Study of Adoptive Immunotherapy in Relapsed and Non-resectable Sarcomas After Multimodal Treatment.

Study Overview
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Brief Summary
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Monocentric, phase I study for advanced sarcoma with adoptive immunotherapy with Cytokine-Induced Killer (CIK). In the first part of the study Patient's' peripheral blood will be collected and CIK cell expansion and storage will occur at the Regina Margherita Children's Hospital Cell Factory. In the second part of the study the Maximum Tolerated Dose (MTD) will be determined in order to find the Recommended Dose for Phase II (RP2D)

Detailed Description
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In the first part of the study the patient's' peripheral blood collected from and CIK cell expansion and storage at the Regina Margherita Children's Hospital Cell Factory. Approximately 40 patients will be enrolled in part 1 (range: 30 - 50 patients). The second part of the study will be a 3+3 dose escalation design to determine the MTD/RP2D. A Safety Monitoring Committee (SMC) will be appointed to make dose escalation decisions. Approximately 30 patients will be enrolled in this part (range: 6 - 36 patients). Only one infusion of autologous CIK cells will be carried out at each cycle, every 21 days at the 1st, 2nd and 3rd dose levels and every 15 days at the 4th, 5th 6th dose levels. A maximum of 6 cycles will be performed (patient with complete disease remission patients who benefit from treatment might also receive more cycles at the Investigator's discretion)

Official Title
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A Phase I Study of Adoptive Immunotherapy With Cytokine-Induced Killer Cells in Relapsed and Non-resectable Sarcomas After Multimodal Treatment.

Conditions
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Sarcoma

Intervention / Treatment
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* Biological: Autologous CIK Dose level 1
* Biological: Autologous CIK Dose level 2
* Biological: Autologous CIK Dose level 3
* Biological: Autologous CIK Dose level 4


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for part 1 Patients with histologically documented unresectable sarcomas which progressed after first or further line treatments for relapsing disease who could be enrolled in Part 2 of study immediately or after a new line of treatment; Karnofsky score ≥ 70% (patients with Karnofsky score ≥ 50% are eligible if it depends solely on orthopedic problems) Estimated life expectancy > 3 months; Adequate bone marrow functions: Signed informed consent; Negative serum or urine pregnancy test within 48 hours from collection of peripheral blood or from lympho cyto apheresis (if post-pubertal female patients); Archived histological tumour sample available Inclusion Criteria for part 2 Patients with histologically documented unresectable sarcomas which progressed after a first or further line treatments for relapsing disease Measurable disease (bone lesions are included); Karnofsky score ≥ 70% (patients with Karnofsky score ≥ 50% are eligible if its depend solely on orthopedic problems) Estimated life expectancy > 3 months; Adequate bone marrow, hepatic and renal functionality Signed informed consent; Archived histological tumour sample available; Patients should have a venous central access; Pregnancy test should be negative 48 hours before treatment for post-pubertal women patients. All post-pubertal patients are to take adequate anti-contraceptive measures during treatment and until 8 weeks after the last dose of treatment. Exclusion Criteria for part 1 History of Human Immunodeficiency Virus, Hepatitis C Virus, Hepatitis B Virus or Hepatitis A Virus infection; Patients receiving chemotherapy and/or immunotherapy and/or anti-tumour agents and/or radiotherapy on more than 10% of bone marrow area two weeks before peripheral blood collection or lymphocytapheresis; Patients with neuro-psychiatric disorders or social or geographic problems that would prohibit the understanding or rendering informed consent and compliance with the requirements of this protocol are excluded. Exclusion Criteria for part 2 Patients with Ewing/Primitive Neuroectodermal Tumor Sarcoma, Rhabdomyosarcoma as well as other rapidly growing sarcomas are not to be included in the study; Presence of Central Nervous System metastases and/or meningeal neoplastic involvement; Patients with seizure disorders; Severe renal, vascular, cardiac, hepatic, lung disorders; Patients with any severe and/or uncontrolled medical conditions such as unstable angina pectoris, heart failure ≥ grade 2, a recent heart attack within 6 months, uncontrolled heart non arrhythmia uncontrolled metabolic disorders, cirrhosis, uncontrolled hypertension Patients with a non-optimal ex-vivo expansion of autologous CIK cells during Part 1 (< 0.5 x 107/kg CIK cells); History of Human Immunodeficiency Virus, Hepatitis C Virus, Hepatitis B Virus or Hepatitis A Virus infection; Presence of bleeding disorders; Patients undergoing renal dialysis; Presence of uncontrolled diabetes Patients unable to swallow oral medications; Patients receiving concomitant steroid or immunotherapy (except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg for adrenal insufficiency). Anticancer chemotherapy or experimental drugs or immunotherapy or radiotherapy 2 weeks before entering the study; Anticancer chemotherapy or experimental drugs or immunotherapy or radiotherapy on target lesions 2 weeks before entering the study; Prior exposure to CIK cells; Major surgery 4 weeks before entering the study; Minor surgery 1 week before entering the study; Patients with allergic reactions or hypersensibility to excipient Pregnant or breast-feeding patients; Patients with neuro-psychiatric disorders or social or geographic problems that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol are excluded.

Ages Eligible for Study
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Minimum Age: 10 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose finding study for the determination of the MTD for the RP2D with cohort of 3 patients plus 3 other patients as scaling design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous CIK Dose level 1<br>autologous CIK at dose level 1 | Biological: Autologous CIK Dose level 1<br>* Lymphocytapheresis of the autologous ex-vivo CIK cell expanded in the Cell factory at first level of dose 20.000.000 cell/kgs days 1 and 22<br>|
| Experimental: Autologous CIK Dose level 2<br>autologous CIK at dose level 2 | Biological: Autologous CIK Dose level 2<br>* Lymphocytapheresis of the autologous ex-vivo CIK cell expanded in the Cell factory at first level of dose 25.000.000 cell/kgs days 1 and 22<br>|
| Experimental: Autologous CIK Dose level 3<br>autologous CIK at dose level 3 | Biological: Autologous CIK Dose level 3<br>* Lymphocytapheresis of the autologous ex-vivo CIK cell expanded in the Cell factory at first level of dose 20.000.000 cell/kgs days 1 and 15<br>|
| Experimental: Autologous CIK Dose level 4<br>autologous CIK at dose level 4 | Biological: Autologous CIK Dose level 4<br>* Lymphocytapheresis of the autologous ex-vivo CIK cell expanded in the Cell factory at first level of dose 25.000.000 cell/kgs days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicity (DLT) associated with CIK autologous cells administration | The MTD will be determined through dose-escalation using a 3+3 cohort design. If less than oner third of evaluable patients in a given cohort (0 of 3 patients or 1 of 6 patients) experiences a DLT; escalation may proceed to the next higher dose level. If one of the first 3 patients enrolled in a given cohort experiences a DLT, at least 3 additional patents will be enrolled in that cohort. If a DLT is observed in one-third or more of patients, the dose at which this occurs will be considered not tolerated and the MTD will have been exceeded. The highest dose level(s) at which less than one-third of patients (0 of 3 patients or 1 of 6 patients) experiences a DLT will be declared the MTD and will be used as RP2D | at week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of autologous CIK cells for pharmacokinetic | Evaluation of the plasma concentration of autologous CIK cells to determine the pharmacokinetics parameter of the autologous CIK cells | At every cycle up to cycle 6 at: a) day 1 pre-dose b) 4 hours post-infusion, c) 24 hours post-infusion, d) day8 , e) day 15 | 
| Progression free Survival | Survival free of disease progression | At month 4 | 
| Evaluation of Major histocompatibility complex class I-related chains A and B on tumor material | Major histocompatibility complex class I-related chains A and B expression in the tumor | pre-dose | 
| Evaluation of UL16 binding proteins on tumor material | UL16 binding proteins expression in the tumor | pre-dose | 
| Quality of live reported by the Patients Using European Organisation of Research and Treatment (EORTC) Quality of Life Questionnaire Questionnaire-Core 30 (QLQ-C30) | Evaluation of the quality of life during treatment | at week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced sarcoma, osteosarcoma, soft tissue sarcoma