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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Medical Oncology

Intervention / Treatment
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* Drug: Anetumab ravtansine (BAY94-9343)
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically confirmed, locally advanced or metastatic solid cancers of the following histological types: predominantly epithelial (≥50% tumor component) pleural or peritoneal mesothelioma epithelial ovarian cancer (fallopian tube and primary peritoneal cancers are eligible) adenocarcinoma of the pancreas, triple-negative adenocarcinoma of the breast non-small-cell adenocarcinoma of the lung gastric cancer (including gastro-esophageal junction) colon cancer cholangiocarcinoma 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anetumab ravtansine<br>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)<br>* 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)<br>Drug: Itraconazole<br>* 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)<br>|

What is the study measuring?
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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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Solid tumors, Mesothelin, Itraconazole, PK DDI, ECG thorough QTC