Phase II Study to Evaluate Safety and Efficacy of CB-103 With Venetoclax in Adolescent and Young Adult Patients With Relapsed/Refractory T-ALL or T-LBL

Study Overview
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Brief Summary
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To learn if the combination of 2 study drugs, CB-103 and venetoclax, can help to control T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic leukemia (T-LBL) in adolescent and young adult patients

Detailed Description
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Primary Objectives: To characterize the safety and tolerability of CB-103 in combination with Venetoclax in adolescent (12 to 18 years), and young adult (19 to 40 years) patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). To assess the efficacy of CB-103 in combination with venetoclax by the overall response rate (ORR), defined as complete remission (CR), plus CR with incomplete blood count recovery (CRi) [1] plus partial remission (PR) [2], in adolescent, and young adult patients with relapsed/refractory T-ALL/T-LBL. Secondary Objectives: To assess whether the ORR to CB-103 in combination with Venetoclax is dependent on pre-treatment expression of Notch and/or BCL2 pathway. To determine the preliminary assessment of CB-103 in combination with Venetoclax by other efficacy parameters such as minimal residual disease (MRD), duration of response (DoR), overall survival (OS) and event-free survival (EFS) in adolescent and young adult patients with relapsed/refractory T-ALL/T-LBL. Exploratory Objectives: To explore potential correlations of ORR to treatment and additional pharmacodynamic (PD) markers, i.e., other oncogenic pathway activations that may co-occur at the start of treatment. To evaluate how many patients are able to transition to Hematopoietic Stem Cell Transplant (HSCT): Either in the patients achieving CR after the induction and reinduction cycles; Or in the patients with PR or stable disease (SD) after the induction and reinduction.

Official Title
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A Phase II Study to Evaluate Safety and Efficacy of CB-103 in Combination With Venetoclax in Adolescent and Young Adult Patients With Relapsed/Refractory T-cell Acute Lymphoblastic Leukemia (T-ALL)

Conditions
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Leukemia, Lymphoblastic, Leukemia

Intervention / Treatment
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* Drug: CB-103
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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• Inclusion Criteria: Adolescent (12 to 18 years), and young adult (19 to 40 years) patients who have relapse or refractory T-cell lymphoblastic leukemia (T-ALL) or T-Cell lymphoblastic lymphoma (T-LBL) according to 2017 WHO classification [29] and NCCN v1 2021 [30]: Patients must have ≥ 5% blasts in the bone marrow as assessed by morphology on standard bone marrow biopsy and aspirate or less than 5% blasts in the bone marrow in presence of extramedullary relapse, excluding isolated central nervous system (CNS) relapse. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood. Patients are eligible independently of Notch pathway activation in the leukemic blasts: However, a fresh marrow/blood sample must be obtained before starting the study treatment to classify the patients as being either Notch positive or negative. Leukemic blasts must express of at least 2 of the following immune phenotyping: CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD34, TCRαβ, TCRγδ, cyCD3 Patients have adequate performance status (ECOG ≤2) for patients ≥16 years old, Lansky score >50 for patients <16 years old. Patients have a life expectancy of at least 4 months. Patients must be 12 to 40 years of age inclusive when signing the informed consent. Patients with asymptomatic CNS disease are eligible • Exclusion Criteria: Mixed phenotype leukemia (excluding T-ALL with myeloid antigen expression) History of another primary invasive malignancy that has not been definitively treated and in remission. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses). Presence of clinically significant uncontrolled CNS pathology such as epilepsy, childhood seizure, paresis, aphasia, stroke, severe brain injuries, organic brain syndrome, or psychosis. Evidence of active cerebral/meningeal disease. Patients may have history of CNS leukemic involvement if definitively treated with prior therapy and no evidence of active disease at the time of consent (see inclusion criterion 3.1.7.). Patients with a cardiac ejection fraction (as measured by either MUGA or echocardiogram) < 50% or with a history of absolute decrease in LVEF of ≥ 15 absolute percentage points are excluded. Patients with uncontrolled, active infections (viral, bacterial, or fungal). Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable. Known active hepatitis B or C infection or known seropositivity for HIV. Liver cirrhosis or other active severe liver disease or with suspected active alcohol abuse. Patients with impairment of GI function or GI disease presence that significantly alter the absorption of CB-103 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Females who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CB-103+Venetoclax<br>Control T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic leukemia (T-LBL) in adolescent and young adult patients. | Drug: CB-103<br>* Given by PO<br>* Other names: Cellestia;Drug: Venetoclax<br>* Given by PO<br>* Other names: ABT-199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety and tolerability of CB-103 in combination with Venetoclax in adolescent and young adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) . | Participants will be studied by assessing the number of participants with With Treatment-Related Adverse Events Assessed by CTCAE v5.0 | through completion of study or average of 1 year | 
| The efficacy of CB-103 in combination with venetoclax will be determined by studying the overall response rate (ORR) of the participants | Defined as complete remission (CR), plus CR with incomplete blood count recovery (CRi) [1] plus partial remission (PR) [2], in adolescent, and young adult patients with relapsed/refractory T-ALL/T-LBL. | through completion of study or average of 1 year |