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

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

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

Study Overview

• Status: Completed
• Conditions: Medical Oncology
• Intervention / Treatment: Drug: Anetumab ravtansine (BAY94-9343); Drug: Itraconazole

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Cancer & Haematology Centre
  • Victoria
    • Richmond, Victoria, Australia, 3122
      • Epworth Healthcare
• Belgium
  • Bruxelles - Brussel, Belgium, 1200
    • CU Saint-Luc/UZ St-Luc
  • Gent, Belgium, 9000
    • UZ Gent
• France
  • Creteil, France, 94010
    • Hôpital Henri Mondor
  • Dijon, France, 21079
    • Centre Georges Francois Leclerc Dijon
  • Marseille, France, 13005
    • Hôpital de la Timone - Marseille
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Nederlands Kanker Instituut
  • Amsterdam, Netherlands, 1081 HV
    • VUmc
  • Nijmegen, Netherlands, 6525 GA
    • Universitair Medisch Centrum St. Radboud
• Spain
  • Barcelona, Spain, 08035
    • Ciutat Sanitaria i Universitaria de la Vall d'Hebron
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz (Clinica de la Concepcion)
  • Málaga, Spain, 29010
    • Hospital Virgen de la Victoria
• United States
  • California
    • Santa Monica, California, United States, 90404
      • UCLA-Santa Monica Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44106-2602
      • University Hospitals Cleveland Medical Center
  • Texas
    • Dallas, Texas, United States, 75230
      • Mary Crowley Medical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Anetumab ravtansine; The evaluation of multiple ECG parameters and the drug-drug interaction (DDI) potential of anetumab ravtansine parameters when administered alone and together with itraconazole 100 mg oral capsules will be conducted in 2 sequential parts. On Cycle 1 Day 1, anetumab ravtansine will be given alone at a dose of 6.5 mg/kg in Part 1 and Part 2. On Cycle 2 Day 1, anetumab ravtansine will be given together with itraconazole at a dose of 0.6 mg/kg in Part 1, and at a dose of 6.5 mg/kg (planned) in Part 2.

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); Drug: 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PR interval duration	ECG evaluation	Up to 2 months per patient
QRS interval duration	ECG evaluation	Up to 2 months per patient
QT interval duration	ECG evaluation	Up to 2 months per patient
Abnormal T/U waves	ECG evaluation	Up to 2 months per patient
Heart rate	ECG evaluation	Up to 2 months per patient
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
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
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
QTcF (QT interval, corrected for heart rate according to Fridericia's formula) interval duration	ECG evaluation	Up to 2 months per patient
QTcP (QT interval, corrected for heart rate using a population-specific correction) interval duration	ECG evaluation	Up to 2 months per patient

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of serious adverse events	Up to 6 months per patient
Incidence of non-serious adverse events	Up to 6 months per patient
Incidence of positive anti-drug antibody titer	Up to 6 months per patient
Incidence of neutralizing antibody titers	Up to 6 months per patient
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
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

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2016
• Primary Completion (Actual): June 27, 2018
• Study Completion (Actual): August 5, 2019

Study Registration Dates

• First Submitted: June 27, 2016
• First Submitted That Met QC Criteria: July 5, 2016
• First Posted (Estimate): July 6, 2016

Study Record Updates

• Last Update Posted (Actual): July 31, 2020
• Last Update Submitted That Met QC Criteria: July 29, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Solid tumors; Phase 1; Itraconazole; Mesothelin; PK DDI; ECG thorough QTC
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Phytogenic; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Maytansine; Itraconazole
• Other Study ID Numbers: 18329; 2017-001978-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No