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

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).

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 SOC therapy (dexamethasone, carfilzomib or pomalidomide) to further define safety and tolerability and provide preliminary efficacy information.

Eligibility Criteria:
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:

  * 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
* MM with extramedullary disease
* 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.