a study of an mmset inhibitor in patients with relapsed and refractory multiple myeloma

Conditions: Multiple Myeloma; Myeloma; Myeloma Multiple

Summary: 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.

Keywords: nsd2 mmset whsc1 t4;14 t(4;14) translocation myeloma rrmm