Relapsed Hematologic MalignancyPhase 1/2Haplo-CIKNCT03821519
Infusion of Donor Derived Cytokine Induced Killer (CIK) Cells in Hematological Patients Relapsed After Haploidentical Stem Cell Transplant
A Phase 1/2 study testing donor-derived CIK cells in people with Relapsed Hematologic Malignancy, run by A.O. Ospedale Papa Giovanni XXIII at 1 site in Italy.
Trial summary
The haematological neoplasia relapse is the cause of higher mortality after allogeneic stem cell transplantation (HSCT). When transplantation fails the most common therapeutic strategy is to increase the antitumor activity of the donor's immune system through the infusion of donor Lymphocytes (DLI). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Relapsed Hematologic Malignancy
- What is being tested?
- donor-derived CIK cells
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteItaly
- Study dates
- 13 Jan 2019to May 2023
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female patients 18 years or older
- Patients treated with haploidentical allogeneic transplantation for hematologic malignancies, excluding Chronic Myeloid Leukemia (CML), such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), myelofibrosis (MF) and myelodysplastic syndrome (MDS)
- To be enrolled to the safety run-in cohort, patients must have:
- Evidence of relapsed disease after allogeneic transplantation, including molecular, cytogenetic or overt hematologic relapse
- To be enrolled to the phase II cohort, patients must have:
- Evidence of relapsed disease after allogeneic transplantation, including, molecular, cytogenetic or overt hematologic relapse, or
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- Mixed chimerism after the day +90, defined as <75% donor in unfractionated bone marrow and/or <75% donor in unfractionated Peripheral blood (PB) and/or <75% donor in fractionated CD3+ peripheral blood.
- Availability of a donor willing to donate peripheral blood mononuclear cells
- Withdrawn of immune suppression at least 3 weeks before the beginning of the cell therapy program
- Written informed consent prior to any study procedures being performed
- For female patients:
- being postmenopausal for at least 1 year before the screening visit,OR
- being surgically sterile, OR
- if they are of childbearing potential, must agree to practice highly effective method of contraception and one additional effective (barrier) method from the time of signing the informed consent until the end of study. Highly effective method of contraception includes: (i) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal; (ii) progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable (intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence) OR
- must agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject from the time of signing the informed consent until the end of study. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.]
- For male patients, even if surgically sterilized (i.e., status postvasectomy): a) with female partners of childbearing potential: must agree to practice barrier contraception (condom with or without spermicide) from the time of signing the informed consent until the end of study and his female partner must agree to practice method of contraception including one of the following: estrogen and progestogen containing hormonal contraception; inhibition of ovulation: oral, intravaginal, transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable (intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion) from the time of signing the informed consent until the end of study.b) must agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject from the time of signing the informed consent until the end of study. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.] c) must agree to refrain from donating sperm
Who cannot join
- The presence of any of the following will exclude a subject from study enrolment 1. Donors positive for HIV, (Hepatitis B virus) HBV, (Hepatitis C virus) HCV, Treponema or unfit to donate peripheral blood mononuclear cells 2. Patients with active grade 2 or more acute or moderate chronic GVHD at study entry or before CIK infusion 3. Patients with rapidly progressive disease or not controlled by palliative supportive treatments, including chemotherapy, and with life expectancy less than 8 weeks 4. Any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
- -
Trial locations and contacts
1 site in 1 country.
Italy1 site, 1 recruiting
- Recruiting
A O Papa Giovanni XXIII
Bergamo, 24127
Alessandro Rambaldi, MD, 035 2673683 ext. 0039, arambaldi@asst-pg23.it
Federico Lussana, MD, 035 2673678 ext. 0039, flussana@asst-pg23.it
About this study
Official title: Phase I/II Trial of Donor Derived Cytokine Induced Killer (CIK) Cells Infusion for Relapsed Hematologic Malignancy After Haploidentical Stem Cell Transplantation
The haematological neoplasia relapse is the cause of higher mortality after allogeneic stem cell transplantation (HSCT). When transplantation fails the most common therapeutic strategy is to increase the antitumor activity of the donor's immune system through the infusion of donor Lymphocytes (DLI). The use of DLI may limit the relapse, but may induce transplantation disease against the host (GvHD), in 40-60% of patients. With advances in transplantation procedures, the use of non-compatible (HLA-mismatched) haploidentical (aplo) donor cells has become feasible and is increasing. However, strategies for immune control of relapse after HSCT from haploidentical donor are hampered by the absence of prospective data that can guide treatment and limit the induction of GvHD in the setting of the HLA difference between the donor and the recipient. Cytokine-induced Killer Cells (CIK) are T lymphocytes from haploidentical donor expressing CD56 (e.g., double positive cells at CD3 / CD56). CIK are a product of advanced cell therapy (Advanced Therapeutic Medicinal Product, ATMP) for somatic cell therapy and have a reduced histocompatibility (MHC) complex: are cytotoxic, anti-tumor cells, possess the characteristics of both T cells and Natural Killer (NK) and show in vivo a very strong cytolytic activity against leukemia, but a low reactivity against the host. Therefore, this study has as its primary objective to investigate the safety of CIK cells deriving from the donor, especially in terms of the onset of GvHD, used as a treatment for relapse after transplantation with haploidentical stem cells. The study will allow to evaluate the possibility of using CIK cells, at the indicated dose combination (5x10 * 6 cells / kg, 5x10 * 6 and 10x10 * 6 cells / kg) as an effective and safe therapy in the context of haploidentical transplantation.
Read the detailed description
Disease relapse is a major cause of mortality following allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. When allogeneic transplant fails the most common therapeutic strategy is to increase the anti-tumor activity of donor immune system through infusion of donor lymphocytes (DLI). Use of DLI can effectively treat limited relapses, but can induce graft-versus-host disease (GvHD) in the range of 40-60% of the patients. With the advances in HSCT procedure, the use of HLA-mismatched (haplo) family donors became feasible and extended the opportunity for HSCT to almost all patients lacking an HLA-matched donor. Due to the promising results of the procedure and the easier access to the donor, the number of haplo-HSCT transplant is steeply increasing. However, strategies aiming at eliciting the immune control of the relapse after haplo-HSCT are hampered by absence of prospective data that guide treatment and the fear of inducing GvHD in this setting of profound HLA disparity between donor and recipient.
- Despite the use of DLI in haplo-HSCT is not a standard practice, DLI are occasionally empirically used, mainly due to the lack of alternative treatment.
- Cytokine Induced Killer (CIK) cells are T lymphocytes expressing the CD56 marker, i.e. CIK are CD3/CD56 double positive cells. CIK cells are produced in vitro by incubating blood leukocytes according to a specific expansion protocol which includes initial stimulation with Interferon-gamma and anti-CD3 antibody, followed by expansion with (Interleukin-2) IL-2. CIK cells are non MHC restricted, cytotoxic, anti-tumoral cells which share characteristics of both T and NK cells and show in vivo a very strong cytolytic activity against leukemia, graft versus leukemia, while being essentially devoid of graft versus host reactivity. They show a natural non-MHC restricted (T Cell Receptor)TCR independent cytotoxicity against malignant targets cells, involving perforin and granzyme release and NKG2D, as well as CD56 and other small target molecules. In the past 15 years the investigators have extensively studied the use of cytokine-induced killer (CIK) cells as alternative cellular therapy to treat disease relapse after HSCT. The key feature of CIK cell therapy in the context of haplo- HSCT is the lower risk of inducing GvHD compared to DLI, that could permit to avoid the devastating effect of acute and chronic GvHD in terms of decreased survival, quality of life, disability and need of additional care. Indeed, beyond the dramatic impact in the quality and quantity of life of patients, costs for the health system of the management of acute and chronic GvHD are exceedingly high. At this regard, CIK cells have been regarded as the cellular therapy that is associated with a more favourable therapeutic index compared to DLI.
- In an early Phase I study the investigators observed remissions in 3 of 11 patients who were treated with infusion of CIK cells at a time when malignant cells were detectable. In each of these 3 cases, the patient had been previously treated unsuccessfully with conventional DLI. Successful remission induction by infusion of CIK cells after unsuccessful DLI suggests that the (Graft Versus Leukemia) GVL activity of CIK cells was attributable to NK-T cells. In a subsequent phase I clinical trial was assessed the feasibility of using CIK cells from HLA-matched sibling donors. Using a dose escalation design, the investigators showed that CIK cells could be given at doses as high as 1x10^8 per kg recipient body weight without causing acute infusion-related toxicity. The investigators recently reported the final results of a phase II multicenter pilot study, showing that CIK cell treatment for the relapse after HSCT is effective with a low toxicity in terms of GvHD compared to DLI. Importantly for the present proposal, in this study, 5 patients were treated in the context of haplo- HSCT. These did not show any different response or safety concern compared to other patients, suggesting the feasibility of this approach in a haploidentical context. Similarly, another study of CIK cellular therapy in HSCT including also patients with haploidentical donors confirmed the feasibility and safety of this approach. Considering that infused T cells are associated with risk of GvHD induction, especially in the haploidentical transplantation setting, novel cellular therapies manipulated to minimize GvHD while enhancing the graft-versus leukemia efficacy need to be tested in early phase clinical trials. Thus, the aim of the present proposal is to use CIK cells as a platform for a safe and effective cellular therapy in the context of haploidentical transplantation. As no dose limiting toxicity has been reached in phase I/II studies and no clear relationship among dose and both toxicity and response emerged so far, in the present study the investigators planned to use the final standard dose of our previous phase II study of 5x106 cells/kg, 5x10^6 and 10x10^6 cells/kg with no schedule modification . Three infusion of CIK cells will be administered every 3 weeks.
- Conditions
- Relapsed Hematologic Malignancy
- Being tested
- donor-derived CIK cells
- Medical subject headings
- Hematologic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
donor-derived CIK cellsBiological
Treatment plan will be based on three infusions of donor derived CIK cells given by 3 weeks intervals at increasing dose levels. No dose changes are allowed and the following planned dose levels will be administered to each patient enrolled: 5x106, 5x106 and 10x106 cells/Kg according to the dose escalating program
| Study group | Role | What they receive |
|---|---|---|
| Relapsed after Haplo transplant | Experimental | Not described Receives: Biological: donor-derived CIK cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of deaths related to study treatment death
Death, with related attributed cause of the event (e.g. treatment, toxicities, disease, other) will be assessed
Measured: Within 3 weeks after the last CIK cells infusion.
Incidence of grade >=III acute GvHD
Will be collected: date of onset, organ involvement and maximum grade of acute GVHD Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.
Measured: Within 3 weeks after the last CIK cells infusion.
Incidence of grade >= III acute GvHD
Will be collected: date of onset, organ involvement and maximum grade of acute GVHD. Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.
Measured: at +100 days after the last infusion of CIK cells
Secondary outcomes (6)
Incidence of any grade acute GvHD
Will be collected: date of onset, organ involvement and maximum grade of acute GVHD. Staging and Grading of Acute GvHD will be evaluated according to Glucksberg criteria.
Measured: at day +100 after last CIK infusion
Incidence of any grade chronic GvHD
Chronic GVHD will be evaluated according to the National Institutes of Health
Consensus Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:
Diagnosis and Staging Working Group Report. The following data will be collected: date of onset, organ involvement, maximum organ score and maximum global scoring of chronic GVHD.
Measured: at days +100, +365 after last CIK infusion
Incidence of Adverse events (AEs) and laboratory abnormalities.
Number, causality and intensity of all adverse events occurring during the study will be evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03 and MedDRA code (current version).
Measured: Up to 365 days from last CIK infusion
Evaluation of Response of Disease
Response of Disease will be assessed based on detection of any evidence of molecular, cytogenetic, chimerism or hematologic disease progression, including loss of complete donor chimerism.
Measured: at day +21, +100 and +365 after the last CIK cell infusion, or before if clinically indicated according to Investigator's judgment. For patients with acute leukemia disease response will be evaluated also after 60 days from the last CIK infusion.
Progression Free Survival
Progression free survival will be estimated as the probability of patients of being alive free of progression (stable disease) or free of disease since enrollment up to
1 year after last cells infusion (day +365). Thus, death for disease, disease relapse and disease progression are treated as events. (Death for other cause than disease will treated as competing events). Patients alive, patients in stable disease and those free of disease at their last follow-up will be censored.
Measured: Since enrollment up to 1 year after last cells infusion (day +365).
Overall Survival
Overall survival will be estimated as the probability of survival irrespective of disease state since enrollment up to 1 year after last cells infusion (day +365).
Patients alive at their last follow-up are censored.
Measured: Since enrollment up to 365 days after last CIK infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2019
- Study start13 Jan 2019
- Primary completionMay 2022 (estimated)
- Study completionMay 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (25)Papers the sponsor has linked to this study.
- Other trials for Relapsed Hematologic MalignancyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Patients relapse after haplo-HSCT for hematologic malignancies
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- A.O. Ospedale Papa Giovanni XXIII
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Rambaldi Alessandro, A.O. Ospedale Papa Giovanni XXIII
- Investigators
- Alessandro Rambaldi, MD, Principal investigator, A.O. Ospedale Papa Giovanni XXIII
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03821519
- Sponsor's protocol ID
- EudraCT 2018-000716-24
- Acronym
- Haplo-CIK
- Status last verified
- Dec 2021
- First submitted
- 22 Jan 2019
- Last updated
- 23 Dec 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Slavin S, Ackerstein A, Morecki S, Gelfand Y, Cividalli G. Immunotherapy of relapsed resistant chronic myelogenous leukemia post allogeneic bone marrow transplantation with alloantigen pulsed donor lymphocytes. Bone Marrow Transplant. 2001 Oct;28(8):795-8. doi: 10.1038/sj.bmt.1703223.
PubMed 11781634Ghiso A, Raiola AM, Gualandi F, Dominietto A, Varaldo R, Van Lint MT, Bregante S, Di Grazia C, Lamparelli T, Galaverna F, Stasia A, Luchetti S, Geroldi S, Grasso R, Colombo N, Bacigalupo A. DLI after haploidentical BMT with post-transplant CY. Bone Marrow Transplant. 2015 Jan;50(1):56-61. doi: 10.1038/bmt.2014.217. Epub 2014 Oct 13.
PubMed 25310304Franceschetti M, Pievani A, Borleri G, Vago L, Fleischhauer K, Golay J, Introna M. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol. 2009 May;37(5):616-628.e2. doi: 10.1016/j.exphem.2009.01.010.
PubMed 19375652de Lima M, Porter DL, Battiwalla M, Bishop MR, Giralt SA, Hardy NM, Kroger N, Wayne AS, Schmid C. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: part III. Prevention and treatment of relapse after allogeneic transplantation. Biol Blood Marrow Transplant. 2014 Jan;20(1):4-13. doi: 10.1016/j.bbmt.2013.08.012. Epub 2013 Sep 7.
PubMed 24018392Introna M, Borleri G, Conti E, Franceschetti M, Barbui AM, Broady R, Dander E, Gaipa G, D'Amico G, Biagi E, Parma M, Pogliani EM, Spinelli O, Baronciani D, Grassi A, Golay J, Barbui T, Biondi A, Rambaldi A. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica. 2007 Jul;92(7):952-9. doi: 10.3324/haematol.11132.
PubMed 17606446Laport GG, Sheehan K, Baker J, Armstrong R, Wong RM, Lowsky R, Johnston LJ, Shizuru JA, Miklos D, Arai S, Benjamin JE, Weng WK, Negrin RS. Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011 Nov;17(11):1679-87. doi: 10.1016/j.bbmt.2011.05.012. Epub 2011 May 25.
PubMed 21664472Introna M, Lussana F, Algarotti A, Gotti E, Valgardsdottir R, Mico C, Grassi A, Pavoni C, Ferrari ML, Delaini F, Todisco E, Cavattoni I, Deola S, Biagi E, Balduzzi A, Rovelli A, Parma M, Napolitano S, Sgroi G, Marrocco E, Perseghin P, Belotti D, Cabiati B, Gaipa G, Golay J, Biondi A, Rambaldi A. Phase II Study of Sequential Infusion of Donor Lymphocyte Infusion and Cytokine-Induced Killer Cells for Patients Relapsed after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017 Dec;23(12):2070-2078. doi: 10.1016/j.bbmt.2017.07.005. Epub 2017 Jul 13.
PubMed 28712935Rettinger E, Huenecke S, Bonig H, Merker M, Jarisch A, Soerensen J, Willasch A, Bug G, Schulz A, Klingebiel T, Bader P. Interleukin-15-activated cytokine-induced killer cells may sustain remission in leukemia patients after allogeneic stem cell transplantation: feasibility, safety and first insights on efficacy. Haematologica. 2016 Apr;101(4):e153-6. doi: 10.3324/haematol.2015.138016. Epub 2016 Jan 14. No abstract available.
PubMed 26768688Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036.
PubMed 14673054Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
PubMed 25113753Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.
PubMed 16609072Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.
PubMed 27895058Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. doi: 10.1038/leu.2008.291. Epub 2008 Oct 30.
PubMed 18971951Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, Gotlib J, Dupriez B, Pardanani A, Harrison C, Hoffman R, Gisslinger H, Kroger N, Thiele J, Barbui T, Barosi G. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013 Aug 22;122(8):1395-8. doi: 10.1182/blood-2013-03-488098. Epub 2013 Jul 9.
PubMed 23838352Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008 Dec 1;112(12):4371-83. doi: 10.1182/blood-2008-03-077974.
PubMed 19029455
Study at a glance
From the registry record, last updated by the sponsor on 23 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Trial of Donor Derived Cytokine Induced Killer (CIK) Cells Infusion for Relapsed Hematologic Malignancy After Haploidentical Stem Cell Transplantation
- ClinicalTrials.gov ID
- NCT03821519
- Acronym / sponsor ID
- Haplo-CIK / EudraCT 2018-000716-24
- Conditions
- Relapsed Hematologic Malignancy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- A.O. Ospedale Papa Giovanni XXIIIUniversity, hospital or other
- Study start
- 13 Jan 2019 (actual)
- Primary completion
- May 2022 (estimated)
- Study completion
- May 2023 (estimated)
- First posted
- 29 Jan 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The haematological neoplasia relapse is the cause of higher mortality after allogeneic stem cell transplantation (HSCT). When transplantation fails the most common therapeutic strategy is to increase the antitumor activity of the donor's immune system through the infusion of donor Lymphocytes (DLI). The use of DLI may limit the relapse, but may induce transplantation disease against the host (GvHD), in 40-60% of patients. With advances in transplantation procedures, the use of non-compatible (HLA-mismatched) haploidentical (aplo) donor cells has become feasible and is increasing. However, strategies for immune control of relapse after HSCT from haploidentical donor are hampered by the absence of prospective data that can guide treatment and limit the induction of GvHD in the setting of the HLA difference between the donor and the recipient. Cytokine-induced Killer Cells (CIK) are T lymphocytes from haploidentical donor expressing CD56 (e.g., double positive cells at CD3 / CD56). CIK are a product of advanced cell therapy (Advanced Therapeutic Medicinal Product, ATMP) for somatic cell therapy and have a reduced histocompatibility (MHC) complex: are cytotoxic, anti-tumor cells, possess the characteristics of both T cells and Natural Killer (NK) and show in vivo a very strong cytolytic activity against leukemia, but a low reactivity against the host. Therefore, this study has as its primary objective to investigate the safety of CIK cells deriving from the donor, especially in terms of the onset of GvHD, used as a treatment for relapse after transplantation with haploidentical stem cells. The study will allow to evaluate the possibility of using CIK cells, at the indicated dose combination (5x10 * 6 cells / kg, 5x10 * 6 and 10x10 * 6 cells / kg) as an effective and safe therapy in the context of haploidentical transplantation.
Detailed description
Disease relapse is a major cause of mortality following allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. When allogeneic transplant fails the most common therapeutic strategy is to increase the anti-tumor activity of donor immune system through infusion of donor lymphocytes (DLI). Use of DLI can effectively treat limited relapses, but can induce graft-versus-host disease (GvHD) in the range of 40-60% of the patients. With the advances in HSCT procedure, the use of HLA-mismatched (haplo) family donors became feasible and extended the opportunity for HSCT to almost all patients lacking an HLA-matched donor. Due to the promising results of the procedure and the easier access to the donor, the number of haplo-HSCT transplant is steeply increasing. However, strategies aiming at eliciting the immune control of the relapse after haplo-HSCT are hampered by absence of prospective data that guide treatment and the fear of inducing GvHD in this setting of profound HLA disparity between donor and recipient.
- Despite the use of DLI in haplo-HSCT is not a standard practice, DLI are occasionally empirically used, mainly due to the lack of alternative treatment.
- Cytokine Induced Killer (CIK) cells are T lymphocytes expressing the CD56 marker, i.e. CIK are CD3/CD56 double positive cells. CIK cells are produced in vitro by incubating blood leukocytes according to a specific expansion protocol which includes initial stimulation with Interferon-gamma and anti-CD3 antibody, followed by expansion with (Interleukin-2) IL-2. CIK cells are non MHC restricted, cytotoxic, anti-tumoral cells which share characteristics of both T and NK cells and show in vivo a very strong cytolytic activity against leukemia, graft versus leukemia, while being essentially devoid of graft versus host reactivity. They show a natural non-MHC restricted (T Cell Receptor)TCR independent cytotoxicity against malignant targets cells, involving perforin and granzyme release and NKG2D, as well as CD56 and other small target molecules. In the past 15 years the investigators have extensively studied the use of cytokine-induced killer (CIK) cells as alternative cellular therapy to treat disease relapse after HSCT. The key feature of CIK cell therapy in the context of haplo- HSCT is the lower risk of inducing GvHD compared to DLI, that could permit to avoid the devastating effect of acute and chronic GvHD in terms of decreased survival, quality of life, disability and need of additional care. Indeed, beyond the dramatic impact in the quality and quantity of life of patients, costs for the health system of the management of acute and chronic GvHD are exceedingly high. At this regard, CIK cells have been regarded as the cellular therapy that is associated with a more favourable therapeutic index compared to DLI.
- In an early Phase I study the investigators observed remissions in 3 of 11 patients who were treated with infusion of CIK cells at a time when malignant cells were detectable. In each of these 3 cases, the patient had been previously treated unsuccessfully with conventional DLI. Successful remission induction by infusion of CIK cells after unsuccessful DLI suggests that the (Graft Versus Leukemia) GVL activity of CIK cells was attributable to NK-T cells. In a subsequent phase I clinical trial was assessed the feasibility of using CIK cells from HLA-matched sibling donors. Using a dose escalation design, the investigators showed that CIK cells could be given at doses as high as 1x10^8 per kg recipient body weight without causing acute infusion-related toxicity. The investigators recently reported the final results of a phase II multicenter pilot study, showing that CIK cell treatment for the relapse after HSCT is effective with a low toxicity in terms of GvHD compared to DLI. Importantly for the present proposal, in this study, 5 patients were treated in the context of haplo- HSCT. These did not show any different response or safety concern compared to other patients, suggesting the feasibility of this approach in a haploidentical context. Similarly, another study of CIK cellular therapy in HSCT including also patients with haploidentical donors confirmed the feasibility and safety of this approach. Considering that infused T cells are associated with risk of GvHD induction, especially in the haploidentical transplantation setting, novel cellular therapies manipulated to minimize GvHD while enhancing the graft-versus leukemia efficacy need to be tested in early phase clinical trials. Thus, the aim of the present proposal is to use CIK cells as a platform for a safe and effective cellular therapy in the context of haploidentical transplantation. As no dose limiting toxicity has been reached in phase I/II studies and no clear relationship among dose and both toxicity and response emerged so far, in the present study the investigators planned to use the final standard dose of our previous phase II study of 5x106 cells/kg, 5x10^6 and 10x10^6 cells/kg with no schedule modification . Three infusion of CIK cells will be administered every 3 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Patients relapse after haplo-HSCT for hematologic malignancies
| Arm | Type | Receives |
|---|---|---|
| Relapsed after Haplo transplant | Experimental | Biological: donor-derived CIK cells |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Male or female patients 18 years or older
- Patients treated with haploidentical allogeneic transplantation for hematologic malignancies, excluding Chronic Myeloid Leukemia (CML), such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), myelofibrosis (MF) and myelodysplastic syndrome (MDS)
- To be enrolled to the safety run-in cohort, patients must have:
- Availability of a donor willing to donate peripheral blood mononuclear cells
- Withdrawn of immune suppression at least 3 weeks before the beginning of the cell therapy program
Key exclusion criteria (2 listed)
- The presence of any of the following will exclude a subject from study enrolment 1. Donors positive for HIV, (Hepatitis B virus) HBV, (Hepatitis C virus) HCV, Treponema or unfit to donate peripheral blood mononuclear cells 2. Patients with active grade 2 or more acute or moderate chronic GVHD at study entry or before CIK infusion 3. Patients with rapidly progressive disease or not controlled by palliative supportive treatments, including chemotherapy, and with life expectancy less than 8 weeks 4. Any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
- -
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| donor-derived CIK cellsTreatment plan will be based on three infusions of donor derived CIK cells given by 3 weeks intervals at increasing dose levels. No dose changes are allowed and the following planned dose levels will be administered to each patient enrolled: 5x106, 5x106 and 10x106 cells/Kg according to the dose escalating program | Biological | Relapsed after Haplo transplant |
Primary outcome
Number of deaths related to study treatment death
Time frame: Within 3 weeks after the last CIK cells infusion.
Death, with related attributed cause of the event (e.g. treatment, toxicities, disease, other) will be assessed
Incidence of grade >=III acute GvHD
Time frame: Within 3 weeks after the last CIK cells infusion.
Will be collected: date of onset, organ involvement and maximum grade of acute GVHD Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.
Incidence of grade >= III acute GvHD
Time frame: at +100 days after the last infusion of CIK cells
Will be collected: date of onset, organ involvement and maximum grade of acute GVHD. Staging and Grading of Acute GvHD will be evaluated according to Glucksberg.
6 secondary outcomes
Incidence of any grade acute GvHD
Time frame: at day +100 after last CIK infusion
Incidence of any grade chronic GvHD
Time frame: at days +100, +365 after last CIK infusion
Incidence of Adverse events (AEs) and laboratory abnormalities.
Time frame: Up to 365 days from last CIK infusion
Evaluation of Response of Disease
Time frame: at day +21, +100 and +365 after the last CIK cell infusion, or before if clinically indicated according to Investigator's judgment. For patients with acute leukemia disease response will be evaluated also after 60 days from the last CIK infusion.
Progression Free Survival
Time frame: Since enrollment up to 1 year after last cells infusion (day +365).
Overall Survival
Time frame: Since enrollment up to 365 days after last CIK infusion
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Dec 2021.
- Background: PubMed 11781634Slavin S, Ackerstein A, Morecki S, Gelfand Y, Cividalli G. Immunotherapy of relapsed resistant chronic myelogenous leukemia post allogeneic bone marrow transplantation with alloantigen pulsed donor lymphocytes. Bone Marrow Transplant. 2001 Oct;28(8):795-8. doi: 10.1038/sj.bmt.1703223.
- Background: PubMed 25310304Ghiso A, Raiola AM, Gualandi F, Dominietto A, Varaldo R, Van Lint MT, Bregante S, Di Grazia C, Lamparelli T, Galaverna F, Stasia A, Luchetti S, Geroldi S, Grasso R, Colombo N, Bacigalupo A. DLI after haploidentical BMT with post-transplant CY. Bone Marrow Transplant. 2015 Jan;50(1):56-61. doi: 10.1038/bmt.2014.217. Epub 2014 Oct 13.
- Background: PubMed 19375652Franceschetti M, Pievani A, Borleri G, Vago L, Fleischhauer K, Golay J, Introna M. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol. 2009 May;37(5):616-628.e2. doi: 10.1016/j.exphem.2009.01.010.
- Background: PubMed 24018392de Lima M, Porter DL, Battiwalla M, Bishop MR, Giralt SA, Hardy NM, Kroger N, Wayne AS, Schmid C. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: part III. Prevention and treatment of relapse after allogeneic transplantation. Biol Blood Marrow Transplant. 2014 Jan;20(1):4-13. doi: 10.1016/j.bbmt.2013.08.012. Epub 2013 Sep 7.
- Background: PubMed 17606446Introna M, Borleri G, Conti E, Franceschetti M, Barbui AM, Broady R, Dander E, Gaipa G, D'Amico G, Biagi E, Parma M, Pogliani EM, Spinelli O, Baronciani D, Grassi A, Golay J, Barbui T, Biondi A, Rambaldi A. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica. 2007 Jul;92(7):952-9. doi: 10.3324/haematol.11132.
- Background: PubMed 21664472Laport GG, Sheehan K, Baker J, Armstrong R, Wong RM, Lowsky R, Johnston LJ, Shizuru JA, Miklos D, Arai S, Benjamin JE, Weng WK, Negrin RS. Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011 Nov;17(11):1679-87. doi: 10.1016/j.bbmt.2011.05.012. Epub 2011 May 25.
- Background: PubMed 28712935Introna M, Lussana F, Algarotti A, Gotti E, Valgardsdottir R, Mico C, Grassi A, Pavoni C, Ferrari ML, Delaini F, Todisco E, Cavattoni I, Deola S, Biagi E, Balduzzi A, Rovelli A, Parma M, Napolitano S, Sgroi G, Marrocco E, Perseghin P, Belotti D, Cabiati B, Gaipa G, Golay J, Biondi A, Rambaldi A. Phase II Study of Sequential Infusion of Donor Lymphocyte Infusion and Cytokine-Induced Killer Cells for Patients Relapsed after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017 Dec;23(12):2070-2078. doi: 10.1016/j.bbmt.2017.07.005. Epub 2017 Jul 13.
- Background: PubMed 26768688Rettinger E, Huenecke S, Bonig H, Merker M, Jarisch A, Soerensen J, Willasch A, Bug G, Schulz A, Klingebiel T, Bader P. Interleukin-15-activated cytokine-induced killer cells may sustain remission in leukemia patients after allogeneic stem cell transplantation: feasibility, safety and first insights on efficacy. Haematologica. 2016 Apr;101(4):e153-6. doi: 10.3324/haematol.2015.138016. Epub 2016 Jan 14. No abstract available.
- Background: PubMed 14673054Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036.
- Background: PubMed 25113753Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
- Background: PubMed 16609072Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.
- Background: PubMed 27895058Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alessandro Rambaldi, MD principal investigator
A.O. Ospedale Papa Giovanni XXIII
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing donor-derived CIK cells in people with Relapsed Hematologic Malignancy, run by A.O. Ospedale Papa Giovanni XXIII at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 23 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Alessandro Rambaldi, MD (+39 035 2673683, arambaldi@asst-pg23.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of deaths related to study treatment death (time frame: Within 3 weeks after the last CIK cells infusion.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03821519, which also lists 25 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Dec 2021.