LP-118 in Combination with Ponatinib, Dexamethasone and Blinatumomab for the Treatment of Adults with Newly-Diagnosed Philadelphia-Chromosome-Positive Acute Lymphoblastic Leukemia
This phase I trial studies the safety, side effects, and best dose of LP-118 in combination with ponatinib, dexamethasone, and blinatumomab in treating patients with newly-diagnosed adults with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). LP-118 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Ponatinib is a tyrosine kinase inhibitor (TKI) that blocks the signal that can cause cancer cell growth. Dexamethasone is a steroid that is used in combination with anti-cancer treatment that helps lower the risk of developing common side effects associated with anti-cancer treatment. Blinatumomab is a bispecific antibody that can bind to cancer cells in the body and destroy them. Giving LP-118 in combination with ponatinib, dexamethasone, and blinatumomab may be a safe treatment for adult patients with newly-diagnosed Ph+ ALL.
Inclusion Criteria
- Ability to understand and willingness to sign an institutional review board (IRB)-approved informed consent
- Age ≥ 18 years at the time of consent
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
- Histological or cytological confirmation of newly diagnosed CD19-positive Philadelphia-chromosome/BCR::ABL1-positive ALL
- Creatinine clearance ≥ 60 mL/min, determined by the Cockroft-Gault formula, or measured by a 24-hour urine collection
- Bilirubin ≤ 1.5 × upper limit of normal (ULN) (The most recent labs prior to enrollment will be used for eligibility if labs are drawn more than once during screening) * Unless liver abnormalities considered due to Gilbert's syndrome or of non-hepatic origin i.e., leukemic involvement. For patients with Gilbert's syndrome, bilirubin ≤ 1.5 x of their baseline bilirubin level will be required
- Aspartate aminotransferase (AST) ≤ 3 × ULN (The most recent labs prior to enrollment will be used for eligibility if labs are drawn more than once during screening) Unless liver abnormalities considered due to Gilbert's syndrome or of non-hepatic origin i.e., leukemic involvement
- Alanine aminotransferase (ALT) ≤ 3 × ULN (The most recent labs prior to enrollment will be used for eligibility if labs are drawn more than once during screening) * Unless liver abnormalities considered due to Gilbert's syndrome or of non-hepatic origin i.e., leukemic involvement
- Individuals of childbearing potential (ICBP) must have a negative serum pregnancy test. NOTE: Individuals who may become pregnant are considered to have childbearing potential unless they are surgically infertile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause)
- ICBP must be willing to use two forms of contraception, one of which must be a barrier method and the other must be a highly effective contraceptive method from the time of informed consent until 6 months after study treatment discontinuation. Male participants with female partners of reproductive potential will need to agree to use contraception methods described above during study treatment and for at least 6 months after completion of all study treatment
- Male participants must agree to refrain from sperm donation during study treatment and for at least 6 months after completion of all study treatment
- Ability to ingest oral medications without a malabsorption condition, known dysphagia, short-gut syndrome, gastroparesis, or other conditions that may limit the ingestion or gastrointestinal absorption, distribution, metabolism and excretion of drugs administered orally, per the enrolling investigator
Exclusion Criteria
- Any prior treatment for ALL except for a single dose of intrathecal (IT) chemotherapy, corticosteroids, hydroxyurea, a single dose of vincristine, cytarabine, leukapheresis, and/or a BCR::ABL1-targeted tyrosine kinase inhibitor. Permitted prior treatment is limited to a duration of no longer than 14 days. Permitted prior treatment must be stopped at least 24 hours prior to starting study therapy
- Women who are pregnant, nursing, or who plan to become pregnant while in the study and for at least 6 months after the last administration of all study treatment. NOTE: breast milk cannot be stored for future use while the mother is being treated on study. Pregnant participants are excluded from this study because ponatinib, blinatumomab, and methotrexate have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ponatinib, blinatumomab, and methotrexate breastfeeding should be discontinued if the patient is treated with ponatinib, blinatumomab, and methotrexate
- Active second malignancy except for localized prostate cancer, basal cell or squamous cell carcinoma of the skin and carcinoma in situ of the skin or cervix
- Unstable or severe uncontrolled medical condition in the opinion of the enrolling investigator (e.g., unstable cardiac function or unstable pulmonary condition; uncontrolled infection)
- Participants with known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV) are eligible if no evidence of active viral replication by blood testing (i.e. negative viral loads). HIV positive participants must be on active anti-retroviral therapy and willing to continue therapy during study treatment
- Uncontrolled cardiac disease as determined by the enrolling investigator
- Major surgery, as determined by the enrolling investigator, within 2 weeks before enrollment
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07614022.
Locations matching your search criteria
United States
North Carolina
Charlotte
Winston-Salem
PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose (MTD) of Bcl-2/Bcl-XL Inhibitor LP-118 (LP-118) given during Course 2, in combination with ponatinib, dexamethasone, and intrathecal (IT) methotrexate in adults with newly diagnosed Ph+ ALL. (Dose Escalation)
II. To identify the recommended dose (RP2D) for LP-118 in combination with ponatinib, dexamethasone, and IT methotrexate during induction in adults with newly diagnosed Ph+ ALL. (Dose Expansion)
SECONDARY OBJECTIVES:
I. To evaluate the following outcomes for all dose levels of LP-118 combined:
Ia. Overall survival;
Ib, Relapse-free survival;
Ic. Event free survival;
Id. Overall complete molecular response (CMR) rate;
Ie. Measurable residual disease (MRD) negativity rate by next-generation sequencing (ClonoSEQ);
If. Isolated central nervous system (CNS) relapse rate;
Ig. Complete response (CR) rate;
Ih. CR with partial hematologic recovery (CRi) rate;
Ii. Overall response rate (CR+CRi rate).
SAFETY OBJECTIVE:
I. To characterize the overall safety and tolerability of LP-118. This will be accomplished descriptively in terms of the outcomes described.
OUTLINE: This is a dose-escalation study of LP-118 in combination with ponatinib, dexamethasone, methotrexate (MTX), and blinatumomab, followed by a dose-expansion study.
INDUCTION COURSE 1: Patients receive ponatinib orally (PO) daily on days 1-14, dexamethasone PO or intravenously (IV) daily on days 1-7, and MTX intrathecally (IT) on day 1 (Omit for patients receiving CNS Treatment). Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. NOTE: Patients with CNS-2 or CNS-3 disease receive additional CNS Treatment along with study treatment (see below) starting with Course 1.
* CNS TREATMENT: Patients receive MTX IT twice weekly, at least 2 days apart, until no leukemia is found in the cerebrospinal fluid (CSF) and/or cranial nerve abnormality (problems with taste, vision, smell, hearing, balance, speech, etc.) has resolved. Patients then receive MTX IT once weekly for 4 doses, followed by once monthly for 12 doses. Patients with leukemia still present or not decreased in CSF at 4 weeks then receive cranial radiation therapy, followed by MTX IT weekly until no leukemia is found in the CSF and/or cranial nerve abnormality has resolved. These patients then receive MTX IT once monthly for 12 doses.
INDUCTION COURSE 2: Patients receive ponatinib PO daily on days 1-21, dexamethasone PO or IV daily on days 1-7, LP-118 PO daily on days 1-21, and MTX IT on days 1 and 15 (Omit for patients receiving CNS Treatment). Treatment continues for 21 days in the absence of disease progression or unacceptable toxicity. Patients with CR/CRi/morphologic leukemic-free state (MLFS) and are MRD negative (-) then proceed to Consolidation Course 3. Patients with CR/CRi/MLFS and are MRD positive (+) then proceed to MRD Treatment Course M. Patients without CR/CRi/MLFS after Induction Course 2 discontinue study treatment.
CONSOLIDATION COURSE 3: Patients receive ponatinib PO daily on days 1-42 of each cycle, dexamethasone IV on day 1 of each cycle, blinatumomab IV continuously on days 1-28 of each cycle, and MTX IT on day 1 and 21 of each cycle (Omit for patients receiving CNS Treatment). Cycles repeat every 42 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR/CRi/MLFS and MRD(-) then proceed to CNS Prophylaxis Course 4. Patients with CR/CRi/MLFS and MRD(+) then proceed to MRD Treatment Course M. Patients with evidence of disease relapse discontinue study treatment.
MRD TREATMENT COURSE M: Patients receive ponatinib PO daily on days 1-42 of each cycle, dexamethasone IV on day 1 of each cycle, and blinatumomab IV continuously on days 1-28 of each cycle. Patients starting Course M after Course 2 receive MTX IT on day 1 and 21 of cycles 1 and 2 only (Omit for patients receiving CNS Treatment). Patients starting Course M after Course 3 receive MTX IT on day 1 and 21 of each cycle (Omit for patients receiving CNS Treatment). Cycles repeat every 42 days for 4 cycles (if starting after course 2) or for 2 cycles (if starting after course 3) in the absence of disease progression or unacceptable toxicity. Patients with CR/CRi/MLFS then proceed to CNS Prophylaxis Course 4. Patients with evidence of disease relapse discontinue study treatment.
CNS PROPHYLAXIS COURSE 4: Patients receive ponatinib PO daily on days 5-14, 19-28, and 33+ of each cycle, methotrexate IV over 4 hours on days 1, 15, and 29 of each cycle, and MTX IT on days 3, 18, 32, and 46 of each cycle (Omit days 32 and 46 for patients treated with IT MTX in Course M AND Course 2). Patients also receive leucovorin IV over 15-30 minutes every 6 hours (Q6H) starting 24 hours after end of each MTX infusion. Treatment continues for 49 days in the absence of disease progression or unacceptable toxicity. Patients with CR/CRi/MLFS and MRD(-) then proceed to Maintenance Course 5. Patients with CR/CRi/MLFS and MRD(+) then proceed to Maintenance Course 5 OR alternate therapy off study per the discretion of the treating clinician. Patients with evidence of disease relapse discontinue study treatment.
MAINTENANCE COURSE 5: Patients receive ponatinib PO daily during each cycle. Cycles repeat every 3 months for up to 2 years in the absence of disease progression or unacceptable toxicity. After 2 years, patients without CMR and/or are MRD(+) continue receiving ponatinib PO daily until achieving CMR and MRD(-) for 2 consecutive tests at least 3 months apart.
All patients also undergo echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) during screening and lumbar puncture, blood sample collection, and bone marrow biopsies throughout the study.
After completion of study treatment, patients are followed up at 30 days and then every 3 months until disease progression or initiation of subsequent anti-cancer treatment, followed by every 6 months thereafter.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationWake Forest University Health Sciences
Principal InvestigatorMadelyn Burkart
- Primary IDONC-LEUK-2405
- Secondary IDsNCI-2026-05218, IRB00127277
- ClinicalTrials.gov IDNCT07614022