Clinical trial NCT05233033: Safety, PK/PD, and Clinical Activity of KT-413 in Adult Patients with Relapsed or Refractory B-cell NHL
Official title: A Phase 1, Multicenter, Open-Label, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, PK/PD, and Clinical Activity of Intravenously Administered KT-413 in Adult Patients with Relapsed or Refractory B-cell NHL
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non Hodgkin Lymphoma
Diffuse Large B Cell Lymphoma
DLBCL
MYD88 Gene Mutation
Lead sponsor: Kymera Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2022-02-10
Enrollment: 7
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 1a/1b study will evaluate the safety, tolerability and the pharmacokinetics/ pharmacodynamics (PK/ PD) of KT-413 in patients with R/R NHL. The Phase 1a stage of the study will explore escalating doses of single-agent KT-413. The Phase 1b stage will be split into 2 expansion cohorts to further characterize the safety, tolerability and the pharmacokinetics/ pharmacodynamics (PK/ PD) of KT-413 in MYD88 mutant and MYD88 wild-type R/R DLBCL.


Eligibility criteria: Inclusion Criteria:

* Phase 1a Only:

  * Histologically confirmed diagnosis of B-cell NHL according to the 2016 World Health Organization (WHO) classification. Diffuse large B-cell lymphoma (DLBCL) includes: DLBCL not otherwise specified (NOS) with or without MYC and BCL2 and/or BCL6 rearrangements; Epstein-Barr virus (EBV) positive DLBCL, NOS; human herpesvirus 8 (HHV8) positive DLBCL, NOS; DLBCL associated with chronic inflammation; and Primary cutaneous DLBCL, leg type. Patients with indolent lymphoma are eligible if they meet criteria for systemic treatment.
  * Clinicopathological diagnosis of Waldenström's Macroglobulinemia (WM) based on the consensus panel criteria from the Second International Workshop on WM
  * Histologically/cytologically confirmed relapsed/refractory Primary Central Nervous System Lymphoma (PCNSL) by cerebrospinal fluid (CSF) or biopsy. PCNSL patients are considered eligible if the Investigator believes that there is no other reasonable treatment alternative.

    * Note: Patients with HIV-associated PCNSL are not eligible.
    * Note: Patients with secondary CNS metastases are eligible assuming they meet other study criteria. Patients with secondary CNS metastases include those who have synchronous systemic and CNS involvement or those who have been previously treated and relapsed with isolated CNS involvement.
* Phase 1b Only: Histologically confirmed diagnosis of DLBCL according to the 2016 WHO classification including: DLBCL not otherwise specified (NOS) with or without MYC and BCL2 and/or BCL6 rearrangements; Epstein-Barr virus (EBV) positive DLBCL, NOS; HHV8+ DLBCL, NOS; DLBCL associated with chronic inflammation; and Primary cutaneous DLBCL, leg type.
* Disease relapsed and/or refractory to at least 2 accepted standard systemic regimens for all indications except PCNSL. For PCNSL, patients must be relapsed and/or refractory to at least 1 prior regimen.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at Screening.
* Adequate organ and bone marrow function, in the absence of growth factors
* Patients of child-bearing potential must use adequate contraceptive measures to avoid pregnancy for the duration of the study as defined in the protocol

Exclusion Criteria:

* Infection with hepatitis B (HBV), hepatitis C (HCV), or active viral infection with human immunodeficiency virus (HIV).
* Radiation treatment within 4 weeks prior to first dose of study drug, unless the tumor site continues to increase in size after the patient has completed radiotherapy treatment.
* Major surgery requiring general anesthesia within 4 weeks prior to first dose of study drug, unless the tumor site continues to increase in size after the patient has completed radiotherapy treatment.
* Ongoing unstable cardiovascular function including history of myocardial infarction within 3 months of planned start of study drug.
* Patient has not recovered from any clinically significant AEs of previous treatments to pre-treatment baseline or Grade 1 prior to first dose of study drug.

Primary outcomes:
measure: To establish the Maximum Tolerated Dose (MTD)
timeFrame: Within first 3 weeks of treatment
measure: Number of Participants with protocol specified Dose Limiting Toxicities (DLTs)
timeFrame: Within first 3 weeks of treatment
measure: Dose recommended for future studies
timeFrame: Within first 3 weeks of treatment
measure: Clinical Laboratory Abnormalities
timeFrame: Clinical laboratory abnormalities will be assessed from the time ICF signature through 30 days post dose or prior to start of a new anticancer therapy
measure: Adverse Event Parameters
timeFrame: Adverse Event Parameters will be assessed from the time ICF signature through 30 days post dose or prior to start of a new anticancer therapy
measure: ECG Parameters
timeFrame: ECG Parameters will be assessed from the time ICF signature through 30 days post dose or prior to start of a new anticancer therapy
Secondary outcomes:
measure: Area under the plasma concentration versus time curve for KT-413 from time zero to last quantifiable time point (AUC0-t)
timeFrame: Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days)
measure: Maximum Plasma Concentration of KT-413 (Cmax)
timeFrame: Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days)
measure: Time of maximum plasma concentration of KT-413 (Tmax)
timeFrame: Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days)
measure: Half-life of KT-413 [if data permits (T1/2)]
timeFrame: Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days)
measure: Amount of KT-413 excreted in urine from time zero to last collected timepoint (Ae0-t)
timeFrame: Urine samples for PK analysis collected during the first cycle (21 day cycle)
measure: Evidence of clinical activity of KT-413 as determined by Objective Response Rate (ORR)
timeFrame: From date of baseline scan until the date of first documented progression or date of death from any cause, whichever came first, about 18 months
measure: Duration of Response (DOR) as assessed by the Investigator
timeFrame: From date of baseline scan until the date of first documented progression or date of death from any cause, whichever came first, about 18 months
measure: Progression-free survival (PFS) as assessed by the Investigator
timeFrame: From time of entry on study through progression, up to 18 months
measure: Disease Control Rate (DCR) as assessed by the investigator
timeFrame: From date of baseline scan until the date of first documented progression or date of death from any cause, whichever came first, about 18 months
measure: Overall Survival (OS) as assessed by the investigator
timeFrame: From time of entry on study through death or date last known alive at end of follow-up, up to 18 months
Other outcomes:
measure: KT-413 levels in peripheral blood mononuclear cells
timeFrame: Blood samples for PD analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days)
Locations:
city: Washington, D.C.
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Comprehensive Cancer Center
state: Virginia
city: London
country: United Kingdom
facility: University College London Hospitals
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: Kymera Therapeutics, Inc.
name: Ashwin Gollerkeri, MD
role: STUDY_DIRECTOR
References: