B-cell Adult Acute Lymphoblastic Leukemia (ALL), Ph-positive Adult Acute Lymphoblastic Leukemia (ALL), Recurrent Adult Acute Lymphoblastic Leukemia (ALL), T-cell Adult Acute Lymphoblastic Leukemia (ALL)
Conditions
Brief summary
This study evaluates the value of bortezomib in combination with specified chemotherapies for the treatment of patients with relapsed or refractory acute lymphoblastic leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVE: Determine the response rate of bortezomib in combination with a chemotherapy backbone of doxorubicin (doxorubicin hydrochloride), vincristine (vincristine sulfate), PEG-asparaginase (pegaspargase), and dexamethasone in patients with relapsed/refractory acute lymphoblastic leukemia. SECONDARY OBJECTIVES: * Estimate the rate of complete response (CR) and CR with incomplete platelet recovery (CRp) on Day 29 after re-induction. * Determine progression-free survival (PFS) at 2 years after re-induction. * Determine failure-free survival (FFS) at 1 year after re-induction. * Overall survival (OS) at 1 year after re-induction. * Assess safety and tolerability of the study drug. * Determine whether bortezomib induces reactive oxygen species (ROS) in circulating acute lymphoblastic leukemia (ALL) blast cells. OUTLINE: Patients receive bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11; doxorubicin hydrochloride intravenously (IV) on day 1; pegaspargase IV or intramuscularly (IM) on Days 5 and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on Days 1 to 14; cytarabine intrathecally (IT) on Day 1 and methotrexate intrathecally (IT) on Day 15. Patients with central nervous system disease receive intrathecal treatment per investigator's discretion. Participants are followed up every 3 months for up to 2 years after completion of study treatment.
Interventions
DRUGBortezomib
Administered subcutaneously (SC) at 1.3 mg/m², on Days 1, 4, 8, and 11.
DRUGDoxorubicin hydrochloride (HCl)
Administered intravenously (IV) over 15 min at 60mg/m², on Day 1.
DRUGPEG-Asparaginase
Administered intravenously (IV) or intramuscularly (IM) 2500 U/m² (maximum 3750 U), on Days 5 and 22.
DRUGVincristine sulfate
Administered by intravenous (IV) push at 1.5 mg/m² (maximum 2 mg), on Days 1, 8, 15, and 22.
DRUGDexamethasone
Administered orally (PO) at 10 mg/m², daily on Days 1 to 14.
DRUGCytarabine
Administered intrathecally (IT) at 100 mg, on Day 1
DRUGMethotrexate
Administered intrathecally (IT) at 15 mg, on Day 15.
Sponsors
National Cancer Institute (NCI)
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Voluntary written informed consent * Female subjects who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse * Male subjects, even if surgically sterilized (ie, status post vasectomy) who: * Agree to practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, OR * Agree to completely abstain from heterosexual intercourse * • Relapsed or refractory B or T cell acute lymphoblastic leukemia that has progressed following at least one prior therapy. Ph+ patients are eligible. Relapsed ALL is defined in patients as the reappearance of leukemia cells in the peripheral blood or bone marrow or appearance of extramedullary disease after a complete remission. Refractory ALL is defined in patients as failure to achieve a complete remission after induction therapy. Complete remission is defined by \<5% leukemia cells in the bone marrow with recovery of peripheral blood counts. Relapsed disease can be documented by bone marrow biopsy (\>5% cells in the bone marrow) or by flow cytometry in the peripheral blood or biopsy of extramedullary disease. * Has received at least 1 line of prior systemic therapy that may NOT have included bortezomib (Velcade); patients who have undergone autologous/allogeneic stem cell transplantation are eligible * Transplant-eligible patients are eligible * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 * No poorly-controlled intercurrent illness including, but not limited to, ongoing or active infection, poorly controlled diabetes, symptomatic congestive heart failure, or psychiatric illness that in the opinion of the investigator would limit compliance with study requirements * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 x (ULN unless elevation is deemed due to leukemia infiltration) * Adequate renal function defined as creatinine clearance of ≥ 30 mL/minute by the Cockcroft-Gault method
Exclusion criteria
* \> 1.5 x ULN total bilirubin * ≥ Grade 2 peripheral neuropathy * Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant * Hypersensitivity to bortezomib, boron, or mannitol * Pregnant or lactating * Serious medical or psychiatric illness likely to interfere with participation in this clinical study * Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy * Participation in clinical trials with other investigational agents not included in this trial throughout the duration of this trial * Radiation therapy within 3 weeks before randomization; enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy * Prior exposure ≥ 350 mg/m² of anthracycline (doxorubicin equivalent) * Left ventricular ejection fraction \< 40%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (RR) | Day 29 | Response Rate (RR) was determined as the sum of complete response (CR) and partial response (PR). Due to overlap, complete response rate without platelet recovery (CRp) is not included in Response Rate (RR). The outcome is reported as the total number without dispersion. * CR = No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) \> 1,000/microliter; platelets \> 100,000/microliter; \< 5% blasts in bone marrow. * CRp = Meets all criteria for CR except platelet count. * PR = Meets all criteria for CR except bone marrow contains 5 to 25% leukemia cells. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Without Platelet Recovery (CRp) | Day 29 | Complete response without platelet recovery (CR) was determined as the number of participants who achieved CRp by Day 29 after induction treatment. The outcome is reported as the total number without dispersion. The outcome reflects only those subjects that meet all complete response (CR) criteria except platelet count; participants that meet all criteria including platelet count are not included in this outcome. CR and CRp are defined below. * CR =.No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) \> 1,000/microliter; platelets \> 100,000/microliter; \< 5% blasts in bone marrow. * CRp = Meets all criteria for CR except platelet count. |
| Progression-free Survival (PFS) | 2 years | Progression-free survival (PFS) was assessed as survival without progression at 2 years. The outcome is reported as the number (without dispersion) of the participants alive without progression. Progression = More than 25% increase in circulating and/or bone marrow blasts, or the development of extramedullary disease. |
| Failure-free Survival (FFS) | 1 year | Failure-free survival (FFS) was assessed as survival without progression or the addition of another systemic therapy, at or within 2 years. The outcome is reported as the number (without dispersion) of the participants alive without progression. Progression is defined below. Progression = More than 25% increase in circulating and/or bone marrow blasts, or the development of extramedullary disease. |
| Complete Response (CR) | Day 29 | Complete response (CR) was determined the number of participants who achieved CR by Day 29 after induction treatment. The outcome is reported as the total number without dispersion. CR is defined as: * CR = No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) \> 1,000/microliter; platelets \> 100,000/microliter; \< 5% blasts in bone marrow. * Not CR = All statuses and conditions if less than or not as defined. |
| Related Adverse Events (Grade 3, 4, 5) | 45 days | Toxicity was assessed as related grade 3, 4, or 5 adverse events (AEs) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The outcome is reported as the total numbers of events (without dispersion) by CTCAE Body System, and whether the event was a hematologic toxicity or non-hematologic toxicity. |
| Induction of Reactive Oxygen Species (ROS) | 2 years | Circulating acute lymphoblastic leukemia (ALL) blast cells were to be evaluated for the presence of reactive oxygen species (ROS). |
| Overall Survival (OS) | 2 years | Overall survival (OS) was assessed as participants remaining alive 2 years after induction therapy. The outcome is reported as the number of participants (without dispersion). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib + Chemotherapy Patients receive bortezomib on Days 1, 4, 8, and 11; doxorubicin hydrochloride on Day 1; PEG-asparaginase on Days 5 and 22; vincristine sulfate on Days 1, 8, 15, and 22; dexamethasone daily on Days 1 to 14; cytarabine on Day 1, and methotrexate on Day 15.
Bortezomib: Administered subcutaneously (SC) at 1.3 mg/m², on Days 1, 4, 8, and 11.
Doxorubicin hydrochloride (HCl): Administered intravenously (IV) over 15 min at 60mg/m², on Day 1.
PEG-Asparaginase: Administered intravenously (IV) or intramuscularly (IM) 2500 U/m² (maximum 3750 U), on Days 5 and 22.
Vincristine sulfate: Administered by intravenous (IV) push at 1.5 mg/m² (maximum 2 mg), on Days 1, 8, 15, and 22.
Dexamethasone: Administered orally (PO) at 10 mg/m², daily on Days 1 to 14.
Cytarabine: Administered intrathecally (IT) at 100 mg, on Day 1
Methotrexate: Administered intrathecally (IT) at 15 mg, on Day 15. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Bortezomib + Chemotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 37.2 years STANDARD_DEVIATION 8.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 18 |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 10 / 18 |
Outcome results
Primary
Response Rate (RR)
Response Rate (RR) was determined as the sum of complete response (CR) and partial response (PR). Due to overlap, complete response rate without platelet recovery (CRp) is not included in Response Rate (RR). The outcome is reported as the total number without dispersion. * CR = No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) \> 1,000/microliter; platelets \> 100,000/microliter; \< 5% blasts in bone marrow. * CRp = Meets all criteria for CR except platelet count. * PR = Meets all criteria for CR except bone marrow contains 5 to 25% leukemia cells.
Time frame: Day 29
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bortezomib + Chemotherapy | Response Rate (RR) | 11 Participants |
Secondary
Complete Response (CR)
Complete response (CR) was determined the number of participants who achieved CR by Day 29 after induction treatment. The outcome is reported as the total number without dispersion. CR is defined as: * CR = No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) \> 1,000/microliter; platelets \> 100,000/microliter; \< 5% blasts in bone marrow. * Not CR = All statuses and conditions if less than or not as defined.
Time frame: Day 29
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bortezomib + Chemotherapy | Complete Response (CR) | 11 Participants |
Secondary
Complete Response Without Platelet Recovery (CRp)
Complete response without platelet recovery (CR) was determined as the number of participants who achieved CRp by Day 29 after induction treatment. The outcome is reported as the total number without dispersion. The outcome reflects only those subjects that meet all complete response (CR) criteria except platelet count; participants that meet all criteria including platelet count are not included in this outcome. CR and CRp are defined below. * CR =.No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) \> 1,000/microliter; platelets \> 100,000/microliter; \< 5% blasts in bone marrow. * CRp = Meets all criteria for CR except platelet count.
Time frame: Day 29
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bortezomib + Chemotherapy | Complete Response Without Platelet Recovery (CRp) | 1 Participants |
Secondary
Failure-free Survival (FFS)
Failure-free survival (FFS) was assessed as survival without progression or the addition of another systemic therapy, at or within 2 years. The outcome is reported as the number (without dispersion) of the participants alive without progression. Progression is defined below. Progression = More than 25% increase in circulating and/or bone marrow blasts, or the development of extramedullary disease.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bortezomib + Chemotherapy | Failure-free Survival (FFS) | 3 Participants |
Secondary
Induction of Reactive Oxygen Species (ROS)
Circulating acute lymphoblastic leukemia (ALL) blast cells were to be evaluated for the presence of reactive oxygen species (ROS).
Time frame: 2 years
Population: Assay development was unsuccessful, and the assessment and analysis were not conducted for any samples.
Secondary
Overall Survival (OS)
Overall survival (OS) was assessed as participants remaining alive 2 years after induction therapy. The outcome is reported as the number of participants (without dispersion).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bortezomib + Chemotherapy | Overall Survival (OS) | 5 Participants |
Secondary
Progression-free Survival (PFS)
Progression-free survival (PFS) was assessed as survival without progression at 2 years. The outcome is reported as the number (without dispersion) of the participants alive without progression. Progression = More than 25% increase in circulating and/or bone marrow blasts, or the development of extramedullary disease.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bortezomib + Chemotherapy | Progression-free Survival (PFS) | 3 Participants |
Secondary
Related Adverse Events (Grade 3, 4, 5)
Toxicity was assessed as related grade 3, 4, or 5 adverse events (AEs) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The outcome is reported as the total numbers of events (without dispersion) by CTCAE Body System, and whether the event was a hematologic toxicity or non-hematologic toxicity.
Time frame: 45 days
Population: Events specifically defined per protocol as Hematologic Toxicity orNon-hematologic Toxicity are included under the specific Body System and as a Hematologic or Non-hematologic Toxicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Hematologic Toxicity | 63 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Blood and Lymphatic System Disorders | 109 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Gastrointestinal Disorders | 9 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Hepatobiliary disorders | 2 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Infections and Infestations | 17 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Investigations | 78 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Metabolism and Nutrition Disorders | 49 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Nervous System Disorders | 1 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Respiratory, Thoracic and Mediastinal Disorders | 1 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Vascular Disorders | 2 Treatment-related adverse events |
| Bortezomib + Chemotherapy | Related Adverse Events (Grade 3, 4, 5) | Non-hematologic Toxicity | 52 Treatment-related adverse events |