Infusion of Donor Derived Cytokine Induced Killer (CIK) Cells in Hematological Patients Relapsed After Haploidentical Stem Cell Transplant (Haplo-CIK)

December 22, 2021 updated by: Rambaldi Alessandro, A.O. Ospedale Papa Giovanni XXIII

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Bergamo, Italy, 24127
        • Recruiting
        • A O Papa Giovanni XXIII
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Federico Lussana, MD
        • Sub-Investigator:
          • Giuseppe Gritti, MD
        • Sub-Investigator:
          • Martino Introna, MD
        • Sub-Investigator:
          • Josee Golay, Biol.SC

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Male or female patients 18 years or older
  2. 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)

  3. 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
    • 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.
  4. Availability of a donor willing to donate peripheral blood mononuclear cells
  5. Withdrawn of immune suppression at least 3 weeks before the beginning of the cell therapy program
  6. Written informed consent prior to any study procedures being performed

  7. For female patients:

    1. being postmenopausal for at least 1 year before the screening visit,OR
    2. being surgically sterile, OR
    3. 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
    4. 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.]
  8. 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

Exclusion Criteria:

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

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Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Relapsed after Haplo transplant
Biological: donor-derived CIK cells
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Within 3 weeks after the last CIK cells infusion.
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.
Within 3 weeks after the last CIK cells infusion.
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.
at +100 days after the last infusion of CIK cells

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of any grade acute GvHD
Time Frame: at day +100 after last CIK 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 criteria.
at day +100 after last CIK infusion
Incidence of any grade chronic GvHD
Time Frame: at days +100, +365 after last CIK infusion

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.
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
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).
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.
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.
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).

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.
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

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.
Since enrollment up to 365 days after last CIK infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

A.O. Ospedale Papa Giovanni XXIII

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 13, 2019

Primary Completion (Anticipated)

May 1, 2022

Study Completion (Anticipated)

May 1, 2023

Study Registration Dates

First Submitted

January 22, 2019

First Submitted That Met QC Criteria

January 28, 2019

First Posted (Actual)

January 29, 2019

Study Record Updates

Last Update Posted (Actual)

December 23, 2021

Last Update Submitted That Met QC Criteria

December 22, 2021

Last Verified

December 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EudraCT 2018-000716-24

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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