Details

Details

Title A randomized, open-label, active-controlled, Phase II study of intravenous anetumab ravtansine (BAY 94-9343) or vinorelbine in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin and progressed on first line platinum/pemetrexed-based chemotherapy

IRB BAY1515

CC 16-186

Hospital Main Campus

Phase Phase 2

Disease Lung - Mesothelioma

Drug BAY 94-9343, Vinorelbine

Description

Description

Primary Objective:
  • Test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS)
Secondary Objectives:
  • Test overall survival (OS)
  • Evaluate patient-reported outcomes (PROs) � symptom burden and health-related quality of life (QoL)
  • Evaluate other indicators of treatment efficacy (indicators of tumor response)
  • Evaluate safety
Other Objectives:
  • Pharmacokinetics (PK)
  • Immunogenicity
  • Biomarkers
Inclusion Criteria

Inclusion Criteria

Eligibility criteria for prescreening
  1. Written informed consent for prescreening.
  2. Unresectable locally advanced or metastatic MPM, confirmed by histology.
  3. Availability of archival or fresh tissue for testing of mesothelin expression level. Note: archival tissue is available and if in the investigator's judgement, there is no additional risk for the patient's safety. Patients with a sarcomatoid histology are not expected to have mesothelin overexpression and should not enter prescreening.
  4. Age ≥ 18 years (age limit may be higher if legally required in a country, e.g. in Japan adult age is considered ≥ 20 years).
  5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 (specified in Appendix 16.1).
  6. Life expectancy of at least 3 months.
  7. No prior treatment with anetumab ravtansine (or any other mesothelin-based therapy) or vinorelbine (or any other vinca-containing compound or spindle poison).
  8. No prior use of targeted agents, experimental therapy or systemic anti-cancer treatment other than ongoing or completed 1st line platinum/pemetrexed (with or without bevacizumab).
Eligibility criteria for full study
  1. Written informed consent for full study.
  2. Histological documentation of MPM overexpressing mesothelin at the moderate and stronger level in at least 30% of tumor cells as determined by centrally performed IHC (modified by amendment 2).
  3. Unresectable locally advanced or metastatic MPM after locally confirmed unequivocal progression on 1st line treatment with platinum (both cis- or carbo-platinum) in combination with pemetrexed. Last dose of previous therapy must be at least 28 days before the start of study treatment (modified by amendment 4, see section 15.2.1.3). Note: Patients progressed on 1st line treatment with platinum plus pemetrexed in combination bevacizumab are allowed.
  4. Patients must have at least 1 measurable lesion according to mRECIST for mesothelioma (specified in Appendix 16.3) i.e. pleural lesion(s) measured using mRECIST or extra-pleural lesion(s) measurable per RECIST 1.1. This will be confirmed by central review of images before the patient can be randomized into the study. Note: In case the only site of disease was previously treated with radiotherapy, there should be evidence of unequivocal PD in this site: measurable pleural disease should be assessed on a contrast enhanced CT/MRI done at the minimum 4 weeks after the end of radiotherapy and compared with previous imaging; unequivocal progression should be judged by the investigator as per mRECIST per MPM (criterion 4 modified by amendment 2, see section 15.1.1.8 and 15.1.1.26).
  5. ECOG PS of 0 or 1 (specified in Appendix 16.1).
  6. Life expectancy of at least 3 months.
  7. Women of childbearing potential (WOCBP) and fertile men must agree to use adequate contraception when sexually active from signing of the ICF for full study until at least 4 months after the last study drug administration. Men being treated with vinorelbine are advised not to father a child during and up to 6 months after treatment; for all male patients, prior to treatment with either study drug, advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control. Highly effective (failure rate of less than 1% per year) contraception methods include:
    • Combined (estrogen and progesteron containing: oral, intravaginal, transdermal) and progesteron-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation.
    • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
    • Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole sexual partner and has received medical assessment of the surgical success).
    • Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient). 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 4 months after last study drug administration. Note: a woman is considered WOCBP, i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. A man is considered fertile after puberty unless permanently sterile by bilateral orchiectomy (criterion 7 modified by amendment 2, see section 15.1.1.9).
  8. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment:
    • Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL).
    • ALT and AST ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer).
    • ALP limit ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer).
    • Amylase and lipase ≤ 1.5 x ULN.
    • Serum creatinine ≤ 1.5 x ULN.
    • Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (see Appendix 16.7).
    • Adequate coagulation, as assessed by the following laboratory test results:
      • International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN (CTCAE Grade ≤ 1).
      • Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN (CTCAE Grade ≤ 1). Note: Patients on stable dose of anti-coagulation therapy will be allowed to participate if they have no sign of bleeding or clotting and INR / PT and PTT / aPTT test results are compatible with the acceptable benefit-risk ratio at the investigator's discretion (see Section 8.1).
    • Platelet count ≥ 100000/mm3 , without platelet transfusion within 3 weeks before the start of study treatment (see Section 8.1).
    • Hemoglobin (Hb) ≥ 9 g/dL, without blood transfusion or erythropoietin within 6 weeks before the start of study treatment (see Section 8.1). Note: Patients receiving chronic low-dose erythropoietin for chronic renal failure are allowed provided no dose adjustment is undertaken within 6 weeks before signing consent for full study and until safety follow-up visit and provided that they fulfill conditions of eligibility criteria (see also exclusion criterion number 18).
    • Absolute neutrophil count (ANC) ≥ 1500/mm3, without biologic response modifiers, such as G-CSF, within 6 weeks before the start of study treatment (see Section 8.1).
  9. Left ventricular ejection fraction (LVEF) ≥ 50% or the lower limit of normal (LLN) according to local institution ranges of normality
Exclusion Criteria

Exclusion Criteria

  1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
  2. Previous (within 5 drug half-lives � if drug half-life in subjects is known - or 28 days, whichever is shorter, before the start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s) (IMP[s]).
  3. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site).
  4. More than 1 previous systemic anti-cancer therapy line (even if therapy used as neoadjuvant or adjuvant treatment) (clarified by amendment 4, see section 15.2.1.19). Note: Patients pre-treated with systemic therapy other than platinum, pemetrexed, bevacizumab (13) (e.g. other cytotoxic drugs, immunotherapy, targeted therapy, hormonal therapy, or any other experimental or approved therapy or device) are not to be enrolled (modified by amendment 4, see section 15.2.1.4).
  5. Patients with corneal epitheliopathy or any eye disorder that may predispose the patients to this condition at the discretion of the investigator in consultation with the ophthalmologist/optometrist (modified by amendment 2), see section 15.1.1.10). Note: Low grades of superficial punctate keratitis, within the range seen in the normal population, should not lead to the exclusion of the patient (note added by amendment 2, see section 15.1.1.11).
  6. Previous or concurrent cancer that is distinct in primary site or histology from mesothelioma within 5 years before randomization. Exceptions: curatively treated
    • Cervical cancer in situ.
    • Non-melanoma skin cancer.
    • Superficial bladder tumors (Non-invasive tumor [Ta], Carcinoma in situ [Tis] and Tumor invades lamina propria [T1]).
  7. Major surgery, open biopsy or significant traumatic injury within 28 days before the start of study treatment.
  8. Pregnant or breast-feeding patients. WOCBP must have a serum pregnancy test performed a maximum of 7 days before the start of study treatment, and a negative result must be documented before the start of study treatment.
  9. Pre-existing cardiac conditions as outlined below:
    • Congestive heart failure ≥ New York Heart Association (NYHA) class 2 (specified in Appendix 16.2).
    • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before the start of study treatment.
    • Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
  10. Clinically significant uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
  11. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or venous pulmonary embolism within 6 months before the start of study treatment; venous thrombotic events such as deep vein thrombosis within 3 months before the start of study treatment.
  12. Ongoing or active infection (bacterial, fungal, or viral) of NCI-CTCAE version 4.03 Grade > 2.
  13. Known history of human immunodeficiency virus (HIV) infection.
  14. Known history of chronic hepatitis B or C.
  15. Patients with seizure disorder requiring medication.
  16. Brain metastases or meningeal tumors or other metastases in the central nervous system (CNS). Patients with neurological symptoms must undergo a contrast CT scan or MRI of the brain and/or other areas of the CNS as applicable within 28 days before the start of study treatment to exclude metastatic disease in the CNS (criterion modified by amendment 4, see section 15.2.1.5).
  17. History of organ allograft, stem cells or bone marrow transplant.
  18. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks before the start of study treatment.
  19. Non-healing wound, ulcer, or bone fracture.
  20. Renal failure requiring peritoneal or hemodialysis.
  21. Known hypersensitivity to anetumab ravtansine or vinorelbine, study drug classes or excipients in the formulation.
  22. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
  23. Unresolved toxicity higher than NCI-CTCAE version 4.03 Grade 1 attributed to any prior therapy/procedure excluding anemia Grade 2 (see Section 6.1.2, inclusion criterion 8) and alopecia of any Grade.
  24. Any prohibited prior or concomitant therapy (see Table 8-1 in Section 8.1).