Overview
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).
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 t(4;14) will receive KTX-1001 at the RP2D alone and in combination with investigational therapy Mezigdomide or SOC therapy (dexamethasone, carfilzomib or pomalidomide) to further define safety and tolerability and provide preliminary efficacy information.
Eligibility
Key Inclusion Criteria for Dose-Expansion:
- ≥ 18 years of age
- ECOG score ≤ 1
- Multiple myeloma (as per IMWG)
- ≥ 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody
- Patients must be refractory to their last prior therapy
- Cohorts A1/A2: 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
- 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)
- Bone marrow plasma cells ≥ 30% (if only criterion for measurability)
- Agreement to enroll into the REMS program (Cohort D- pomalidomide cohort only)
Key Exclusion Criteria for Dose-Expansion:
- Treatment with the following therapies in the specified time period prior to first dose:
- Patients in Cohorts B1 and B2 must not have received prior mezigdomide treatment
- Carfilzomib in the immediate last prior line of therapy for patients enrolled in Cohorts C1 and C2
- Pomalidomide in the immediate last prior line of therapy for patients enrolled in cohort D
- 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
- 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
- Strong CYP1A2 inhibitors for patients receiving pomalidomide (Cohort D)
- Active malignancy not related to myeloma requiring therapy within \< 2 years prior to enrollment, or not in complete remission, with exceptions defined in protocol.
