Addition of Gemcitabine to Pre Allo-HSCT Conditioning for Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia, Adult Clinical Trial

Official title:

Addition of Gemcitabine to the Standard Reduced Busulfan and Cyclophosphamide (BUCY2) Pre Allogeneic Hematopoietic Stem Cell Transplantation Conditioning for Acute Lymphoblastic Leukemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03339700
• Other study ID #: INCMNSZ REF 2235
• Status: Recruiting
• Phase: Phase 2
• Start date: September 15, 2018
• Est. completion date: September 2021

Study information

• Verified date: January 2020
• Source: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Contact: Eucario Leon Rodriguez, M.D.
• Phone: 525554870900
• Email: eucarios[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main purpose of the project is to evaluate the disease free survival and overall survival in patients diagnosed with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) adding gemcitabine to the standard institutional conditioning regimen based on two alkylating drugs, reduced busulfan and cyclophosphamide (reduced BUCY 2).

Description:

In the last decade, hematopoietic stem cell transplantation (HSCT) has become an efficient strategy for the treatment of high risk acute lymphoblastic leukemias. Lymphoid acute leukemias (ALL) 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. Many studies have shown a decrease in relapse and an increase in overall survival with allogeneic HSCT, however, despite the fact that results in ALL have improved in the past years, achieving complete remission (CR) in approximately 75% of the patients, the relapse rate remains high and long term survival is lower than 50% depending on age and disease characteristics. On the other hand, it has been stated that relapse is higher when an allo-HSCT is performed in second CR, obtaining poorer results compared to performing HSCT in first CR, although better than chemotherapy alone (87% probability of relapse).

It is necessary to implement strategies that increase efficiency of pre transplant conditioning regimens in patients diagnosed with ALL undergoing an allo-HSCT in order to reduce relapse and increase overall survival. The hypothesis is that adding gemcitabine to the standard institutional conditioning regimen (reduced BUCY 2) in patients with ALL undergoing an allo-HSCT, the relapse free survival as well as the overall survival will improve, because it has been demonstrated in other malignant hematological diseases that gemcitabine plus two alkylating agents, facilitates synergism with busulfan and melphalan, inhibiting the DNA damage repair and causing a higher cytotoxic effect.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: September 2021
• Est. primary completion date: September 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Diagnosis of acute lymphoblastic leukemia in 2nd complete remission or primary refractory disease, candidates to hematopoietic stem cell transplantation.

• Hemoglobin = 10 g/dl, Absolute Neutrophil Count = 1 x 103/mm3, and Platelets = 100,000 /µL

• Eastern Cooperative Oncology Group status (ECOG) =2 oR Karnofsky =80%

• Signed Informed Consent

• Left ventricular ejection fraction (LVEF) >40%

• Normal liver function enzyme tests

• Preserved renal function

Exclusion Criteria:

• Patients not willing to participate or to sign the informed consent

• Patients who do not meet the inclusion criteria

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia, Adult
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Gemcitabine
4800mg/m2, intravenous (IV), divided 4 days, 1200mg/m2/day, during days -5 to -2
• Busulfan
12mg/kg, Oral, divided in 4 days, 3mg/kg/day Oral, during days -7 to -4.
• Cyclophosphamide
80mg/kg, intravenous (IV), divided in 2 days, 40mg/kg/day IV, during days -3 and -2.

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Bone Marrow HSC (allogeneic HSCT) transfusion, day 0

Locations

Country	Name	City	State
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Mexico City	Distrito Federal

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Country where clinical trial is conducted

Mexico, 

References & Publications (9)

Anderlini P, Saliba RM, Ledesma C, Chancoco C, Alousi AM, Shpall EJ, Popat UR, Hosing CM, Khouri IF, Nieto Y, Ciurea S, Younes A, Fanale MA, Acholonu S, Valverde R, Champlin RE. Gemcitabine, fludarabine and melphalan as a reduced-intensity conditioning regimen for allogeneic stem cell transplant in relapsed and refractory Hodgkin lymphoma: preliminary results. Leuk Lymphoma. 2012 Mar;53(3):499-502. doi: 10.3109/10428194.2011.615427. Epub 2011 Oct 24. — View Citation

Braakhuis BJ, Ruiz van Haperen VW, Boven E, Veerman G, Peters GJ. Schedule-dependent antitumor effect of gemcitabine in in vivo model system. Semin Oncol. 1995 Aug;22(4 Suppl 11):42-6. — View Citation

Csoka K, Liliemark J, Larsson R, Nygren P. Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin Oncol. 1995 Aug;22(4 Suppl 11):47-53. — View Citation

Matsuda A, Sasaki T. Antitumor activity of sugar-modified cytosine nucleosides. Cancer Sci. 2004 Feb;95(2):105-11. Review. — View Citation

Nieto Y, Thall P, Valdez B, Andersson B, Popat U, Anderlini P, Shpall EJ, Bassett R, Alousi A, Hosing C, Kebriaei P, Qazilbash M, Frazier E, Gulbis A, Chancoco C, Bashir Q, Ciurea S, Khouri I, Parmar S, Shah N, Worth L, Rondon G, Champlin R, Jones RB. High-dose infusional gemcitabine combined with busulfan and melphalan with autologous stem-cell transplantation in patients with refractory lymphoid malignancies. Biol Blood Marrow Transplant. 2012 Nov;18(11):1677-86. doi: 10.1016/j.bbmt.2012.05.011. Epub 2012 May 27. — View Citation

Peters GJ, Ruiz van Haperen VW, Bergman AM, Veerman G, Smitskamp-Wilms E, van Moorsel CJ, Kuiper CM, Braakhuis BJ. Preclinical combination therapy with gemcitabine and mechanisms of resistance. Semin Oncol. 1996 Oct;23(5 Suppl 10):16-24. Review. — View Citation

Plunkett W, Huang P, Searcy CE, Gandhi V. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol. 1996 Oct;23(5 Suppl 10):3-15. Review. — View Citation

Spasokoukotskaja T, Arnér ES, Brosjö O, Gunvén P, Juliusson G, Liliemark J, Eriksson S. Expression of deoxycytidine kinase and phosphorylation of 2-chlorodeoxyadenosine in human normal and tumour cells and tissues. Eur J Cancer. 1995;31A(2):202-8. — View Citation

Wang E, Gulbis A, Hart JW, Nieto Y. The emerging role of gemcitabine in conditioning regimens for hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014 Sep;20(9):1382-9. doi: 10.1016/j.bbmt.2014.04.025. Epub 2014 May 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Free Survival	Time between transplantation and relapse or last follow-up	3 years
Secondary	Overall Survival	Time between transplantation and dead or last follow-up	5 years