Chemo Sensitization Before Hematopoietic Stem Cell Transplantation in Patients With Acute Leukemia in Complete Remission

NCT ID: NCT02605460

Last Updated: 2020-01-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-02-28

Study Completion Date

2021-11-30

Brief Summary

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The purpose of this study is to evaluate the disease free survival and the overall survival in patients with acute leukemia in first or second complete remission after administrating a CXCR4 antagonist, as a chemo sensitization strategy, plus chemotherapy as the conditioning regimen for autologous or allogeneic hematopoietic stem cell transplantation (HSCT).

Detailed Description

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In the last decade, HSCT has become an efficient strategy for the treatment of many malignant and non-malignant hematological diseases, being the most common, according to the European Bone Marrow Transplantation (EBMT), acute leukemias. Both myeloid and lymphoid acute leukemias are considered malignant clonal diseases of the hematopoietic stem cells, and represent a therapeutic challenge due to the high relapse rate and mortality using conventional chemotherapy regimens. HSC reside mainly within the bone marrow, protected by a microenvironment or niche, which is perivascular, created partly by mesenchymal stromal cells and endothelial cells. Interactions between these cells and many adhesion molecules are considered a key factor for growing, transformation, and migration of neoplastic cells. The main pathway involved in the cellular transit regulation is chemokine receptor 4 (CXCR4) and its chemokine ligand 12 (CXCL12), responsible of mediating interactions between the HSC and stromal cells, and whose blocking through other cytokines and antagonists of the CXCR4 receptor (plerixafor) favors chemotaxis and HSC output to peripheral blood. Such strategy has become an effective technique to increase mobilization and harvesting in patients undergoing stem cell transplantations.

On the other hand, some preclinical studies have shown that the activation of CXCL12 pathway favors tumor growth, promoting survival and invasion of the malignant cells, recruiting stromal cells that facilitate their proliferation and promote angiogenesis directly. In such way, this pathway has been considered a therapeutic target to block their activity and inhibit tumor progression.

Patients with acute leukemia in first or second complete remission undergoing autologous or allogeneic hematopoietic stem cell transplantation (HSCT), commonly present low response rates and low survival due to persistent minimal residual disease, despite conventional high dose chemotherapy regimens. It is necessary to create strategies to increase the destruction rate of neoplastic cells in patients with acute leukemia candidates to HSCT. Our hypothesis is that the administration of a CXCR4 antagonist as part of the conditioning regimen in patients with acute leukemia candidates to HSCT will allow the mobilization and sensitization of leukemia blast cells, eradicating efficiently the minimal residual disease, responsible of posterior relapse, and will achieve a higher response rate and survival of patients undergoing this procedure.

Conditions

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Acute Myeloid Leukemia Acute Lymphoid Leukemia

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Unique

Patients will receive reduced Busulfan and Cyclophosphamide (BUCY) 2 conditioning regimen, consisting in the administration of two medications: Busulfan and Cyclophosphamide Plus: CXCR4 Antagonist. Then they will undergo a Hematopoietic Stem Cell Transplantation (Autologous or Allogeneic)

Group Type OTHER

Busulfan

Intervention Type DRUG

12mg/kg, Oral, divided in 4 days, 3mg/kg/day Oral, during days -7, -6, -5 y -4.

Cyclophosphamide

Intervention Type DRUG

80mg/kg, Intravenous (IV), divided in 2 days, 40mg/kg/day IV, during days -3 y -2.

CXCR4 Antagonist

Intervention Type DRUG

24mg, Subcutaneous (SC), in one day, 24mg/day SC, during day -4.

Hematopoietic Stem Cell Transplantation

Intervention Type PROCEDURE

Peripheral blood HSC (autologous HSCT) or Bone Marrow HSC (allogeneic HSCT) transfusion, day 0

Interventions

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Busulfan

12mg/kg, Oral, divided in 4 days, 3mg/kg/day Oral, during days -7, -6, -5 y -4.

Intervention Type DRUG

Cyclophosphamide

80mg/kg, Intravenous (IV), divided in 2 days, 40mg/kg/day IV, during days -3 y -2.

Intervention Type DRUG

CXCR4 Antagonist

24mg, Subcutaneous (SC), in one day, 24mg/day SC, during day -4.

Intervention Type DRUG

Hematopoietic Stem Cell Transplantation

Peripheral blood HSC (autologous HSCT) or Bone Marrow HSC (allogeneic HSCT) transfusion, day 0

Intervention Type PROCEDURE

Other Intervention Names

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Myleran Cytoxan Plerixafor Mozobil Bone Marrow Transplantation

Eligibility Criteria

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Inclusion Criteria

* Diagnosis of Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL), candidates to HSCT
* Allogeneic HSCT: High risk AML in first complete remission (CR), AML in second CR, and ALL in first or second CR with a matched or half-matched (haploidentical) related or unrelated donor
* Autologous HSCT: Intermediate risk AML in first CR, ALL in first or second CR without a donor
* Normal liver function enzyme tests
* Preserved renal function
* Eastern Cooperative Oncology Group score ≤2 or Karnofsky ≥80%
* Left ventricle ejection fraction (LVEF) \>40%
* Hemoglobin (Hb) ≥ 10 g/dl, Absolute Neutrophil Count ≥ 1 x 103/mm3, and Platelets ≥ 100,000 /µL
* Signed Informed Consent

Exclusion Criteria

* Patients not willing to participate or to sign the informed consent
Minimum Eligible Age

18 Years

Maximum Eligible Age

60 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Eucario Leon Rodriguez, M.D.

Role: PRINCIPAL_INVESTIGATOR

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Monica M Rivera Franco, M.D.,MSc

Role: PRINCIPAL_INVESTIGATOR

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Locations

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Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Mexico City, Mexico City, Mexico

Site Status RECRUITING

Countries

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Mexico

Central Contacts

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Eucario Leon Rodriguez, M.D.

Role: CONTACT

525554870900 ext. 2255

Monica M Rivera Franco, M.D.,MSc

Role: CONTACT

525554870900 ext. 2254

Facility Contacts

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Eucario Leon Rodriguez, M.D.

Role: primary

525554870900 ext. 2255

Monica M Rivera Franco, M.D.

Role: backup

525554870900 ext. 2254

References

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Jantunen E. Novel strategies for blood stem cell mobilization: special focus on plerixafor. Expert Opin Biol Ther. 2011 Sep;11(9):1241-8. doi: 10.1517/14712598.2011.601737.

Reference Type BACKGROUND
PMID: 21806478 (View on PubMed)

DiPersio JF, Ho AD, Hanrahan J, Hsu FJ, Fruehauf S. Relevance and clinical implications of tumor cell mobilization in the autologous transplant setting. Biol Blood Marrow Transplant. 2011 Jul;17(7):943-55. doi: 10.1016/j.bbmt.2010.10.018. Epub 2010 Oct 22.

Reference Type BACKGROUND
PMID: 20971201 (View on PubMed)

Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res. 2011 Apr 15;17(8):2074-80. doi: 10.1158/1078-0432.CCR-10-2636. Epub 2011 Feb 24.

Reference Type BACKGROUND
PMID: 21349998 (View on PubMed)

Redjal N, Chan JA, Segal RA, Kung AL. CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. Clin Cancer Res. 2006 Nov 15;12(22):6765-71. doi: 10.1158/1078-0432.CCR-06-1372.

Reference Type BACKGROUND
PMID: 17121897 (View on PubMed)

Nervi B, Ramirez P, Rettig MP, Uy GL, Holt MS, Ritchey JK, Prior JL, Piwnica-Worms D, Bridger G, Ley TJ, DiPersio JF. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood. 2009 Jun 11;113(24):6206-14. doi: 10.1182/blood-2008-06-162123. Epub 2008 Dec 2.

Reference Type BACKGROUND
PMID: 19050309 (View on PubMed)

Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, Kulkarni S, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Vij R, Westervelt P, DiPersio JF. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood. 2012 Apr 26;119(17):3917-24. doi: 10.1182/blood-2011-10-383406. Epub 2012 Feb 2.

Reference Type BACKGROUND
PMID: 22308295 (View on PubMed)

Other Identifiers

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INCMNSZ REF 917

Identifier Type: -

Identifier Source: org_study_id

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