Clinical trial NCT05775406: Safety and Clinical Activity of KT-253 in Adult Patients with High Grade Myeloid Malignancies, Acute Lymphocytic Leukemia, Lymphoma, Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myeloid Malignancies
Acute Lymphocytic Leukemia
Lymphomas
Advanced Solid Tumors
Keywords: KT-253
MDM2
High Grade MDS/MPN
ALL
AML
Lymphoma
Solid tumor
Lead sponsor: Kymera Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2023-03-20
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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, myelofibrosis, and R/R solid tumors. The study will identify the pharmacologically optimal dose(s) (MTD) of KT-253 as the recommended Phase 2 dose (RP2D), based on all safety, PK, PD, and efficacy data.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. 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.
3. 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:

1. 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.
   * Known presence of p53 mutations in tumor tissue or blood, which are known to completely inactivate p53 transcriptional activity
2. 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).
   * Exposures to anticancer therapy or investigational therapy within 2 weeks or 5 half-lives whichever is longer prior to the first dose of study drug.
   * Received immunotherapy/biologic treatment or investigational therapy within 4 weeks prior to first dose of KT-253, including tumor vaccines and checkpoint inhibitors.
3. Advanced high grade myeloid malignancies, and Acute Lymphocytic Leukemia (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.

Primary outcomes:
measure: Incidence and severity of adverse events
timeFrame: From the time of signing ICF through 30 days after last dose of study drug or prior to start of a new anticancer therapy
measure: Maximum Tolerated Dose (MTD) and recommended Phase 2 dose (RP2D) in Patients
timeFrame: 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 outcomes:
measure: Area under the Plasma Concentration versus Time Curve (AUC) of KT-253
timeFrame: Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days)
measure: Maximum Plasma Concentration of KT-253 (Cmax)
timeFrame: Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days)
measure: Time to maximum plasma concentration of KT-253 (Tmax)
timeFrame: Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days)
measure: Evidence of Clinical Activity of KT-253 in AML patients
timeFrame: 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
measure: Evidence of Clinical Activity of KT-253 in ALL patients
timeFrame: 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
measure: Evidence of Clinical Activity of KT-253 in High/Very High-Risk Myelodysplastic syndromes (MDS) patients
timeFrame: 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
measure: Evidence of Clinical Activity of KT-253 in MDS/ Myeloproliferative Neoplasms (MPN) patients
timeFrame: 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
measure: Evidence of Clinical Activity of KT-253 in R/R Lymphoma patients
timeFrame: From Baseline scan until first documented progression or death from any cause, whichever comes first , about 18 months
measure: Evidence of Clinical Activity of KT-253 in R/R Solid Tumor patients
timeFrame: From Baseline scan until first documented progression or death from any cause, whichever comes first, about 18 months
measure: Duration of Response (DoR) in Patients Treated with KT-253
timeFrame: From date of first of response to the date of documented first progression or death whichever comes first, about 18 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth Research Institute
state: Arizona
city: Sacramento
country: United States
facility: University of California, Davis Comprehensive Cancer Center
state: California
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Oklahoma City
country: United States
facility: OU Health Stephenson Cancer Center
state: Oklahoma
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
Study officials:
affiliation: Kymera Therapeutics, Inc.
name: Ashwin Gollerkeri, MD
role: STUDY_DIRECTOR
References: