Clinical trial NCT01025778: Haploidentical Stem Cell Transplantation for Children With Therapy Resistant Leukemia
Official title: Clofarabine Based Remission Induction Followed by Haploidentical Stem Cell Transplantation in Children With Refractory Hematological Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Keywords: Haploidentical hematopoietic stem cell transplantation
Graft versus host disease
Donor lymphocyte infusion
Graft versus leukemia effect
Immunological recovery
Bridge to transplant approach
Therapy resistant leukemia
Hematological malignancy
Lead sponsor: Lund University Hospital
Sponsor class: OTHER
First posted: 2009-12-04
Enrollment: 7
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Despite substantial progress in the treatment pediatric acute leukemia a significant number of children will experience primary or secondary resistance to the treatment. In other words it will be not possible to achieve remission using standard chemotherapy (primary resistance) or the patients will develop chemotherapy resistant relapse (secondary resistance). Children failing to achieve remission or children relapsing after previous allogeneic stem cell transplantation have short life expectancy and palliative treatment still remains the most reasonable option as the escalation of conventional chemotherapy is not longer effective.

The role of Graft versus Leukemia effect was postulated as one of the mechanisms contributing to the leukemia control/eradication after transplantation of hematopoietic stem cells.

In this study the investigators combine intensified multiagent Clofarabine containing chemotherapy with post-induction treatment intensification using reduced intensity conditioning followed by haploidentical hematopoietic stem cell transplantation. Introducing a new drug to the treatment of resistant leukemia the investigators want to achieve a response which allows us to proceed to immediate haploidentical transplantation. Using a haploidentical donor the investigators can avoid time consuming search for an unrelated donor and perform the transplantation at the optimal time-point. Combating therapy resistant leukemia the investigators would like to evoke and utilize potential Graft-versus-Leukemia effect which is much more pronounced in the haploidentical setting, as it is well documented that allogeneic transplantation with a matched donor is not effective in resistant disease. The use of best KIR mismatch donor and post-transplant donor lymphocyte infusion will be implemented in order to develop/intensify graft versus leukemia effect.


Eligibility criteria: Inclusion Criteria:

Target population

1. Refractory acute lymphoblastic leukemia

   * Chemoresistant isolated or combined bone marrow relapse

     * Relapse after during/after conventional treatment
     * Relapse ≥6 months after allogeneic stem cell transplantation
   * Primary induction failure
   * Isolated extramedullary relapse after previous HSCT (\>6 months)
2. Refractory acute myeloblastic leukemia including sAML

   * Chemoresistant relapse

     * Relapse after during/after conventional treatment
     * Relapse ≥6 months after allogeneic stem cell transplantation
   * Primary induction failure

Inclusion criteria to start induction treatment with multidrug regimen

1. Age ≥ 1 and ≤21 years
2. Patients with previous HCST ≥ 6 m
3. Provide signed written informed consent patients', and patients' parents /guardians

   * Older children should be capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent as well.
4. Cardiac output SF ≥25%
5. Have adequate renal and hepatic functions as indicated by the following laboratory values:

   * Calculated creatinine clearance ≥90 ml/min/1.73 m2
   * Serum bilirubin ≤1.5 X upper limit of normal (ULN)
   * Aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 X ULN
   * Alkaline phosphatase ≤ 2.5 X ULN
6. Performance score of ≥70% (Lansky or Karnofsky)
7. A suitable haploidentical family member available for stem cell donation, \> 18 years of age, fulfilling institutional criteria for blood and marrow donation.
8. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

Inclusion criteria to proceed to transplant after induction

1. Cardiac output SF ≥25%
2. Have adequate renal and hepatic functions as indicated by the following laboratory values:

   * Calculated creatinine clearance ≥90 ml/min/1.73 m2
   * Serum bilirubin ≤1.5 X upper limit of normal (ULN)
   * Aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 X ULN
   * Alkaline phosphatase ≤ 2.5 X ULN
3. Performance score of ≥70% (Lansky or Karnofsky)
4. A suitable haploidentical family member available for stem cell donation, \> 18 years of age, fulfilling institutional criteria for blood and marrow donation.
5. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.
6. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.
7. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:

1. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
2. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea.

   The patient must have recovered from all acute toxicities from any previous therapy.
3. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment.
4. Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
5. Pregnant or lactating patients.
6. Any significant concurrent malignant disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Primary outcomes:
measure: Event free survival
timeFrame: 1 year from transplantation
Secondary outcomes:
measure: Evaluation of induction efficacy by response rate and the number of children proceeding to transplant
timeFrame: 3 months from induction start
measure: Tolerance, safety and quality of life
timeFrame: 1 year from transplantation
measure: Hematological and immunological recovery
timeFrame: 100 days fron tranplantation
measure: Incidence of graft versus host disease
timeFrame: 100 days from transplantation
Other outcomes:
Locations:
city: Lund
country: Sweden
facility: Lund University Hospital
Study officials:
affiliation: Lund University Hospital
name: Jacek Toporski, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. doi: 10.1111/j.1365-2141.2009.07882.x. Epub 2009 Aug 29.
citation: Hijiya N, Gaynon P, Barry E, Silverman L, Thomson B, Chu R, Cooper T, Kadota R, Rytting M, Steinherz P, Shen V, Jeha S, Abichandani R, Carroll WL. A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia. 2009 Dec;23(12):2259-64. doi: 10.1038/leu.2009.185. Epub 2009 Sep 10.
citation: Stern M, Ruggeri L, Mancusi A, Bernardo ME, de Angelis C, Bucher C, Locatelli F, Aversa F, Velardi A. Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood. 2008 Oct 1;112(7):2990-5. doi: 10.1182/blood-2008-01-135285. Epub 2008 May 20.
citation: Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. doi: 10.1200/JCO.2005.03.8554.
citation: Toporski J, Krol L, Dykes J, Hakansson Y, Pronk C, Turkiewicz D. The combination of clofarabine, etoposide, and cyclophosphamide shows limited efficacy as a bridge to transplant for children with refractory acute leukemia: results of a monitored prospective study. Pediatr Hematol Oncol. 2021 Apr;38(3):216-226. doi: 10.1080/08880018.2020.1838012. Epub 2020 Nov 5.