Ipilimumab and Nivolumab in patients with malignant Pleural Mesothelioma: INITIATE

Phase 1

• Conditions: Malignant pleural mesothelioma; MedDRA version: 19.0Level: LLTClassification code 10027408Term: Mesothelioma malignant advancedSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2016-001599-31-NL
• Lead Sponsor: Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-08-22
• Last Update Posted: 19 September 2016

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Signed informed consent form
• Age = 18 years
• WHO-ECOG performance status 0 or 1
• Able to comply with the study protocol, in the investigator’s judgment
• Patients with histologically confirmed diagnosis of the recurrence of MPM. Any pleural MPM subtype is permitted for inclusion in the study.
• Progressive disease after at least one prior systemic treatment with a platinum-based doublet (both cisplatin and carboplatin are allowed) for unresectable MPM. All prior cytotoxic toxicities must have resolved to grade = 1 prior to registration
• Measurable disease on CT scan, according to modified RECIST Criteria for Mesothelioma (Byrne MJ, 2004)
• Life expectancy = 12 weeks
• Adequate hematologic and organ function, defined by the following laboratory results, obtained within 14 days prior to the first study treatment:
- Absolute neutrophil count (ANC) = 1500 cells/µL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
- WBC count = 3000 cells/µL
- Lymphocyte count = 250 cells/µL
- Platelet count = 100.000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
- Hemoglobin = 5.6 mmol/L
- Serum albumin = 25 gr/L
- AST, ALT and alkaline phosphatase = 2.5 x ULN, with the following exceptions: patients with documented liver or bone metastases: alkaline phosphatase = 5 x ULN
- Serum bilirubin = 1.5 x ULN
Patients with known Gilbert disease who have serum bilirubin level = 3 x ULN may be enrolled
- INR and aPTT = 1.5 x ULN
Patients receiving therapeutic anticoagulation should be on a stable dose
- Creatinine clearance = 45 mL/min
Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration or Modification of Diet in Renal Disease formulae may be used; 24-hour urine collection is not required
• Women who are not postmenopausal (= 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus) and men with partners of childbearing potential, must agree to use adequate contraception (double barrier birth control) for the whole duration of study treatment and for 3 months after the last dose of therapy
• Women of childbearing potential must have a negative serum or urine pregnancy test within 48 hours prior the first dose of treatment
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 16
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 17

Exclusion Criteria

• Medical or psychological impediment to comply with the protocol
• Patients with only peritoneal MPM
• Prior malignancy except adequately treated basal cell or squamous cell skin cancer, superficial or in-situ cancer of the bladder or other cancer for which the patient has been disease-free for at least five years
• Concomitant participation in another clinical trial (by the investigator’s judgement)
• Uncontrolled pleural/peritoneal effusion, pericardial effusion or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy should be treated prior to enrolment.
• Previous treatment with any checkpoint inhibitor
• Pregnant or lactating women
• Patients with brain metastases
• History of or active autoimmune disease (e.g. pneumonitis; rheumatoid arthritis; severe form of psoriasis; uncontrolled type I diabetes or hypothyroidism)
• History of idiopathic pulmonary fibrosis (including pneumonitis) or unresolved drug-induced pneumonitis, organizing pneumonia, or active pneumonitis on screening chest CT scan
• History of relevant gastrointestinal disease, including, but not limited to, Crohn’s disease, ulcerative colitis, recurrent diverticulitis
• Prior allogenic bone marrow transplantation or prior solid organ transplantation
• History of HIV
• Patients with history of HBV infection are eligible if serological profile is compatible with past/resolved infection (defined as negative HBsAg test and positive antibody to HBV core antigen [anti-HBc] antibody test) and HBsAg test and HBV-DNA are both negative prior to Cycle 1, Day 1
• Patients with history of HCV infection must be screened for HCV-RNA PCR test prior to Cycle 1, Day 1, and are eligible if the test turns negative
• Other serious concomitant disease, including:
- Active tuberculosis
- Severe infections within 4 weeks prior to Cycle 1, Day 1
- Significant cardiovascular disease (NYHA class III or IV), myocardial infarction within the previous 6 months, unstable angina, or unstable arrhythmias
- Significant pulmonary (asthma or COPD) or hepatic disease or other illness considered by the investigator to constitute an unwarranted high risk for investigational treatment
• Major surgical procedures within 28 days prior to Cycle 1, Day 1
• Concurrent medications:
- Treatment with systemic immunosuppressive medications, including but not limited to prednisone (with specific exceptions; see below), cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1.
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.
- The use of systemic prednisone at the dosage of 10 mg/day or lower (or equivalent) is allowed.
• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of the study is the disease control rate (DCR) at 12 weeks of the combination treatment of Nivolumab and Ipilimumab in patients with progressive MPM.;Secondary Objective: - to determine the safety profile of the combination treatment of Nivolumab plus Ipilimumab in patients with advanced MPM<br>- to determine DCR at 6 months, PFS and OS in the study population<br>- to determine objective response rate (ORR) as defined by modified RECIST criteria<br>- to determine the immunological changes of tumors before and after 6 weeks of treatment. This research will include PD-L1 status and other possible biomarkers.<br>;Primary end point(s): DCR at 12 weeks;Timepoint(s) of evaluation of this end point: At 12 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): PFS, OS, ORR, safety;Timepoint(s) of evaluation of this end point: PFS, ORR and OS: 6 weekly until week 48. Thereafter 12 weekly<br>Safety: 2 weekly during treatment, thereafter every 6 weekly until week 48. Thereafter 12 weekly