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

NCT03782363 | Withdrawn Phase 1 DMC

• 1 other identifier: ISG-CAST
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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)

Conditions

Sarcoma

Keywords

advanced sarcoma; osteosarcoma; soft tissue sarcoma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Plasma concentration of autologous CIK cells for pharmacokinetic

  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

  At month 4

• Evaluation of Major histocompatibility complex class I-related chains A and B on tumor material

  pre-dose

• Evaluation of UL16 binding proteins on tumor material

  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)

  at week 6

Study Arms (4)

Autologous CIK Dose level 1

EXPERIMENTAL

autologous CIK at dose level 1

Biological: Autologous CIK Dose level 1

Autologous CIK Dose level 2

EXPERIMENTAL

autologous CIK at dose level 2

Biological: Autologous CIK Dose level 2

Autologous CIK Dose level 3

EXPERIMENTAL

autologous CIK at dose level 3

Biological: Autologous CIK Dose level 3

Autologous CIK Dose level 4

EXPERIMENTAL

autologous CIK at dose level 4

Biological: Autologous CIK Dose level 4

Interventions

Autologous CIK Dose level 1 BIOLOGICAL

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

Autologous CIK Dose level 1

Autologous CIK Dose level 2 BIOLOGICAL

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

Autologous CIK Dose level 2

Autologous CIK Dose level 3 BIOLOGICAL

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

Autologous CIK Dose level 3

Autologous CIK Dose level 4 BIOLOGICAL

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

Autologous CIK Dose level 4

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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;

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Italian Sarcoma Group: lead
• Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna: collaborator

Study Sites (1)

Ospedale Infantile Regina Margherita - Unit of Paediatric Oncoematology

Torino, 10126, Italy

Location

Related Publications (9)

• Schmidt-Wolf IG, Lefterova P, Mehta BA, Fernandez LP, Huhn D, Blume KG, Weissman IL, Negrin RS. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol. 1993 Dec;21(13):1673-9.

  PMID: 7694868 BACKGROUND

• Introna M, Franceschetti M, Ciocca A, Borleri G, Conti E, Golay J, Rambaldi A. Rapid and massive expansion of cord blood-derived cytokine-induced killer cells: an innovative proposal for the treatment of leukemia relapse after cord blood transplantation. Bone Marrow Transplant. 2006 Nov;38(9):621-7. doi: 10.1038/sj.bmt.1705503. Epub 2006 Sep 18.

  PMID: 16980990 BACKGROUND

• Mesiano G, Todorovic M, Gammaitoni L, Leuci V, Giraudo Diego L, Carnevale-Schianca F, Fagioli F, Piacibello W, Aglietta M, Sangiolo D. Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors. Expert Opin Biol Ther. 2012 Jun;12(6):673-84. doi: 10.1517/14712598.2012.675323. Epub 2012 Apr 14.

  PMID: 22500889 BACKGROUND

• Olioso P, Giancola R, Di Riti M, Contento A, Accorsi P, Iacone A. Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: a pilot clinical trial. Hematol Oncol. 2009 Sep;27(3):130-9. doi: 10.1002/hon.886.

  PMID: 19294626 BACKGROUND

• Heimann TG, Githens S. Rat pancreatic duct epithelium cultured on a porous support coated with extracellular matrix. Pancreas. 1991 Sep;6(5):514-21. doi: 10.1097/00006676-199109000-00003.

  PMID: 1946307 BACKGROUND

• Gammaitoni L, Giraudo L, Macagno M, Leuci V, Mesiano G, Rotolo R, Sassi F, Sanlorenzo M, Zaccagna A, Pisacane A, Senetta R, Cangemi M, Cattaneo G, Martin V, Coha V, Gallo S, Pignochino Y, Sapino A, Grignani G, Carnevale-Schianca F, Aglietta M, Sangiolo D. Cytokine-Induced Killer Cells Kill Chemo-surviving Melanoma Cancer Stem Cells. Clin Cancer Res. 2017 May 1;23(9):2277-2288. doi: 10.1158/1078-0432.CCR-16-1524. Epub 2016 Nov 4.

  PMID: 27815354 BACKGROUND

• Chan JK, Hamilton CA, Cheung MK, Karimi M, Baker J, Gall JM, Schulz S, Thorne SH, Teng NN, Contag CH, Lum LG, Negrin RS. Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study. Clin Cancer Res. 2006 Mar 15;12(6):1859-67. doi: 10.1158/1078-0432.CCR-05-2019.

  PMID: 16551871 BACKGROUND

• Kim HM, Lim J, Yoon YD, Ahn JM, Kang JS, Lee K, Park SK, Jeong YJ, Kim JM, Han G, Yang KH, Kim YJ, Kim Y, Han SB. Anti-tumor activity of ex vivo expanded cytokine-induced killer cells against human hepatocellular carcinoma. Int Immunopharmacol. 2007 Dec 15;7(13):1793-801. doi: 10.1016/j.intimp.2007.08.007. Epub 2007 Aug 31.

  PMID: 17996690 BACKGROUND

• Schmidt-Wolf IG, Finke S, Trojaneck B, Denkena A, Lefterova P, Schwella N, Heuft HG, Prange G, Korte M, Takeya M, Dorbic T, Neubauer A, Wittig B, Huhn D. Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. Br J Cancer. 1999 Nov;81(6):1009-16. doi: 10.1038/sj.bjc.6690800.

  PMID: 10576658 BACKGROUND

MeSH Terms

Conditions

Sarcoma; Osteosarcoma

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue

Study Officials

• Franca Faggioli, MD

  Ospedale Infantile Regina Margherita - Unit of Paediatric Oncoematology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Dose finding study for the determination of the MTD for the RP2D with cohort of 3 patients plus 3 other patients as scaling design

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 20, 2018
• Study Start: December 18, 2020
• Primary Completion: April 1, 2023
• Study Completion: April 1, 2023
• Last Updated: December 22, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)