Total Therapy for Infants with Acute Lymphoblastic Leukemia, The TINI 2 Study
This phase I/II trial studies the safety, side effects, best dose, and effectiveness of adding a drug called blinatumomab to usual chemotherapy for treating infant patients with acute lymphoblastic leukemia (ALL). This trial also studies the effectiveness of adding a drug called ziftomenib to usual chemotherapy in treating infant patients with persistent ALL disease and a KMT2A gene mutation. Blinatumomab is in a class of medications called bispecific T-cell engager antibodies. It works by slowing or stopping the growth of cancer cells in the body. Ziftomenib blocks signals passed from one molecule to another inside cancer cells that are needed for cancer cell survival. Drugs used in chemotherapy, such as dexamethasone, vorinostat, bortezomib, pegaspargase, mitoxantrone, cytarabine, hydrocortisone, vincristine, and mercaptopurine, 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. Adding ziftomenib and/or blinatumomab ot usual chemotherapy may help improve treatment for infant ALL.
Inclusion Criteria
- Newly-diagnosed CD19-positive acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia. Subjects with bilineage or biphenotypic acute leukemia are eligible provided they express CD19. Subjects with mature B cell ALL are eligible if they express CD19 and carry a KMT2A rearrangement as determined by fluorescence in situ hybridization (FISH)
- Limited prior therapy, including hydroxyurea for 72 hours or less, systemic glucocorticoids for one week or less, cytarabine for 72 hours or less, one dose of vincristine, and one dose of intrathecal chemotherapy
- Less than or equal to 365 days of age
- POST-TRANSPLANT ELIGIBILITY FOR TREATMENT WITH ZIFTOMENIB
- Subject enrolled on TINI 2 at diagnosis
- Subject’s leukemia cells harbor a KMT2A rearrangement as determined by FISH
- Subject received a stem cell transplant and is at least 30 days post-transplant
- Subject has had bone marrow recovery defined as absolute neutrophil count (ANC) >= 0.5 x 10^9/L
- Subject has had bone marrow recovery defined as platelets >= 20 x 10^9/L
- Lansky >= 50
- Creatinine clearance (CrCl) >= 60 mL/min (as measured by a nuclear glomerular filtration rate [GFR] scan), or calculated by the Schwartz formula and normalized to a body surface area (BSA) of 1.73 m^2 OR creatinine clearance or radioisotope GFR > 70 mL/min/1.73 m^2, OR a serum creatinine based on age/gender as follows: * Age: Male (maximum serum creatinine); female (maximum serum creatinine) ** < 6 months: 0.4 mg/dL; 0.4 mg/dL ** 6 months to < 1 year: 0.5 mg/dL; 0.5 mg/dL ** >= 1 to < 2 years: 0.6 mg/dL; 0.6 mg/dL ** >= 2 to < 6 years: 0.8 mg/dL; 0.8 mg/dL
- Total bilirubin < upper limit of normal (ULN) for age, or if total bilirubin is > ULN, direct bilirubin is < 1.4 mg/dL
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 4 x ULN for age
- Shortening fraction of > 27% by echocardiogram
- Ejection fraction of > 50% by gated radionuclide study
- Corrected QT interval (QTc) less than 460 ms
Exclusion Criteria
- Subjects with prior therapy, other than therapy specified in inclusion criteria
- Subjects with mature B-cell ALL that lack a KMT2A rearrangement or acute myelogenous (AML) or T-cell ALL
- Subjects with Down syndrome
Additional locations may be listed on ClinicalTrials.gov for NCT05848687.
Locations matching your search criteria
United States
California
Los Angeles
Palo Alto
Oregon
Portland
Texas
Houston
San Antonio
PRIMARY OBJECTIVE:
I. To determine the ability of blinatumomab to increase disease clearance and sustain remission in subjects when compared to historical TINI protocol IB controls as determined by the proportion of all enrolled subjects that are minimal residual disease (MRD) negative following Induction Intensification by flow cytometry and next generation sequencing MRD assays.
SECONDARY OBJECTIVES:
I. Determine the minimum safe and biologically-effective dose of ziftomenib in combination with chemotherapy during reinduction in upfront refractory subjects.
II. To estimate the 3-year event-free survival and overall survival of infants with ALL who are treated on study.
OUTLINE: This is a phase I dose-escalation study of ziftomenib followed by a phase II study.
REMISSION INDUCTION: Patients receive dexamethasone orally (PO), via nasogastric (NG) tube, or intravenously (IV) twice daily (BID) on days 1-4, 8-11, and 15-18, vorinostat PO or NG on days 1-4, 8-11, and 15-18, bortezomib IV on days 1, 4, 8, 11, 15, and 18, pegaspargase IV on day 5, and mitoxantrone IV on days 8 and 9 in the absence of disease progression or unacceptable toxicity. Patients also undergo a lumbar puncture to receive the combination of methotrexate, cytarabine, and hydrocortisone (MHA) intrathecally (IT) on days 1, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity.
INDUCTION INTENSIFICATION: Patients receive dexamethasone PO, NG, or IV on day 1 and blinatumomab IV on days 1-28 in the absence of disease progression or unacceptable toxicity. Patients with central nervous system (CNS)2/3 or traumatic diagnostic lumbar puncture recieve MHA IT on days 8 and 15 in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION I: Patients receive high-dose methotrexate IV on days 1 and 15, bortezomib IV on days 8, 11, 22, and 25, vorinostat PO or NG on days 8-11 and 22-25, and dexamethasone PO or NG BID on days 8-11 and 22-25 in the absence of disease progression or unacceptable toxicity. Patients also receive MHA IT on days 1 and 15 in the absence of disease progression or unacceptable toxicity.
RE-INDUCTION BLOCK I: Patients who are KMT2A rearrangement negative or KMT2A rearrangement positive and MRD < 0.1% at the end of Induction Intensification are assigned to Arm I. Patients who are KMT2A rearrangement positive and MRD >= 0.1% at the end of Induction Intensification are assigned to Arm II.
ARM I: Patients receive mitoxantrone IV on days 1 and 2, dexamethasone PO, NG, or IV BID on days 1-4, 8-11, and 15-18, vorinostat PO or NG on days 1-4, 8-11, and 15-18, bortezomib IV on days 1, 4, 8, 11, 15, and 18, and pegaspargase IV on days 3 and 18 in the absence of disease progression or unacceptable toxicity. Patients also receive MHA IT on day 1 (and day 15 for patients with CNS3 or traumatic diagnostic lumbar punctures) in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive ziftomenib PO or NG on days 1-35, mitoxantrone IV on days 8 and 9, dexamethasone PO, NG, or IV BID on days 8-11, 15-18, and 22-25, vorinostat PO or NG on days 8-11, 15-18, and 22-25, bortezomib IV on days 8, 11, 15, 18, 22, and 25, and pegaspargase IV on days 10 and 25 in the absence of disease progression or unacceptable toxicity. Patients also receive MHA IT on day 1 (and day 15 for patients with CNS3 or traumatic diagnostic lumbar punctures) in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples for ziftomenib pharmacokinetic (PK) studies on days 1, 7, 15, and 35.
RE-INDUCTION BLOCK II: Patients receive blinatumomab IV on days 1-28 and dexamethasone PO, NG, or IV on day 1 in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION II: Patients receive high-dose methotrexate IV on days 1 and 15, bortezomib IV on days 8, 11, 22, and 25, vorinostat PO or NG on days 8-11 and 22-25, and dexamethasone PO or NG BID on days 8-11 and 22-25 in the absence of disease progression or unacceptable toxicity. Patients also receive MHA IT on days 1 and 15 in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive dexamethasone PO, NG, or IV BID on days 1-5, vincristine IV on day 1, mercaptopurine PO or NG on days 1-83, methotrexate PO, IV, or intramuscularly (IM) on days 1, 8, 15, 22, 29, 35, 42, 49, 56, 63, 70, 77 (on days 1, 29, and 56 of cycles that do not have IT treatment on those days). Patients with CNS1 also receive MHA IT on days 1, 29, and 56 of cycles 1-2 and on days 1 and 29 of cycle 3. Patients with CNS2 also receive MHA IT on days 1, 29, and 56 of cycles 1-3 and on days 1 and 29 of cycle 4. Patients with CNS3 also receive MHA IT on days 1, 29, and 56 of cycles 1-4 and on day 1 of cycle 5. Treatment repeats every 83 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity.
POST-STEM CELL TRANSPLANT (SCT) MAINTENANCE: Patients who are KMT2A rearrangement positive and go off-study for SCT may re-enroll and receive ziftomenib PO or NG daily for up to 2 years in the absence of disease progression or unacceptable toxicity.
All patients also undergo chest x-ray, echocardiography (ECHO), bone marrow aspiration and/or biopsy, and collection of blood and cerebrospinal fluid (CSF) samples throughout the trial.
After completion of study treatment, patients are followed every 4 months for 1 year, every 6 months for the 2nd year, and then yearly thereafter until the patient is in remission for 10 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationStanford Cancer Institute Palo Alto
Principal InvestigatorTanja Andrea Gruber
- Primary IDPEDSHEMALL0015
- Secondary IDsNCI-2023-04129
- ClinicalTrials.gov IDNCT05848687