SC-PEG Asparaginase vs. Oncaspar in Pediatric Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma

Acute Lymphoblastic Leukemia Clinical Trial

Official title:

Randomized Study of Intravenous Calaspargase Pegol (SC-PEG Asparaginase) and Intravenous Oncaspar in Children and Adolescents With Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01574274
• Other study ID #: 11-001
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 2012
• Est. completion date: July 2027

Study information

• Verified date: April 2024
• Source: Dana-Farber Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is being conducted to learn about the effects of SC-PEG, which is a new form of a chemotherapy drug called asparaginase. Asparaginase is used to treat ALL and lymphoblastic lymphoma. The standard form of asparaginase, called Elspar, is given in the muscle once a week for 30 weeks. There are other forms of asparaginase. The investigators will be studying two of these: Oncaspar and Calaspargase Pegol (SC-PEG). The investigators have previously studied giving Oncaspar in the vein (instead of the muscle) every 2 weeks in patients with ALL, and have shown that this dosing did not lead to any more side effects than Elspar given weekly in the muscle. The study drug, SC-PEG, is very similar but not identical to Oncaspar. SC-PEG has been given in the vein to children and adolescents with ALL as part of other research studies, and it appears to last longer in the blood after a dose than Oncaspar. It has not yet been approved by the FDA. The goal of this research study is to learn whether the side effects and drug levels of SC-PEG given in the vein every 3 weeks are similar to Oncaspar given into the vein about every 2 weeks.

The study will also help to determine whether changing treatment for children and adolescents with ALL with high levels of minimal residual disease may improve cure rates. Measuring minimal disease (MRD) is a laboratory test that finds low levels of leukemia cells that the investigators cannot see under the microscope. In the past, it has been shown that children and adolescents with ALL with high levels of MRD after one month of treatment are less likely to be cured than those with low levels of MRD. Therefore, on the study, the bone marrow and blood at the end of the first month of treatment will be measured in participants with leukemia, and changes in therapy will be implemented based on this measurement. It is not known for sure that changing treatment will improve cure rates. MRD levels can only be measured if the marrow is filled with cancer cells at the time of diagnosis. Therefore, MRD studies will only be done in children and adolescents with ALL and not in those with lymphoblastic lymphoma.

Another part of the study is to determine whether giving antibiotics during the first month of treatment even to participants without fever will prevent serious infections in the blood and other parts of the body. About 25% of children and adolescents with ALL and lymphoblastic lymphoma who receive standard treatment develop a serious blood infection from a bacteria during the first month of treatment. Typically, antibiotics (medicines that fight bacteria) are given by vein only after a child with leukemia or lymphoma develops a fever or have other signs of infection. In this study, antibiotics will be given by mouth or in the vein to all participants during the first month of treatment, whether or not they develop fever.

Another goal of the study to learn how vitamin D levels relate to bone problems (such as broken bones or fractures) that children and adolescents with ALL and lymphoblastic lymphoma experience while on treatment. Some of the chemotherapy drugs used to treat ALL and lymphoblastic lymphoma can make bones weaker, which make fractures more likely. Vitamin D is a natural substance from food and sunlight that can help keep bones strong. The investigators will study how often participants have low levels of vitamin D while receiving chemotherapy, and, for those with low levels, whether giving vitamin D supplements will increase those levels.

Another focus of the study is to learn more about the biology of ALL and lymphoblastic lymphoma by doing research on blood, bone and spinal fluid bone marrow samples. The goal of this research is to improve treatment for children with leukemia in the future.

Description:

To determine whether or not children and adolescents with ALL or lymphoblastic lymphoma are eligible to participate in this study, screening tests will be performed, which may include the following: medical history, bone marrow tests, assessment of your tumor, blood tests and/or an EKG.

Participants who enroll in this study will receive with anti-leukemia drugs called chemotherapy. During study treatment, the study doctors will continue to perform tests on blood, bone marrow and spinal fluid to assess how the disease is responding to the study treatment and to look for possible side effects. Scans (for example, x-ray, CT scan or MRI scan) may also be done after beginning study treatment to look for possible side effects. If the disease was initially diagnosed by a scan, it will also be repeated during the study treatment to assess how it is responding.

There are three different treatment groups in which leukemia and lymphoblastic lymphoma can be divided and they differ slightly in the types and amounts of chemotherapy drugs used during the 2-years of therapy. Participants are assigned to the different categories based on the features of their leukemia or lymphoma, such as their age, white blood cell count, and results of other tests. The three different treatment groups are called "Standard Risk", "High Risk" and "Very High Risk".

Participants will be given several different chemotherapy drugs during many periods of treatment (called "phases"). These drugs are known to kill lymphoblastic cancer cells. Some of the drugs are given by mouth, some into the veins (intravenously), and others as an injection (a shot) into the muscle. Some chemotherapy drugs will be given directly into your spinal fluid (called intrathecal chemotherapy) during a lumbar puncture (spinal tap). This treatment helps prevent the cancer cells from coming back in the spinal fluid and brain.

The first phase of treatment is steroid prophase. This phase of treatment is typically given in the hospital. This phase of treatment will begin immediately.

after enrolling on the study.

The second phase of treatment is remission induction. This phase will begin immediately after the steroid prophase and will last four weeks. Participants typically remain in the hospital for most (sometimes all) of this phase.

At the end of the remission induction phase, participants will undergo tests to determine if they are in remission. This testing will involve getting samples of blood, bone marrow and spinal fluid to look for cancer cells under the microscope. This testing will also involve getting repeat scans if these were not normal at the time of diagnosis. Remission means that cancer cells cannot be detected under the microscope in the blood, marrow and spinal fluid, and that any cancer previously seen on a scan has significantly improved or is no longer seen. Participants must be in remission to go onto the next phases of treatment; alternative treatments will be discussed with participants who are not in remission at the end of the induction phase.

The Consolidation I phase begins once it is determined that a participant is in remission. This phase lasts about three weeks. This phase of treatment is given in the hospital, but participants may be able to leave the hospital after the first week of the phase. The purpose of this phase is to further reduce the number of cancer cells in the body.

The next phase is the Central Nervous System (CNS) phase, and is usually given in the outpatient setting. Participants may need to be admitted to the hospital during this phase of treatment if a complication develops, such as infection. This phase of therapy begins immediately after the Consolidation I phase and lasts about 3 weeks. Treatment involves a series of lumbar punctures with anti-leukemia drugs given intrathecally over a two week period. Anti-leukemia drugs will also be given by mouth and by vein during this phase as well. Some participants may receive radiation therapy during this phase, although most do not. The decision to treat with radiation or not is based on characteristics of the cancer at diagnosis and whether or not cancer cells were seen in spinal fluid at that time. Radiation therapy is a painless procedure, the purpose of which is to prevent leukemia from coming back in the brain. For participants who receive radiation therapy, it will be given in either 8 or 10 daily treatments, depending on how many leukemia cells were seen in the spinal fluid under the microscope at diagnosis.

The next phase of the study is Consolidation II. This phase begins about 3 weeks after starting the CNS phase and lasts for about 27 weeks. During this phase, chemotherapy is given in three-week cycles, with some drugs given in clinic and some drugs given by mouth at home. Participants are typically treated as outpatients during this phase.

The last phase is called Continuation. This is also usually given as an outpatient. The goal of this phase is to rid the body of all remaining cancer cells. The cycles of chemotherapy during this phase are repeated every 3 weeks, with some drugs given in clinic and some drugs given by mouth at home. This phase will ends two years after remission was documented.

The randomization in this study involves the two forms of asparaginase, Oncaspar and SC-PEG asparaginase. Because no one knows which of the study options is best, participants will be "randomized" into one of the study groups: to receive Oncaspar or to receive SC-PEG. Randomization means that participants are put into a group by chance. Participants who are placed in the Oncaspar group will receive a single dose of Oncaspar on Day 7 of the Remission Induction phase, and then every 2 weeks for 30 weeks starting in the CNS phase (16 total doses of Oncaspar). Participants placed in the SC-PEG group will receive SC-PEG asparaginase on Day 7 of the remission induction phase and then every 3 weeks beginning in the CNS phase (11 total doses of SC-PEG).

Minimal Residual Disease (MRD) testing is a way to look for very low levels of leukemia in the body that cannot be seen under the microscope. These test will be done in a laboratory at Dana-Farber Cancer Institute. If the MRD results are in the low range on Day 32, thre will be no change to the treatment program described above. If the MRD results are in the high range, then it will be recommended that treatment be changed.

Participants will receive a fluoroquinolone antibiotic beginning during the first phase of treatment and continuing until the neutrophils and monocytes (two types of white blood cells in the blood that help fight infection) have increased. The goal of giving the antibiotics is to prevent infection during the first few weeks of treatment.

Participants who agree to have extra blood drawn to test for vitamin D levels in the blood will have 1 teaspoon of blood drawn at the following times: start of treatment, at the end of the first month of treatment, at the start of the continuation phase, and at the end of treatment. Participants will receive the results of these tests. If the vitamin D level is low, the study doctor will recommend that the participant take a vitamin D supplement. Participants may choose not to have blood drawn to check vitamin D levels, or may choose not to take the vitamin D supplement.

Participants will be asked at the time of study entry if they agree to provide additional blood and bone marrow samples for research. These additional samples will be used to learn more about the biology of ALL and lymphoblastic lymphoma. Stored specimens may also be used for future research regarding leukemia.

After completing all treatment, participants will be asked to come in for physical exams and blood work every month for the first six months after the final treatment, then every two months for the next 6 months, then every four months for the next year, and then every six months for the next year. After that we will ask you to come in once a year.

The investigators would like to keep track of the medical condition of all participants for the rest of their lives. This will be done by reviewing medical records of participants. The investigators may telephone participants who have finished treatment to see how they are doing if they have not been seen by their doctor for at least a year.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 240
• Est. completion date: July 2027
• Est. primary completion date: July 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 365 Days to 21 Years

Eligibility

Inclusion Criteria:

• Confirmed diagnosis of ALL or lymphoblastic leukemia

• No prior therapy except short courses of corticosteroids, a single dose of IT cytarabine or emergent radiation to the mediastinum or other life-threatening masses

Exclusion Criteria:

• Have received more than 7 days of corticosteroids in the preceding 4 weeks or more than 28 days of corticosteroids in the preceding 6 months

• Have received any chemotherapy or radiotherapy for previous malignancy

• Receiving any other investigational agent

• Known to be HIV positive

• Uncontrolled intercurrent illness

• Pregnant or breastfeeding

• History of previous malignancy

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Lymphoma
• Lymphoma
• Lymphoma, Non-Hodgkin
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• SC-PEG
11 doses Intravenously over one hour
• Oncaspar
16 doses Intravenously over one hour

Locations

Country	Name	City	State
Canada	McMaster University	Hamilton	Ontario
Canada	Hospital Sainte Justine, University of Montreal	Montreal	Quebec
Canada	Centre Hospitalier U. de Quebec	Quebec City	Quebec
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Columbia University Medical Center, Morgan Stanley Children's Hospital of New York-Presbyterian	New York	New York
United States	Montefiore Medical Center	New York	New York
United States	Hasbro Children's Hospital	Providence	Rhode Island

Sponsors (3)

Lead Sponsor	Collaborator
Dana-Farber Cancer Institute	National Cancer Institute (NCI), Shire

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Eff — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Asparaginase-Related Toxicity	Asparaginase-related toxicity rate is defined as the percentage of patients who experience allergy (all grades), symptomatic pancreatitis (grade 2 or worse), thrombotic or bleeding complications requiring intervention (grade 2 or worse) with treatment attribution of possibly, probably or definite based on Common Terminology Criteria for Adverse Events (CTCAE) v4.	30-week post-induction asparaginase treatment period. Toxicities assessed on an ongoing basis (at least 1 per month) while participant is on study, an average of 2 years.
Primary	Induction and Post-Induction Nadir Serum Asparaginase Activity Level	Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods.	Samples for nadir serum asparaginase activity levels were assayed at 4,11,18,and 25 days after 1st dose, and then prior to asparaginase dose given during post-induction, at Week 7, 13, 19, and 25.
Secondary	Frequency of Infections	Number of episodes of bacteremia, fungemia and invasive fungal infections during the remission induction phase	2 years
Secondary	Outcome	Rates of complete remission, relapse, induction death, remission death, and second malignant neoplasms in participants	2 years
Secondary	Outcome of Participants With Very-high Risk Disease	Rates of relapse, remission death and second malignant neoplasm in participants with high minimal residual disease (MRD) and/or high risk cytogenetics who are treated with a more intensified regimen	2 years
Secondary	Feasibility of Vitamin D Screening/Supplementation	Vitamin D-levels at various times during treatment, proportion of participants with low vitamin D levels, proportion of participants who agree to Vitamin D supplementation	2 years
Secondary	Feasibility of Prospective Screening for ABGD	Number of samples from participants with T-ALL in which a successful result was obtained by quantitative polymerase chain reaction (qPCR) to assess absence of biallelic TCRy deletions (ABGD); frequency of ABGD in T-ALL	2 years
Secondary	Feasibility of Prospective Screening for Genetic Abnormalities	Number of samples from participants with B-ALL in which a successful result was obtained in prospective screening for abnormalities (eg, mutations, deletions, rearrangements) of IKZF1, CRLF2 and JAK1/2 in patients with newly diagnosed B-ALL; proportion of participants with B-ALL found to have one of these abnormalities.	2 years
Secondary	Relationship Between Apoptotic/Anti-apoptotic Proteins and Response to CT	Levels of pro- and anti-apoptotic proteins in participant samples from diagnosis; correlation of these levels to clinical response (induction failure, high MRD, relapse).	2 years