Phase Ib Study of Anetumab Ravtansine in Combination With Pemetrexed and Cisplatin in Mesothelin-expressing Solid Tumors

Study Overview
=================
Brief Summary
-----------------
Determine the safety, tolerability and maximum tolerated dose of anetumab ravtansine (BAY 94-9343) in combination with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 in subjects with mesothelin-expressing predominantly epithelial mesothelioma or nonsquamous non-small-cell lung cancer.

Official Title
-----------------
An Open Label Phase Ib Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Maximum Tolerated Dose of Anetumab Ravtansine in Combination With Pemetrexed 500 mg/m2 and Cisplatin 75 mg/m2 in Subjects With Mesothelin-expressing Predominantly Epithelial Mesothelioma or Nonsquamous Non-small-cell Lung Cancer

Conditions
-----------------
Medical Oncology

Intervention / Treatment
-----------------
* Drug: BAY 94-9343
* Drug: Pemetrexed
* Drug: Cisplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects may be male or female, and must be aged =/>18 years on the date of signing the informed consent form. Subjects must have histologically confirmed, unresectable, locally advanced or metastatic pleural or peritoneal predominantly (>50% of tumor component) epithelial mesothelioma or nonsquamous non-small-cell lung cancer (NSCLC). Both chemotherapy-naive and previously treated subjects will be eligible; however, newly diagnosed NSCLC subjects eligible for FDA-approved therapies should have received the same before enrollment (e.g. subjects with epidermal growth factor receptor [EGFR]-mutated and anaplastic lymphoma kinase [ALK]-translocated NSCLC should have received FDA-approved targeted therapies). Subjects must have at least 1 measurable or evaluable tumor lesion according to RECIST 1.1 (for nonsquamous NSCLC) or mRECIST (for epithelial pleural mesothelioma). Subjects with resected primary tumors who have documented metastases are eligible. 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, liver, kidney, and coagulation functions. Exclusion Criteria: Subjects who have a previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, or any previous cancer curatively treated >3 years before the start of study Treatment. Subjects who have a history or current evidence of bleeding disorder, i.e. any hemorrhage / bleeding event of CTCAE (Common Terminology Criteria for Adverse Events) Grade ≥2 within 4 weeks before the start of study Treatment. Subjects who have new or progressive brain or meningeal or spinal metastases. Subjects who have a history or current evidence of uncontrolled cardiovascular disease i.e. NYHA (New York Heart Association) Class III or IV. Subjects who have a history or current evidence of uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg at screening despite optimal medical management. Subjects who have a history or current evidence of malignant biliary obstruction requiring biliary stent. Subjects who have had solid organ or bone marrow Transplantation. Subjects who have a history of hypersensitivity to any of the study drugs or their excipients, or a history of severe hypersensitivity to any other Antigen. Subjects who have a history of human immunodeficiency virus (HIV) infection or subjects who have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Subjects who have an active clinically serious infection of CTCAE Grade ≥2 or non-healing wound unrelated to the primary Tumor. Subjects who have received systemic cancer therapy, radiotherapy, investigational drug treatment outside of this study within 4 weeks before the start of study treatment, granulocyte colony stimulating factors, (G-CSF) or granulocyte macrophage-stimulating factors (GM-CSF), erythropoietin-stimulating agents within 3 weeks before the start of general screening, drugs with known renal toxicity and strong cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers within 2 weeks before the treatment. Subjects who have started oral or parenteral anticoagulation therapy within 2 weeks before the start of anetumab ravtansine until end of treatment visit.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAY 94-9343 + Pemetrexed + Cisplatin<br>Investigating the combination of anetumab ravtansine (BAY 94-9343) with Pemetrexed (500 mg/m2) and Cisplatin (75 mg/m2) in Part 1 (dose escalation cohorts) and Part 2 (two MTD expansion cohorts) | Drug: BAY 94-9343<br>* In Part 1 of the study, anetumab ravtansine (BAY 94-9343) will be administered by 1-hour IV infusion with a starting dose of 5.5mg/kg(BW) on Day 1 of every treatment cycle (Q3W). In Part 2 of the study, anetumab ravtansine (BAY 94-9343) will be administered on Day 2 of Cycle 1 and then on Day 1 of Cycle 2 and all subsequent cycles (Q3W)<br>Drug: Pemetrexed<br>* Administered at the dose of 500 mg/m2 body surface area (BSA) by 10-minute IV infusion on Day 1 of every treatment cycle (Q3W) in both parts of the study<br>Drug: Cisplatin<br>* Administered at the dose of 75 mg/m2 (BSA) by 2-hour IV infusion on Day 1 of every treatment cycle (Q3W) in both parts of the study<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | MTD is defined as the highest dose of oral anetumab ravtansine (BAY 94-9343) administered in combination with IV pemetrexed and cisplatin that can be given such that not more than 1 of 6 subjects at a given dose level experience a DLT (dose-limiting toxicity). | Up to 2 years | 
| Number of subjects with adverse events and serious adverse events as a measure of safety and tolerability |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of anetumab ravtansine (BAY 94-9343), pemetrexed and cisplatin | C (treatment cycle), D (day); Each cycle is defined as a period of 21 days | - BAY 94-9343: C1D1,D2,D3,D8,D15, C2D1, C3D1,D2,D3,D8,D15, C4D1, C6D1 and subsequent cycles every 3rd cycle up to 2 years or until discontinuation of study treatment, whichever comes first - Pemetrexed: C1D1, D2, D3 - Cisplatin: C1D1, D2, D3 | 
| Tumor response evaluation following mRECIST criteria to determine the number of patients with CR, PR, SD or PD | CR (complete response); PR (partial response); SD (stable disease); PD (progressive disease); Each cycle is defined as a period of 21 days | Baseline, every 8 weeks up to cycle 12; then every 12 weeks from cycle 13 up to 2 years, or until discontinuation of study treatment, whichever comes first | 
| Number of patients with a positive titer of anti-drug antibodies | Each cycle is defined as a period of 21 days | Day1 of C1, C3, C6 and subsequent cycles every 3rd cycle up to 2 years or until discontinuation of study treatment, whichever comes first | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lung cancer, Phase 1, Solid tumors, Mesothelioma, Pemetrexed, Cisplatin