		At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 168h, 336h and 504h between 43rd and 64th days of the study

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