A Study of an MMSET Inhibitor in Patients With Relapsed and Refractory Multiple Myeloma

Study Overview
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Brief Summary
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A Phase I study to evaluate the safety of a novel, orally available, selective, and potent small molecule inhibitor of the histone lysine methyl transferase MMSET (also known as NSD2/WHSC1) to prevent the dimethylation of H3K36 in adult patients with relapsed or refractory multiple myeloma (RRMM).

Detailed Description
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This is a Phase I, open-label, dose escalation and expansion study in adult patients with RRMM. In the dose escalation phase (Part A), patients will be evaluated for DLTs during Cycle 1 (28 days). The KTX-1001 MTD, RP2D, and schedule will be determined. In the dose expansion phase (Part B), patients with translocation t(4;14) or a GOF mutation in MMSET (eg, E1099K) will be enrolled. Patients will receive KTX-1001 at the RP2D to further define safety and tolerability and provide preliminary efficacy information.

Official Title
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A Phase 1 Study of KTX-1001, an Oral, First-In-Class, Selective, and Potent MMSET Catalytic Inhibitor That Suppresses H3K36me2 in Patients With Relapsed and Refractory Multiple Myeloma

Conditions
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Multiple Myeloma, Myeloma, Myeloma Multiple

Intervention / Treatment
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* Drug: KTX-1001


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: ≥ 18 years of age ECOG score ≤ 2 Relapsed or refractory multiple myeloma (as per IMWG) ≥ 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody Patients must have exhausted available therapeutic options that are expected to provide a meaningful clinical benefit, either through disease relapse, treatment refractory disease, intolerance, or refusal of the therapy t(4;14) confirmed by standard of care FISH testing, or GOF mutation in MMSET confirmed by local sequencing test (Part B dose expansion cohorts only) Measurable disease, including at least 1 of the following criteria: Serum M protein ≥ 0.50 g/dL (by SPEP) Serum IgA ≥ 0.50 g/dL (IgA myeloma patients) Urine M protein ≥ 200 mg/24 h (by UPEP) sFLC involved light chain ≥ 10 mg/dL (100 mg/L) (patients with abnormal sFLC ratio) ≥ 1 extramedullary lesion ≥ 1 cm in size and able to be followed by imaging assessments (Part A dose escalation cohorts only) Bone marrow plasma cells ≥ 10% (Part A dose escalation cohorts only) Key Exclusion Criteria: Treatment with the following therapies in the specified time period prior to first dose: Radiation, chemotherapy, immunotherapy, or any other anticancer therapy ≤ 2 weeks Cellular therapies ≤ 8 weeks Autologous transplant < 100 days Allogenic transplant ≤ 6 months, or > 6 months with active GVHD Major surgery ≤ 4 weeks History of or current plasma cell leukemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, and skin changes) syndrome, solitary bone lesion or bone lesions as the only evidence for plasma cell dyscrasia, myelodysplastic syndrome or a myeloproliferative neoplasm or light chain amyloidosis Active CNS disease Inadequate bone marrow function Inadequate renal, hepatic, pulmonary, and cardiac function Active, ongoing, or uncontrolled systemic viral, bacterial, or fungal infection. Permitted prophylactic medications, antimicrobials or antiretroviral therapies defined in protocol. Use of acid reducing agents and strong inhibitors or inducers of CYP3A4 within 14 days or 5 half-lives prior to first dose Active malignancy not related to myeloma requiring therapy within < 3 years prior to enrollment, or not in complete remission, with exceptions defined in protocol.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KTX-1001<br>KTX-1001 will be administered orally, daily for 28 days. | Drug: KTX-1001<br>* KTX-1001 will be administered orally, daily for 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicity (DLTs) | Treatment-emergent adverse events (AEs), treatment-related AEs, and clinically significant changes in laboratory test results will be evaluated | Cycle 1 (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of KTX-1001 |  | Cycle 1 (28 days) | 
| Time to achieve Cmax (tmax) for KTX-1001 |  | Cycle 1 (28 days) | 
| Area under the plasma concentration-time curve (AUC) for KTX-1001 |  | Cycle 1 (28 days) | 
| Objective response rate (ORR) for KTX-1001 | Per IMWG Consensus Criteria for Response and Minimal Residual Disease Assessment in Multiple Myeloma | Cycle 1 (28 days) | 
| Duration of response (DOR) for KTX-1001 |  | Cycle 1 (28 days) | 
| Progression-free survival (PFS) for KTX-1001 |  | Cycle 1 (28 days) | 
| Overall survival (OS) for KTX-1001 |  | Cycle 1 (28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSD2, MMSET, WHSC1, T4;14, T(4;14), translocation, myeloma, RRMM