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

Официальное название

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

Обзор

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).

Подробное описание

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.

Вмешательства

• Препарат Cohort A1 & A2: KTX-1001
  KTX-1001: Orally for 28 days each cycle until progression. Dexamethasone: Orally once weekly
• Препарат Cohort B1 & B2: KTX-1001+Mezigdomide
  Drug: KTX-1001: Orally for 28 days each cycle until progression Drug: Dexamethasone: Orally once weekly Drug: Mezigdomide Dexamethasone: Orally once weekly
• Препарат Cohort C1 & C2: KTX-1001 + Carfilzomib (KYPROLIS®)
  Drug: KTX-1001: Orally for 28 days each cycle until progression Drug: Dexamethasone: Orally once weekly Drug: Carfilzomib (KYPROLIS®): IV, once weekly for 3 weeks in each 28-day cycle
• Препарат Cohort D: KTX-1001+ pomalidomide (Pomalyst, Imnovid)
  Drug: KTX-1001: Orally for 28 days each cycle until progression Drug: Dexamethasone: Orally once a week Drug: Pomalidomide (Pomalyst, Imnovid): Orally, for 21 days in each 28-day cycle

Первичные конечные точки

• Dose Escalation: Determination of Recommended Phase 2 Dose (RP2D) and/or Maximum Tolerated Dose (MTD) Dose Expansion: Provide preliminary efficacy data on the antitumor effects of KTX-1001 in combination with other anti-myeloma therapy [Срок оценки: Cycle 1 (28 days)]

Вторичные конечные точки (3)

• Disease Specific Response to KTX-1001± Combination Therapy [Срок оценки: Duration of Study]
• Pharmacokinetics & Pharmacodynamics KTX-1001± Combination Therapy [Срок оценки: Duration of Study]
• Safety profile of KTX-1001± Combination Therapy [Срок оценки: Duration of Study]

Критерии участия

Key Inclusion Criteria for Dose-Expansion:

• ≥ 18 years of age
• ECOG score ≤ 1
• Multiple myeloma (as per IMWG)

• Prior therapy for MM: Participants must have received at least 1 and up to 3 prior lines of therapy as defined by IMWG, and the following drug classes: PI, IMiD, and anti-CD38 antibody. For mezigdomide combination Cohorts B1 and B2, participants must have received at least 2 prior lines of therapy
• Participants must have a confirmed diagnosis of progressive MM (per IMWG), t(4;14) confirmed by fluorescence in situ hybridization (FISH) testing performed in a centralized Clinical Laboratory Improvement Amendments (CLIA) accredited laboratory via fresh tumor biopsy.
• 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: participants with previously treated stable CNS disease are eligible, except for Cohorts B1 and B2 for which known CNS myeloma involvement is completely excluded.
• 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 7 days or 5 half-lives (whichever is longer) 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 13 центров

• UCSF Medical Center - Hematology and Blood and Marrow Transplant Clinic — San Francisco
• Mayo Clinic Hospital - Florida — Jacksonville
• The Winship Cancer Institute of Emory University — Atlanta
• Massachusetts General Hospital — Boston
• Dana-Farber Cancer Institute — Boston
• Mayo Clinic - Transplant Center - Rochester — Rochester
• Hackensack University Medical Center — Hackensack
• Memorial Sloan-Kettering Cancer Center — New York
• … и ещё 5 центров

Франция · 4 центра

• Universitaire de Lille — Villeneuve-d'Ascq
• Centre Hospitalier Universitaire de Nantes (CHU de Nantes) - Hotel-Dieu — Nantes
• Centre Hospitalier Universitaire de Poitiers (CHU de Poitiers) — Poitiers
• Institut Universitaire du Cancer de Toulouse - Oncopole — Toulouse

Испания · 4 центра

• Clínica Universidad de Navarra — Pamplona
• Hospital ClÃ-nic de Barcelona — Barcelona
• Hospital Universitario 12 de Octubre — Madrid
• Instituto de Investigacion Biomedica de Salamanca (IBSAL) — Salamanca

Канада · 1 центр

• University Health Network (UHN) - Princess Margaret Cancer Centre (Princess Margaret Hospi — Toronto

Идентификаторы

NCT: NCT05651932 · KTX-MMSET-001 · EUCTR No: 2022-500801-41-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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