Safety and Clinical Activity of KT-253 in Adult Patients With High Grade Myeloid Malignancies, Acute Lymphocytic Leukemia, Lymphoma, Solid Tumors

Study Overview
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Brief Summary
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This Phase 1 study will evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and clinical activity of KT-253 in adult patients with relapsed or refractory (R/R) high grade myeloid malignancies, acute lymphocytic leukemia (ALL), R/R lymphoma, and R/R solid tumors. The study will identify the pharmacologically optimal dose(s) of KT-253 as the recommended Phase 2 dose (RP2D), based on all safety, PK, PD, and efficacy data.

Detailed Description
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This is an open-label Phase 1 (dose escalation) first-in-human study (FIH) of KT-253 in adult patients. This study will be initiated in patients with lymphomas, and solid tumors and then subsequently in patients with advanced high grade myeloid malignancies and ALL. Therefore, the study is comprised of two arms to characterize the safety and tolerability of ascending doses of KT-253 in each arm. Arm A will consist of patients with lymphomas and advanced solid tumors and Arm B will consist of patients with high grade myeloid malignancies and ALL.

Official Title
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A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Intravenously Administered KT-253 in Adult Patients With High Grade Myeloid Malignancies and Acute Lymphocytic Leukemia, Lymphoma and Advanced Solid Tumors

Conditions
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Myeloid Malignancies, Acute Lymphocytic Leukemia, Lymphomas, Advanced Solid Tumors

Intervention / Treatment
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* Drug: KT-253


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Participants: Eastern Cooperative Oncology Group performance status: 0-2. Resolved acute effects of any prior therapy except for alopecia to baseline severity or Grade ≤1 NCI CTCAE and Grade ≤2 neuropathy Adequate organ function at screening Solid Tumors and Lymphoma (Arm A) ONLY Histologically or pathologically confirmed solid tumor or lymphoma. Relapsed and/or refractory (R/R) disease to at least two prior standard-of-care treatments or tumors for whom standard therapies are not available. Advanced high grade myeloid malignancies, and Acute Lymphocytic Leukemia (Arm B) ONLY Primary diagnosis of AML, ALL, High/Very High-risk MDS, MDS/MPN. Must be relapsed/refractory to standard therapies. Exclusion Criteria: All Participants: Ongoing unstable cardiovascular function. Major surgery requiring general anesthesia within 4 weeks prior to first dose of study drug. History of or active concurrent malignancy unless disease-free for ≥ 2 years. Exposures to anticancer therapy within 2 weeks or 5 half-lives whichever is shorter; or 4 weeks from any biologics/immunotherapies or any investigational therapy prior to the first dose of study drug. Known presence of p53 mutation in tumor tissue Solid Tumors and Lymphoma (Arm A) ONLY Known active uncontrolled or symptomatic central nervous system (CNS) metastases. Autologous or allogenic hematopoietic stem cell transplant (HSCT) within six months prior to first dose of study drug or participant has progressed within six months from the day of stem cell infusion (for lymphoma participants only). Advanced high grade myeloid malignancies, and ALL (Arm B) ONLY Active CNS leukemia. Participants with symptoms suggestive of CNS disease will require a lumbar puncture to rule out CNS disease. Prior chemotherapy/radiation (including craniospinal radiation) within 2 weeks prior to the first dose of study drug. Received allogeneic hematopoietic cell transplantation (HCT) <12 weeks prior to first dose or donor lymphocyte infusion (DLI) without conditioning <4 weeks prior to first dose. Received autologous stem cell transplant (ASCT) < 4 weeks prior to first dose or the patient has not recovered from transplant associated toxicities to ≤ grade 1 prior to the first dose of study drug. Received chimeric antigen receptor therapy or other modified T cell therapy <3 weeks prior to the first dose. Patients with signs or symptoms of Grade ≥ 2 acute or chronic graft versus host disease (GVHD) within 2 weeks of enrollment.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation Arm A in patients with R/R Solid Tumors and Lymphomas<br>KT-253 dosed intravenous (IV) once every three weeks in 21-day cycles | Drug: KT-253<br>* KT-253 will be administered intravenously per the defined protocol frequency and dose level.<br>|
| Experimental: Phase 1 Dose Escalation Arm B in patients with R/R High Grade Myeloid Malignancies and ALL<br>KT-253 dosed IV once every three weeks in 21-day cycles | Drug: KT-253<br>* KT-253 will be administered intravenously per the defined protocol frequency and dose level.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events | Adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 | From the time of signing ICF through 30 days after last dose of study drug or prior to start of a new anticancer therapy | 
| Maximum Tolerated Dose (MTD) and recommended Phase 2 dose (RP2D) in Patients | MTD and RP2D will be determined in patients with R/R high grade myeloid malignancies, ALL, and separately, in patients with lymphomas and advanced solid tumors | From the time of the first dose of study drug through 30 days after the last dose of study drug or prior to start of a new anticancer therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the Plasma Concentration versus Time Curve (AUC) of KT-253 | To determine the AUC from plasma concentrations in patients | Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days) | 
| Maximum Plasma Concentration of KT-253 (Cmax) | To determine the Cmax from plasma concentrations in patients | Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days) | 
| Time to maximum plasma concentration of KT-253 (Tmax) | To determine the Tmax from plasma concentrations in patients | Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days) | 
| Evidence of Clinical activity of KT-253 in AML patients | Percentage of patients with Morphologic leukemia free state (MLFS), complete remission (CR), CR with partial hematologic recovery (CRh) according to the European LeukemiaNet (ELN) response criteria. | From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months | 
| Evidence of Clinical activity of KT-253 in ALL patients | Hematological remission rate defined as CR and CRh per NCCN guidelines | From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months | 
| Evidence of Clinical activity of KT-253 in High/Very High-Risk Myelodysplastic syndromes (MDS) patients | CR or CR equivalent, partial remission (PR),CR with limited count recovery, CRh, and hematologic improvement (HI) per revised International Working Group (IWG) criteria | From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months | 
| Evidence of Clinical activity of KT-253 in MDS/ Myeloproliferative Neoplasms (MPN) patients | Percentage of patients with CR, PR, and Marrow Response per MDS/MPN IWG | From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months | 
| Evidence of Clinical activity of KT-253 in R/R Lymphoma patients | Overall Response Rate (ORR) based on Investigator's assessment as per Lugano criteria 2014 for Lymphomas | From Baseline scan until first documented progression or death from any cause, whichever comes first , about 18 months | 
| Evidence of Clinical activity of KT-253 in R/R Solid Tumor patients | Overall Response Rate (ORR) defined as percentage of patients with Complete Response or Partial Response per RECIST 1.1 | From Baseline scan until first documented progression or death from any cause, whichever comes first, about 18 months | 
| Duration of Response (DoR) in Patients Treated with KT-253 | Duration of Response (DoR) in R/R high grade myeloid malignancies and ALL, R/R lymphoma and R/R solid tumor patients treated with KT-253 | From date of first of response to the date of documented first progression or death whichever comes first, about 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALL, Lymphoma, Solid tumor, MDM2, High Grade MDS/MPN, AML, KT-253