Phase II/III Randomized Study of Bortezomib and Sorafenib Tosylate in Patients With De Novo Acute Myeloid Leukemia With or Without High Allelic Ratio FLT3/ITD Mutations

Status
Active
Cancer Type
Leukemia
Trial Phase
Phase III
Eligibility
Under 30, Male and Female
Study Type
Biomarker/Laboratory analysis
Treatment
NCD ID
NCT01371981
Protocol IDs
COG-AAML1031 (primary)
AAML1031
Study Sponsor
Children's Oncology Group

Summary

Rationale

Bortezomib(bore-TEZ-oh-mib)

A drug used to treat multiple myeloma. It is also used to treat mantle cell lymphoma in patients who have already received at least one other type of treatment and is being studied in the treatment of other types of cancer. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. Also called PS-341 and velcade.
and sorafenib tosylate(soh-RAF-eh-nib TOH-suh-layt)

A drug used to treat advanced kidney cancer and a type of liver cancer that cannot be removed by surgery. It is also being studied in the treatment of other types of cancer. Sorafenib tosylate stops cells from dividing and may prevent the growth of new blood vessels that tumors need to grow. It is a type of kinase inhibitor and a type of antiangiogenesis agent. Also called BAY 43-9006, Nexavar, and sorafenib.
may stop the growth of cancer(KAN-ser)

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.
cells(sel)

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.
by blocking some of the enzymes(EN-zime)

A protein that speeds up chemical reactions in the body.
needed for cell growth. DrugsAny substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic. used in chemotherapy(KEE-moh-THAYR-uh-pee)

Treatment with drugs that kill cancer cells.
work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy)(KOM-bih-NAY-shun KEE-moh-THAYR-uh-pee)

Treatment using more than one anticancer drug.
may kill more cancer cells. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia(uh-KYOOT MY-eh-loyd loo-KEE-mee-uh)

An aggressive (fast-growing) disease in which too many myeloblasts (immature white blood cells that are not lymphoblasts) are found in the bone marrow and blood. Also called acute myeloblastic leukemia, acute myelogenous leukemia, acute nonlymphocytic leukemia, AML, and ANLL.
.

Purpose

This randomized(RAN-duh-mized KLIH-nih-kul TRY-ul)

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.
phase II/III trialA trial to study response to a new treatment and the effectiveness of the treatment compared with the standard treatment regimen. is studying how well giving bortezomib and sorafenib tosylate together works in treating patients with newly diagnosed(DY-ug-NOH-sis)

The process of identifying a disease, such as cancer, from its signs and symptoms.
acute myeloid leukemia with or without mutations.(myoo-TAY-shun)

Any change in the DNA of a cell. Mutations may be caused by mistakes during cell division, or they may be caused by exposure to DNA-damaging agents in the environment. Mutations can be harmful, beneficial, or have no effect. If they occur in cells that make eggs or sperm, they can be inherited; if mutations occur in other types of cells, they are not inherited. Certain mutations may lead to cancer or other diseases.

Objectives

Primary

  1. To compare event-free survival (EFS) and overall survival (OS) of patients with de novo acute myeloid leukemia (AML) with or without high allelic ratio FLT3/ITD+ mutations who are randomized to standard therapy versus bortezomib/standard combination therapy.
  2. To determine the feasibility of combining bortezomib with standard chemotherapy in patients with de novo AML.
  3. To compare the OS and EFS of high-risk patients treated with intensive Induction II with historical controls from COG-AAML03P1 and COG-AAML0531.
  4. To determine the feasibility of combining sorafenib with standard chemotherapy in patients with de novo high allelic ratio FLT3/ITD+ AML.

Secondary

  1. To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic ratio FLT3/ITD+ AML.
  2. To compare the percentage of patients converting from positive MRD to negative MRD after Intensive Induction II with historical controls from
  3. To compare OS, disease-free survival (DFS), cumulative incidence of relapse, and treatment-related mortality from end of Intensification I between patients allocated to best allogenic donor stem cell transplant (SCT) and comparable patients on COG-AAML0531 who did not receive allogenic donor SCT.
  4. To compare OS, DFS, cumulative incidence of relapse, treatment-related mortality, and severe toxicity between patients allocated to matched family donor SCT on COG-AAML103P1 and COG-AAML0531.
  5. To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy and SCT for AML.
  6. To compare the changes in shortening fraction/ejection fraction over time between patients treated with and without dexrazoxane.
  7. To refine the use of minimal-residual disease (MRD) detection with 4-color flow cytometry. (exploratory)
  8. To evaluate the prognostic significance of molecular MRD and its contribution to risk identification with multidimensional flow cytometry (MDF)-based MRD in patients with translocations amenable to quantitative RT-PCR (e.g., t(8;21), inv(16), t(9;11), WT1 expression). (exploratory)
  9. To determine the leukemic involvement of the hematopoietic early progenitor cell and its role in defining response to therapy. (exploratory)
  10. To define the leukemic stem cell population in patients with AML. (exploratory)
  11. To determine the prevalence and prognostic significance of molecular abnormalities of WT1, RUNX1, MLL-PTD, TET2, c-CBL, KIT, and other novel AML-associated genes in pediatric AML. (exploratory)
  12. To correlate the expression of CD74 antigen as well as PSMB5 gene expression and mutation with response to bortezomib. (exploratory)
  13. To evaluate the changes in protein expression and unfolded protein response (UPR) in patients with AML. (exploratory)
  14. To determine the expression level of wild-type FLT3, and correlate with outcome and in vitro sensitivity to FLT3 inhibition. (exploratory)
  15. To obtain sorafenib and metabolite steady state pharmacokinetics and pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib. (exploratory)
  16. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen. (exploratory)
  17. To collect biology specimens at diagnosis, treatment time points, and relapse for future biology studies. (exploratory)