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

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Full Title:: 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

Summary/Purpose:: 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:: 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.

Treatments:: Drug : KTX-1001

KTX-1001 will be administered orally, daily for 28 days.

Study Arms:: Experimental : KTX-1001
KTX-1001 will be administered orally, daily for 28 days.

Study Design:: Allocation: N/A; Intervention Model: Single Group Assignment; Primary Purpose: Treatment; Masking: None (Open Label)

Eligibility criteria:

/li>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.

Locations / Centres:: University Health Network (UHN) - Princess Margaret Cancer Centre (Princess Margaret Hospital), Toronto, Ontario – Recruiting