Philadelphia Positive Acute Lymphoblastic Leukemia
Conditions
Keywords
Leukemia, Philadelphia-Chromosome positive, cancer
Brief summary
The purpose of this research study is to see if a drug called LP-118 is safe and effective for treating adults with Philadelphia chromosome-positive (Ph+) B cell acute lymphoblastic leukemia (ALL), when given with ponatinib, dexamethasone, methotrexate and blinatumomab (the standard treatment for this type of cancer).
Detailed description
Philadelphia-Chromosome/BCR::ABL1-Positive (Ph+) acute lymphoblastic leukemia (ALL) is a type of blood cancer that happens when a specific genetic change occurs in the DNA of certain blood cells, leading to uncontrolled growth of cells. Ph+ ALL is a more aggressive form of leukemia compared to other types but with specific medications called tyrosine kinase inhibitors, treatment outcomes have significantly improved. Unfortunately, some patients still do experience relapsed disease, when their leukemia comes back after treatment, which is challenging to treat. Therefore, research is ongoing to determine ways to improve therapy and outcomes for patients with Ph+ ALL. The purpose of this study is to learn more about LP-118 and its side effects and decide on acceptable doses when combined with Food and Drug Administration (FDA) approved therapy for adult patients with Ph+ ALL. All participants will receive standard of care treatment for newly diagnosed Ph+ ALL consisting of the FDA approved drugs ponatinib, dexamethasone, intrathecal (injection into the spinal canal, also called "spinal tap") and systemic methotrexate and blinatumomab. This study will investigate different dose levels of LP-118 when given with his treatment combination to determine the most effective doses that can be safely given to patients with Ph+ ALL. This means that enrolled patients will receive progressive increasing or decreasing doses of LP-118 until the highest effective and safe dose is determined, while closely monitoring patients for any side effects or reactions. The highest dose is the dose that is the most effective dose that can be safely given to patients. This study will also preliminarily investigate if the addition of LP-118 improves treatment responses and outcomes for patients. If this trial is successful, the effectiveness of LP-118 added to this treatment regimen to treat Ph+ ALL will be studied in the next phase of clinical trials.
Interventions
DRUGLP-118
s LP-118 dosing will be dependent on the dose level to which a participant is assigned: * 50mg PO * 100mg PO * 200mg PO * 300mg PO
Sponsors
Wake Forest University Health Sciences
Newave Pharmaceutical Inc
Atrium Health Wake Forest Baptist
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to understand and willingness to sign an IRB-approved informed consent. * Age ≥ 18 years at the time of consent. * 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) - 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) - 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. * Alanine aminotransferase (ALT) - 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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimation of the Maximum Tolerated Dose (MTD) for LP-118 (Dose Escalation) | The DLT monitoring period is from Day 1 of Course 2 until the end of Course 2 (approximately 21 days). | Binary variable indicating if a Dose Limiting Toxicity (DLT) occurred. |
| Identification of the Recommended Phase 2 Dose (RP2D) LP-118 (Dose Expansion) | The DLT monitoring period is from Day 1 of Course 2 until the end of Course 2 (approximately 21 days). | Binary variable indicating if a Dose Limiting Toxicity (DLT) occurred. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS). | At most 10 years. | The time from treatment administration to death from any cause, or until last contact if the patient has not died |
| Relapsed-Free Survival (RFS). | At most 10 years. | Time from Complete Remission (CR) or Complete Remission with Incomplete Hematologic Recovery (CRi) to disease relapse or death (whichever occurs first) or otherwise censored at the date of the last disease assessment. |
| Event-Free Survival (EFS). | At most 10 years. | Time from start of therapy until failure to achieve CR/CRi, relapse, or death from any cause or otherwise censored at the date of the last disease assessment. |
| Overall Complete Molecular Response (CMR) rate. | At most 10 years. | Binary variable indicating if a CMR at any time while on study. |
| Measurable Residual Disease (MRD) rate. | Approximately 3 years. | Binary variable indicating if MRD was achieved. |
| Isolated Central Nervous System (CNS) relapse rate. | At most 10 years. | Binary variable indicating if isolated CNS relapse occurred. |
| Complete Response (CR) rate. | Approximately 3 years. | Complete clinical remission defined as the disappearance of leukemia as indicated by \<5% marrow blasts and the absence of peripheral blasts or extramedullary disease, with recovery of hematopoiesis defined by Absolute Neutrophil Count (ANC) ≥1000/μL and platelets ≥100,000/μL. |
| Complete clinical remission with incomplete count recovery (CRi) | Approximately 3 years. | Complete clinical remission with incomplete count recovery (CRi) defined as complete clinical remission except with ANC\< 1000/μL and/or platelets \<100,000/μL |
| Overall Response (OR) rate. | Approximately 3 years. | A binary variable indicating if a CR or CRi was achieved. |
| Occurrence of toxicities per Common Terminology Criteria V5.0 | Approximately 3 years. | Binary variables indicating the occurrence of toxicities per Common Terminology Criteria V5.0. |
Countries
United States
Contacts
CONTACTDianna Auman, RN
PRINCIPAL_INVESTIGATORMadelyn Burkart, MD
Wake Forest University Health Sciences
Outcome results
None listed