Recurrent Adult Lymphoblastic Lymphoma, Recurrent B Acute Lymphoblastic Leukemia, Recurrent T Acute Lymphoblastic Leukemia, Refractory B Acute Lymphoblastic Leukemia, Refractory Lymphoblastic Lymphoma, Refractory T Acute Lymphoblastic Leukemia
Conditions
Brief summary
This phase Ib/II trial studies the effects of tagraxofusp and low-intensity chemotherapy in treating patients with CD123 positive acute lymphoblastic leukemia or lymphoblastic lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Tagraxofusp consists of human interleukin 3 (IL3) linked to a toxic agent called DT388. IL3 attaches to IL3 receptor positive cancer cells in a targeted way and delivers DT388 to kill them. Chemotherapy drugs, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tagraxofusp with chemotherapy may help control CD123 positive relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the overall response rate (complete response \[CR\] + CR with inadequate count recovery \[CRi\]) of the regimen within 3 cycles. SECONDARY OBJECTIVES: I. Evaluate other clinical efficacy endpoints (CR rate, minimal residual disease \[MRD\] negativity, duration of response \[DOR\], relapse-free survival \[RFS\] overall survival \[OS\]). II. Determine the proportion of patients proceeding to allogeneic stem cell transplantation (allo-SCT). III. Determine the safety of the combination regimen. EXPLORATORY OBJECTIVES: I. To determine CD123 expression levels pre- and post-therapy. II. To correlate baseline CD123 expression with response rates and duration of response. III. To evaluate change in apoptotic protein expression and alterations in cellular signaling pathways using cytometry by time of flight (CyTOF). IV. To determine baseline gene expression profile in order to identify ALL subtypes and correlate with clinical outcomes and response to single-agent tagraxofusp-erzs (tagraxofusp). OUTLINE: TAGRAXOFUSP AND CHEMOTHERAPY PHASE: CYCLE 1: Patients receive tagraxofusp-erzs intravenously (IV) over 15 minutes on days 1-5. CYCLES 2 AND 4: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-3, cyclophosphamide IV over 3 hours twice daily (BID) and mesna IV on days 4-6, vincristine IV over 15 minutes on days 4 and 15, dexamethasone IV over 30 minutes or orally (PO) on day 4-7 and 14-17, methotrexate intrathecally (IT) on day 5, and filgrastim-sndz subcutaneously (SC) or pegfilgrastim SC on day 8, and cytarabine IT on day 10. Patients may receive rituximab IV over 4-6 hours on days 4 and 14. CYCLES 3 AND 5: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-3, methotrexate IV over 24 hours on day 4, cytarabine IV over 3 hours BID on days 5-6, filgrastim-sndz SC or pegfilgrastim SC on day 6, methotrexate IT and cytarabine IT on day 11. Patients may receive rituximab IV over 4-6 hours on days 4 and 11. Beginning about 12 hours after the day 4 dose of methotrexate, patients may also receive leucovorin IV over 15 minutes, 4 times a day for about 8 doses. CYCLES 6 AND 8: Patients receive cyclophosphamide IV over 3 hours BID and mesna IV on days 1-3, vincristine IV over 15 minutes on days 1 and 11, dexamethasone IV over 30 minutes or PO on day 1-4 and 11-14, and filgrastim-sndz SC or pegfilgrastim SC on day 5. CYCLES 7 AND 9: Patients receive methotrexate IV over 24 hours on day 1, cytarabine IV over 3 hours BID on days 2-3, and filgrastim-sndz SC or pegfilgrastim SC on day 4. Beginning about 12 hours after the day 1 dose of methotrexate, patients may receive leucovorin IV over 15 minutes, 4 times a day for about 8 doses. Cycle 1 is 21 days. Treatment repeats every 28 days for cycles 2-9 in the absence of disease progression or unacceptable toxicity. TAGRAXOFUSP AND MAINTENANCE PHASE: CYCLES 1-3, 5-7, 9-11, 13-15: Patients receive mercaptopurine PO three time daily (TID) on days 1-28, prednisone PO once daily (QD) on day 1-5, methotrexate PO once every week (QW) and vincristine IV over 15 minutes every 4 weeks. CYCLES 4, 8, and 12: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-5. Treatment repeats every 28 days for 15 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.
Interventions
DRUGCyclophosphamide
Given IV
DRUGCytarabine
Given IT
DRUGDexamethasone
Given IV or PO
BIOLOGICALFilgrastim-sndz
Given SC
DRUGLeucovorin
Given IV
DRUGMercaptopurine
Given PO
DRUGMesna
Give IV
DRUGMethotrexate
Given IT
BIOLOGICALPegfilgrastim
Given SC
DRUGPrednisone
Given PO
BIOLOGICALRituximab
Given IV
BIOLOGICALTagraxofusp-erzs
Given IV
DRUGVincristine
Given IV
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients 18-70 years of age with relapsed/refractory CD123+ B- or T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma. CD123 positivity may be confirmed by either flow cytometry or immunohistochemistry * Performance status =\< 2 (Eastern Cooperative Oncology Group \[ECOG\] scale) * Total serum bilirubin =\< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, in which case patients are eligible as long as direct bilirubin =\< 2 x ULN * Alanine aminotransferase (ALT) =\< 2.5 x ULN, unless due to disease involvement of the liver or hemolysis, in which case an ALT =\< 10 x ULN is acceptable * Aspartate aminotransferase (AST) =\< 2.5 x ULN, unless due to disease involvement of the liver or hemolysis, in which case an ALT =\< 10 x ULN is acceptable * Serum creatinine =\< 1.5 mg/dL * Serum albumin \>= 3.2 g/dL (32 g/L). Albumin infusions are not permitted in order to enable eligibility * For females of childbearing potential, a negative pregnancy test must be documented within 1 week of starting treatment * Female and male patients who are fertile must agree to use an effective form of contraception (birth control methods while on study, such as birth control pills or injections, intrauterine devices (IUDs), or double-barrier methods (for example, a condom in combination with spermicide) with their sexual partners for 4 months after the end of treatment * Signed informed consent * Willingness and ability to adhere to study visit schedule and other protocol requirements, including follow-up for survival assessment
Exclusion criteria
* Active serious infection not controlled by oral or intravenous antibiotics * Known active central nervous system (CNS) leukemia * Diagnosis of Philadelphia chromosome-positive ALL or Burkitt leukemia/lymphoma * Active graft versus host disease (GVHD) * Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or squamous cell carcinoma) that in the investigator's opinion will shorten survival to less than 1 year * Known hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) * Clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication) * Patients with a cardiac ejection fraction (as measured by either multigated acquisition \[MUGA\] or echocardiogram) less than the lower limit of normal * No clinically significant abnormalities on 12-lead electrocardiogram * Uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study * Persistent clinically significant toxicities grade \>= 2 from previous chemotherapy (excluding alopecia, nausea, fatigue, and liver function tests \[as mandated in the inclusion criteria\]) * Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Exception: Treatment with hydroxyurea and/or dexamethasone are allowed prior to study treatment, without window of exclusion * Pregnant and lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception for 4 months after last study treatment. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control for 4 months after last study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With a Response | Within 3 cycles of treatment initiation | Response is defined as Complete Response CR + Complete Response with inadequate count recovery (CRi) - (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. (CRi): Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L; neutrophils \< 1 x 10\^9/L). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With a Complete Response | Within 3 cycles of treatment initiation | Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. |
| Relapsed-free Survival (RFS) | Up to two years, 5 months, and 4 days | Time from date of treatment start until the date of first objective documentation of disease-relapse. |
| Overall Survival | Up to two years, 5 months, and 4 days | Kaplan-Meier method will be used to estimate the overall survival. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Treatment (Tagraxofusp, Chemotherapy) See Detailed Description
Cyclophosphamide: Given IV
Cytarabine: Given IT
Dexamethasone: Given IV or PO
Filgrastim-sndz: Given SC
Leucovorin: Given IV
Mercaptopurine: Given PO
Mesna: Give IV
Methotrexate: Given IT
Pegfilgrastim: Given SC
Prednisone: Given PO
Rituximab: Given IV
Tagraxofusp-erzs: Given IV | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Phase I Treatment (Tagraxofusp, Chemotherapy) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 31 Years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 1 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 4 / 4 |
Outcome results
Primary
Participants With a Response
Response is defined as Complete Response CR + Complete Response with inadequate count recovery (CRi) - (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. (CRi): Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L; neutrophils \< 1 x 10\^9/L).
Time frame: Within 3 cycles of treatment initiation
Population: Of the four participants registered on study, three participants were evaluable for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Treatment (Tagraxofusp, Chemotherapy) | Participants With a Response | 0 Participants |
Secondary
Overall Survival
Kaplan-Meier method will be used to estimate the overall survival.
Time frame: Up to two years, 5 months, and 4 days
Population: Of the four participants registered on study, three participants were evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Treatment (Tagraxofusp, Chemotherapy) | Overall Survival | 3.8 Months |
Secondary
Participants With a Complete Response
Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR.
Time frame: Within 3 cycles of treatment initiation
Population: Of the four participants registered on study, three participants were evaluable for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Treatment (Tagraxofusp, Chemotherapy) | Participants With a Complete Response | 0 Participants |
Secondary
Relapsed-free Survival (RFS)
Time from date of treatment start until the date of first objective documentation of disease-relapse.
Time frame: Up to two years, 5 months, and 4 days
Population: Of the four participants registered on study, three participants were evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Treatment (Tagraxofusp, Chemotherapy) | Relapsed-free Survival (RFS) | NA Months |