Feasibility of the Combination of Chemotherapy (Carbo/Caelyx or Carbo/Doxorubicin) With Tocilizumab (mAb IL-6R) and Peg-Intron in Patients With Recurrent Ovarian Cancer

Study Overview
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Brief Summary
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The purpose of this interventional study is to determine the feasibility to combine standard chemotherapy (Carbo/Caelyx or doxorubicin) for recurrent ovarian cancer with immunotherapy (Tocilizumab and Peg-Intron). This study combines standard chemotherapy Carboplatin-Caelyx or doxorubicin with a monoclonal antibody against IL-6R (tocilizumab). High IL-6 levels correlate with poor prognosis and chemoresistance in ovarian cancer patients. In cases of chemoresistant ovarian cancer, therefore, modulation of the IL-6 pathway, by blocking the IL-6 receptor, may represent a promising strategy to both abolish drug resistance and amplify host immunity in patients with recurrent ovarian cancer. Blockade of the IL-6/IL-6R pathway may enhance immunogenic cell death and restore local normal DC maturation. In addition, the use of interferon-alpha (Peg-Intron) allows the full maturation of DC, thereby enhancing the anti-tumor response.

Official Title
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Chemo-Immunotherapy: Observational Trial of Carboplatin-pegylated Liposomal Doxorubicin (PLD) or Doxorubicin Combination Chemotherapy With Tocilizumab, a Humanized Monoclonal Antibody Against the Human Interleukin-6 (IL-6) Receptor, and Pegylated Interferon Alpha (Peg-Intron) for Patients With Recurrent Ovarian Cancer.

Conditions
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Recurrent Ovarian Cancer

Intervention / Treatment
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* Drug: tocilizumab and interferon alpha 2-b
* Drug: Carboplatin and Caelyx or doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven epithelial ovarian cancer Progression of disease or relapse after previous therapy with platinum Measurable disease (RECIST 1.1) or elevated CA125 > 2 times the upper normal limit (UNL) within 3 months and confirmed Age ≥18 years WHO performance status 0-2 Adequate bone marrow function: WBC ≥3.0 x 109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l Adequate liver function: bilirubin ≤1.5 x UNL range, ALAT and/or ASAT 2.5 x UNL (<5x UNL in case of liver metastases), Alkaline Phosphatase ≤5 x UNL Adequate renal function: the calculated creatinine clearance should be 50 mL/min Survival expectation > 3 months Patients must be accessible for treatment and follow-up Written informed consent according to the local Ethics Committee requirements Exclusion Criteria: Chemotherapy within past 3 months Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix Serious other diseases as recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias Known hypersensitivity reaction to any of the components of the treatment Pregnancy or lactating Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent Infection with tuberculosis and hepatitis B or C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1<br>Carboplatin/Caelyx | Drug: Carboplatin and Caelyx or doxorubicin<br>* Standard chemotherapeutic care given in every arm as standard care. A total of 6 cycles is the aim.<br>|
| Experimental: Group 2<br>Carboplatin/Caelyx or doxorubicin plus Tocilizumab | Drug: tocilizumab and interferon alpha 2-b<br>* During first three chemotherapy cycles, tocilizumab and/or Peg-Intron are added. Tocilizumab is given in a dose-escalation scheme (1,2,4,8mg/kg n=3) and Peg-Intron is adminstered subcutaneously 1.0ug/kg<br>Drug: Carboplatin and Caelyx or doxorubicin<br>* Standard chemotherapeutic care given in every arm as standard care. A total of 6 cycles is the aim.<br>|
| Experimental: Group 3<br>Carboplatin/Caelyx or doxorubicin plus Tocilizumab plus Peg-Intron | Drug: tocilizumab and interferon alpha 2-b<br>* During first three chemotherapy cycles, tocilizumab and/or Peg-Intron are added. Tocilizumab is given in a dose-escalation scheme (1,2,4,8mg/kg n=3) and Peg-Intron is adminstered subcutaneously 1.0ug/kg<br>Drug: Carboplatin and Caelyx or doxorubicin<br>* Standard chemotherapeutic care given in every arm as standard care. A total of 6 cycles is the aim.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The feasibility (NCI-CTCv4.0) to combine carboplatin and PLD or doxorubicin with tocilizumab as well as with tocilizumab and Peg-Intron | The safety (NCI-CTCv4.0)and efficacy (immune-monitoring)of the new combination will be measured . | two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of chemo-immunotherapy on the immune system | Study the effect of chemo-immunotherapy on the immune system by assessing changes in plasma signature (eg IL6, IL8, VEGF, CRP) dendritic cell phenotype and T- and B-cell responses to known tumor antigens in ovarian cancer (eg NY-ESO, p53), antibodies to antigens associated with immunogenic cell death (CRT, HMGB1) and in tumor tissue by gene array | two years | 
| The relation between anti-tumor immunity and clinical outcome | Study the relation between anti-tumor immunity and clinical outcome (response (RECIST 1.1), progression free survival (PFS) and overall survival(OS)) | two years |