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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase 1a Dose Escalation | Experimental |
| |
| Phase 1b Dose Expansion MYD88MT | Experimental | KT-413 given at the RP2D identified in Phase 1a Dose Escalation in patients with MYD88 mutant DLBCL. |
|
| Phase 1b Dose Expansion MYD88WT | Experimental | KT-413 given at the RP2D identified in Phase 1a Dose Escalation in patients with MYD88 wild type DLBCL. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| KT-413 | Drug | KT-413 will be supplied as 10mg/mL concentration frozen solution to be administered intravenously per the protocol defined dose level. |
|
| Measure | Description | Time Frame |
|---|---|---|
| To establish the Maximum Tolerated Dose (MTD) | Phase 1a | Within first 3 weeks of treatment |
| Number of Participants with protocol specified Dose Limiting Toxicities (DLTs) | Phase 1a | Within first 3 weeks of treatment |
| Dose recommended for future studies | Phase 1a/1b | Within first 3 weeks of treatment |
| Clinical Laboratory Abnormalities | Incidence and severity of clinical laboratory abnormalities in serum chemistry, hematology, coagulation parameters, and urinalysis tests as assessed by CTCAE v5.0 (Phase 1a/1b) | 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 |
| Adverse Event Parameters | Incidence and severity of adverse events as assessed by CTCAE v5.0 (Phase 1a/1b) | 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 |
| ECG Parameters | Changes in the ECG parameters, including heart rate and measures PR, QRS, QT, and QTc intervals as assessed by CTCAE v5.0 Phase 1a/1b | ECG Parameters will be assessed from the time ICF signature through 30 days post dose or prior to start of a new anticancer therapy |
| Measure | Description | Time Frame |
|---|---|---|
| Area under the plasma concentration versus time curve for KT-413 from time zero to last quantifiable time point (AUC0-t) | Phase 1a/1b | Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days) |
| Maximum Plasma Concentration of KT-413 (Cmax) |
| Measure | Description | Time Frame |
|---|---|---|
| KT-413 levels in peripheral blood mononuclear cells | Phase 1a/1b | Blood samples for PD analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days) |
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.
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:
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| Name | Affiliation | Role |
|---|---|---|
| Ashwin Gollerkeri, MD | Kymera Therapeutics, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| MedStar Georgetown University Hospital | Washington D.C. | District of Columbia | 20007 | United States | ||
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Phase 1a/1b |
| Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days) |
| Time of maximum plasma concentration of KT-413 (Tmax) | Phase 1a/1b | Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days) |
| Half-life of KT-413 [if data permits (T1/2)] | Phase 1a/1b | Blood samples for PK analysis collected at multiple visits during cycle 1 and cycle 2 (each cycle is 21 days) |
| Amount of KT-413 excreted in urine from time zero to last collected timepoint (Ae0-t) | Phase 1a/1b | Urine samples for PK analysis collected during the first cycle (21 day cycle) |
| Evidence of clinical activity of KT-413 as determined by Objective Response Rate (ORR) | Phase 1a/1b | 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 |
| Duration of Response (DOR) as assessed by the Investigator | Phase 1a/1b | 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 |
| Progression-free survival (PFS) as assessed by the Investigator | Phase 1b | From time of entry on study through progression, up to 18 months |
| Disease Control Rate (DCR) as assessed by the investigator | Phase 1b | 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 |
| Overall Survival (OS) as assessed by the investigator | Phase 1b | From time of entry on study through death or date last known alive at end of follow-up, up to 18 months |
| Norton Cancer Institute |
| Louisville |
| Kentucky |
| 40207 |
| United States |
| Henry Ford Health System | Detroit | Michigan | 48202 | United States |
| Memorial Sloan Kettering Cancer Center | New York | New York | 10065 | United States |
| MD Anderson Cancer Center | Houston | Texas | 77030 | United States |
| University of Virginia Comprehensive Cancer Center | Charlottesville | Virginia | 22903 | United States |
| University College London Hospitals | London | United Kingdom |
| University Hospital Southampton NHS Foundation Trust | Southampton | United Kingdom |
| ID | Term |
|---|---|
| D008228 | Lymphoma, Non-Hodgkin |
| D016403 | Lymphoma, Large B-Cell, Diffuse |
| ID | Term |
|---|---|
| D008223 | Lymphoma |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D016393 | Lymphoma, B-Cell |
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