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.
Brief Title
Safety and Clinical Activity of KT-253 in Adult Patients with High Grade Myeloid Malignancies, Acute Lymphocytic Leukemia, Lymphoma, Solid Tumors
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Myeloid Malignancies
Acute Lymphocytic Leukemia
Lymphomas
Advanced Solid Tumors
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.
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.
Inclusion 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.
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.
Gender
All
Gender Based
false
Keywords
KT-253
MDM2
High Grade MDS/MPN
ALL
AML
Lymphoma
Solid tumor
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT05775406
Org Class
Industry
Org Full Name
Kymera Therapeutics, Inc.
Org Study Id
KT253-AL-101
Overall Status
Completed
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
Adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0
Outcome Measure
Incidence and severity of adverse events
Outcome Time Frame
From the time of signing ICF through 30 days after last dose of study drug or prior to start of a new anticancer therapy
Outcome Description
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
Outcome Measure
Maximum Tolerated Dose (MTD) and recommended Phase 2 dose (RP2D) in Patients
Outcome Time Frame
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
Outcome Description
To determine the AUC from plasma concentrations in patients
Outcome Time Frame
Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days)
Outcome Measure
Area under the Plasma Concentration versus Time Curve (AUC) of KT-253
Outcome Description
To determine the Cmax from plasma concentrations in patients
Outcome Time Frame
Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days)
Outcome Measure
Maximum Plasma Concentration of KT-253 (Cmax)
Outcome Description
To determine the Tmax from plasma concentrations in patients
Outcome Time Frame
Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days)
Outcome Measure
Time to maximum plasma concentration of KT-253 (Tmax)
Outcome Description
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.
Outcome Time Frame
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
Outcome Measure
Evidence of Clinical Activity of KT-253 in AML patients
Outcome Description
Hematological remission rate defined as CR and CRh per NCCN guidelines
Outcome Time Frame
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
Outcome Measure
Evidence of Clinical Activity of KT-253 in ALL patients
Outcome Description
CR or CR equivalent, partial remission (PR),CR with limited count recovery, CRh, and hematologic improvement (HI) per revised International Working Group (IWG) criteria
Outcome Time Frame
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
Outcome Measure
Evidence of Clinical Activity of KT-253 in High/Very High-Risk Myelodysplastic syndromes (MDS) patients
Outcome Description
Percentage of patients with CR, PR, and Marrow Response per MDS/MPN IWG
Outcome Time Frame
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
Outcome Measure
Evidence of Clinical Activity of KT-253 in MDS/ Myeloproliferative Neoplasms (MPN) patients
Outcome Description
Overall Response Rate (ORR) based on Investigator's assessment as per Lugano criteria 2014 for Lymphomas
Outcome Time Frame
From Baseline scan until first documented progression or death from any cause, whichever comes first , about 18 months
Outcome Measure
Evidence of Clinical Activity of KT-253 in R/R Lymphoma patients
Outcome Description
Overall Response Rate (ORR) defined as percentage of patients with Complete Response or Partial Response per RECIST 1.1
Outcome Time Frame
From Baseline scan until first documented progression or death from any cause, whichever comes first, about 18 months
Outcome Measure
Evidence of Clinical Activity of KT-253 in R/R Solid Tumor patients
Outcome Description
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
Outcome Time Frame
From date of first of response to the date of documented first progression or death whichever comes first, about 18 months
Outcome Measure
Duration of Response (DoR) in Patients Treated with KT-253
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Aditi Shastri
Investigator Email
ASHASTRI@montefiore.org
Investigator Phone
718-920-4826