ALL, Childhood, Lymphoblastic Leukemia, Acute, Lymphoblastic Leukemia, Acute, Childhood
Conditions
Brief summary
This is a pilot study utilizing Marqibo® (vincristine sulfate liposome injection) combined with dexamethasone, mitoxantrone and asparaginase (UK ALL R3) for relapsed acute lymphoblastic leukemia (ALL).
Detailed description
This study will utilize Marqibo® as a replacement for standard vincristine in combination with chemotherapy for children with relapsed ALL. The hypothesis is that the incorporation of Marqibo® with combination chemotherapy will be safe and feasible. In the context of this pilot study, overall outcomes and efficacy will be a secondary objective. It is hypothesized that data from this combination may show improved efficacy including, complete remission (CR), minimal residual disease (MRD) negativity, and progression free survival (PFS) rates and safety (i.e., neurotoxicity) in comparison to outcomes in historical regimens, including the UK ALL R3 with standard vincristine.
Interventions
DRUGMarqibo
The focus of the study design and statistical analysis is to determine whether Marqibo® can be substituted for standard vincristine and successfully administered to patients with relapsed ALL in three different treatment cohorts: (A) treatment with the UK ALL R3 regimen; (B) treatment with UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. Secondary objectives include estimating rates of serious toxicities and therapy delays in each of these cohorts.
Sponsors
Spectrum Pharmaceuticals, Inc
Therapeutic Advances in Childhood Leukemia Consortium
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
Age -Patients must be ≥ 1 and ≤ 21 years of age at the time of enrollment. Diagnosis * Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotypic acute leukemia with ≥ 5% blasts in the bone marrow (M2 or M3), with or without extramedullary disease) or a diagnosis of lymphoblastic lymphoma. * Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, or mixed phenotypic acute leukemia with any level of detectable disease (minimal residual disease level acceptable) with or without extramedullary disease Performance Level -Karnofsky \> 50% for patients \> 16 years of age and Lansky \> 50% for patients ≤ 16 years of age. Prior Therapy * Patients must have recovered from the acute toxic effects (≤ Grade 2 or baseline) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study, unless otherwise specified. Subjects with disease related cytopenias will be eligible. * Patients must have relapsed or refractory disease after attaining at least a first remission. They may be in first to third relapse.. * Patients with Philadelphia chromosome t(9;22) positive disease must have received at least two prior tyrosine kinase inhibitors. * Patients who have experienced their relapse after a Hematopoietic stem cell transplantation (HSCT) are eligible, provided they have no evidence of graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the time of enrollment. * Prior anthracycline lifetime cumulative exposure: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy. 1. Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy (See Appendix 2 for anthracycline calculation worksheet). 2. Cohorts B & C: There is no limit on prior anthracycline exposure. * Hematopoietic growth factors: It must have been at least seven days since the completion of therapy with granulocyte colony-stimulating factor (GCSF) or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®). * Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond seven days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair or vice chair. * Monoclonal antibodies: At least three half-lives (or 30 days-whichever is longer) of the antibody must have elapsed after the last dose of monoclonal antibody. (e.g., Rituximab = 66 days, Epratuzumab = 69 days) * Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines, chimeric antigen receptor T-cells. * Recent prior chemotherapy: At least 10 days after standard vincristine and the completion of any type of chemotherapy induction regimen. At least 3 weeks after radiation therapy. At least 30 days after the completion of any investigational neoplastic agent is also required. An investigational agent is defined as any drug that is not approved and licensed for sale by the FDA for institutions in the United States, by Health Canada for institutions in Canada and by The Therapeutic Goods Administration for institutions in Australia. Exceptions: * There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such; it is allowable to enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or triple IT therapy within 14 days of enrollment as part of their evaluation to diagnose disease relapse. The IT therapy given within 14 days of initiation of protocol specified chemotherapy, may substitute for the day 1 IT in cohorts A and B * Subjects with rapidly progressive disease may receive hydroxyurea until they begin study therapy; * Patients who relapse while on maintenance-type ALL therapy or are receiving maintenance therapy for disease stabilization will not require a wash-out period before entry into this study. However, there must be at least 10 days after any dose of standard vincristine. Renal and Hepatic Function * Renal function: Patient's serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times normal, the patient must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70milliliter/min/1.73m2. Alternatively, a 24-hour creatinine clearance may also be used. * Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be \< 5 x institutional upper limit of norm ULN. Total bilirubin must be ≤ 1.5 x ULN (except in the case of subjects with documented Gilbert's disease ≤ 5 × ULN). Cardiac Function -Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥ 55% by echocardiogram, cardiac MRI or multigated acquisition scan (MUGA). Reproductive Function * Female patients must not be pregnant and those of childbearing potential must have a negative urine or serum pregnancy test confirmed within one week prior to enrollment. * Female patients with infants must agree not to breastfeed their infants while on this study. * Male and female patients of childbearing potential must agree to use an effective method of contraception during the study.
Exclusion criteria
Patients will be excluded if they have isolated testicular disease. Patients will be excluded if they have previously received Marqibo®. Patients will be excluded if they have a known allergy to any of the drugs used in the study, with the exception that patients with an allergy to PEG-asparaginase who can receive Erwinia asparaginase are eligible. Patients unable to receive any formulation of asparaginase may only enroll on cohort C Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment. Patients who require azole antifungal agents will be excluded. Azoles must be discontinued at least one week prior to the start of Marqibo®. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, another investigational agent or immunotherapy during the study period. Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from any cause will be excluded. Patients will be excluded if they have, significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or adherence with the protocol treatment or procedures or interfere with consent, study participation, follow up, or interpretation of study results.Patients with Down syndrome will not be eligible for enrollment on Cohort A Patients with a known history of human immunodeficiency virus (HIV) will will be excluded due to the increased risk of complications such as severe infection and unknown interaction of Marqibo® with antiretroviral drugs. Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above the ULN per the institution normal ranges).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | 9 weeks | Number of Participants with Dose Limiting Toxicities as a Measure of Safety and Tolerability at different dose levels of Marqibo. Dose Level 1 = 1.5 mg/m\^2. Dose Level 2 = 2.0 mg/m\^2. Cohort A and B accrued at both Dose Levels. Cohort C accrued only at Dose Level 2. |
Countries
Australia, Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Dose Level 1: Marqibo and UK ALL R3 Backbone * Marqibo® (1.5 mg/m\^2): given by intravenous (IV) infusion on days 1, 8, 15 and 22.
* Dexamethasone orally twice daily on days 1-5 and 15-19.
* Mitoxantrone: given by intravenous (IV) infusion on days 1 and 2.
* PEG-asparaginase: given as an injection into the muscle on says 3 and 17.
* Methotrexate IT: given intrathecally (used to treat the brain and spinal cord and is given using a needle inserted into the spinal canal) on days 1 and 8.
Marqibo: The focus of the study design and statistical analysis is to determine whether Marqibo® can be substituted for standard vincristine and successfully administered to patients with relapsed ALL in three different treatment cohorts: (A) treatment with the UK ALL R3 regimen; (B) treatment with UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. Secondary objectives include estimating rates of serious toxicities and therapy delays in each of these cohorts. | 12 |
| Cohort A Dose Level 2: Marqibo and UK ALL R3 Backbone * Marqibo® (2.0 mg/m\^2): given by intravenous (IV) infusion on days 1, 8, 15 and 22.
* Dexamethasone orally twice daily on days 1-5 and 15-19.
* Mitoxantrone: given by intravenous (IV) infusion on days 1 and 2.
* PEG-asparaginase: given as an injection into the muscle on says 3 and 17.
* Methotrexate IT: given intrathecally (used to treat the brain and spinal cord and is given using a needle inserted into the spinal canal) on days 1 and 8.
Marqibo: The focus of the study design and statistical analysis is to determine whether Marqibo® can be substituted for standard vincristine and successfully administered to patients with relapsed ALL in three different treatment cohorts: (A) treatment with the UK ALL R3 regimen; (B) treatment with UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. Secondary objectives include estimating rates of serious toxicities and therapy delays in each of these cohorts. | 4 |
| Cohort B Dose Level 1: Marqibo and Lower Intensity UK ALL R3 Backbone * Marqibo® (1.5 mg/m\^2): given by intravenous (IV) infusion on days 1, 8, 15 and 22.
* Dexamethasone orally twice daily on days 1-5 and 15-19.
* PEG-asparaginase: given as an injection into the muscle on days 3 and 17.
* Methotrexate IT: given intrathecally (used to treat the brain and spinal cord and is given using a needle inserted into the spinal canal) on days 1 and 8.
Marqibo: The focus of the study design and statistical analysis is to determine whether Marqibo® can be substituted for standard vincristine and successfully administered to patients with relapsed ALL in three different treatment cohorts: (A) treatment with the UK ALL R3 regimen; (B) treatment with UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. Secondary objectives include estimating rates of serious toxicities and therapy delays in each of these cohorts. | 6 |
| Cohort B Dose Level 2: Marqibo and Lower Intensity UK ALL R3 Backbone * Marqibo® (2.0 mg/m\^2): given by intravenous (IV) infusion on days 1, 8, 15 and 22.
* Dexamethasone orally twice daily on days 1-5 and 15-19.
* PEG-asparaginase: given as an injection into the muscle on days 3 and 17.
* Methotrexate IT: given intrathecally (used to treat the brain and spinal cord and is given using a needle inserted into the spinal canal) on days 1 and 8.
Marqibo: The focus of the study design and statistical analysis is to determine whether Marqibo® can be substituted for standard vincristine and successfully administered to patients with relapsed ALL in three different treatment cohorts: (A) treatment with the UK ALL R3 regimen; (B) treatment with UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. Secondary objectives include estimating rates of serious toxicities and therapy delays in each of these cohorts. | 2 |
| Cohort C Dose Level 2: Marqibo and Maintenance Regimen * Marqibo® (2.0 mg/m\^2): given by intravenous (IV) infusion on day 1
* Dexamethasone orally twice daily on days 1-5
* Methotrexate: given orally on days 1 and 8
* Mercaptopurine: given orally daily on days 1-13
Marqibo: The focus of the study design and statistical analysis is to determine whether Marqibo® can be substituted for standard vincristine and successfully administered to patients with relapsed ALL in three different treatment cohorts: (A) treatment with the UK ALL R3 regimen; (B) treatment with UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. Secondary objectives include estimating rates of serious toxicities and therapy delays in each of these cohorts. | 5 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort A Dose Level 1: Marqibo and UK ALL R3 Backbone | Cohort A Dose Level 2: Marqibo and UK ALL R3 Backbone | Cohort B Dose Level 1: Marqibo and Lower Intensity UK ALL R3 Backbone | Cohort B Dose Level 2: Marqibo and Lower Intensity UK ALL R3 Backbone | Cohort C Dose Level 2: Marqibo and Maintenance Regimen |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 27 Participants | 12 Participants | 4 Participants | 5 Participants | 2 Participants | 4 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Continuous | 12.4 years | 12.3 years | 8.7 years | 12 years | 12.7 years | 15.8 years |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 20 Participants | 10 Participants | 2 Participants | 4 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 29 participants | 12 participants | 4 participants | 6 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 12 Participants | 5 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 17 Participants | 7 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 4 | 0 / 6 | 0 / 2 | 0 / 5 |
| other Total, other adverse events | 12 / 12 | 4 / 4 | 6 / 6 | 2 / 2 | 5 / 5 |
| serious Total, serious adverse events | 7 / 12 | 4 / 4 | 0 / 6 | 1 / 2 | 5 / 5 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability
Number of Participants with Dose Limiting Toxicities as a Measure of Safety and Tolerability at different dose levels of Marqibo. Dose Level 1 = 1.5 mg/m\^2. Dose Level 2 = 2.0 mg/m\^2. Cohort A and B accrued at both Dose Levels. Cohort C accrued only at Dose Level 2.
Time frame: 9 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A Dose Level 1: Marqibo and UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | DLT | 0 Participants |
| Cohort A Dose Level 1: Marqibo and UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | No DLT | 12 Participants |
| Cohort A Dose Level 2: Marqibo and UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | DLT | 2 Participants |
| Cohort A Dose Level 2: Marqibo and UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | No DLT | 2 Participants |
| Cohort B Dose Level 1: Marqibo and Lower Intensity UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | DLT | 0 Participants |
| Cohort B Dose Level 1: Marqibo and Lower Intensity UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | No DLT | 6 Participants |
| Cohort B Dose Level 2: Marqibo and Lower Intensity UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | No DLT | 1 Participants |
| Cohort B Dose Level 2: Marqibo and Lower Intensity UK ALL R3 Backbone | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | DLT | 1 Participants |
| Cohort C Dose Level 2: Marqibo and Maintenance Regimen | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | DLT | 0 Participants |
| Cohort C Dose Level 2: Marqibo and Maintenance Regimen | Number of Participants With Dose Limiting Toxicities as a Measure of Safety and Tolerability | No DLT | 5 Participants |