Study of REM-422 in Patients With AML or Higher Risk MDS

Official title

A Phase 1, Multicenter, Open-Label Study of REM-422, an MYB mRNA Degrader, in Patients With Relapsed/Refractory AML or Higher-Risk MDS

Overview

The goal of this study is to determine the safety and antitumor effects of REM-422, a MYB mRNA degrader, in people with Higher Risk MDS and relapsed/refractory AML

Detailed description

This is a Phase 1, open-label, non-randomized, multicenter study investigating REM-422, a potent, selective, and oral small molecule mRNA degrader that reduces expression of the MYB transcription factor for patients with higher risk MDS or relapsed/refractory AML.

This study includes a Dose Escalation Phase and a Dose Expansion Phase. The purpose of the Dose Escalation Phase is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of REM-422 in patients with higher risk MDS or relapsed/refractory AML. The purpose of Dose Expansion is to further evaluate the safety and anti-tumor activity of the RP2D carried forward from Dose Escalation.

Participation in this study will continue until disease progression, therapy intolerance, or participant withdrawal.

Interventions

• Drug REM-422
  REM-422 is a first in class, small molecule mRNA inhibitor that reduces expression of the MYB transcription factor REM-422 will be administered orally once daily

Primary outcome measures

• Frequency and severity of Treatment Emergent Adverse Events (TEAEs) [Time frame: 24 months]
• Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) [Time frame: Assessed at the end of Cycle 1 (each cycle is 28 days) for each participant for approximately 24 months]

Secondary outcome measures (12)

• AML: Rate of Complete Response (remission) (CR) [Time frame: 24 months]
• AML: Rate of CR with partial hematologic recovery (CRh) [Time frame: 24 months]
• AML: Duration of CR [Time frame: 24 months]
• AML: Duration of CRh [Time frame: 24 months]
• AML: Overall response rate (ORR) (CR + CRh + CRi + PR) with incomplete hematologic recovery [CRi] + partial response [PR]) per modified IWG response criteria 2003 based on Investigator assessment [Time frame: 24 months]
• AML: Duration of response (DOR) [Time frame: 24 months]
• MDS: Rate of Compete Response (CR) [Time frame: 24 months]
• MDS: Duration of Complete Response (CR) [Time frame: 24 months]
• MDS: Overall Response Rate (ORR) [Time frame: 24 months]
• MDS: Duration of Response (DOR) [Time frame: 24 months]
• Determine pharmacokinetic profile (Cmax) of REM-422 [Time frame: 24 months]
• Determine pharmacokinetic profile (Cmin) of REM-422 [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

• Be able to provide informed consent.
• Be 18 or older at the time of informed consent.
• Disease criteria:

Histologically confirmed diagnosis of either:

• R/R AML, defined as relapse after transplantation, second or later relapse, refractory to initial induction or reinduction treatment or to initial treatment with hypomethylating (HMA)-based combinations, relapse after initial treatment, or otherwise considered relapsed or refractory in the opinion of the Investigator.
• High-risk and very-high-risk (VHR) MDS (higher-risk) per the International Prognostic Scoring System-Revised (IPSS-R) and/or International Prognostic Scoring System-Molecular (IPSS-M).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Has agreed to undergo serial blood and bone marrow sampling.
• Participants must have completed systemic non-investigational therapy at least 14 days prior to initiating REM-422. Hydroxyurea is permissible for controlling peripheral leukemic blasts prior to enrollment and for up to 28 days following initiation of REM-422.
• Toxicities from prior therapy must be either stable or recovered to ≤ Grade 1.
• Participants must be able to swallow and retain oral medications.
• Oxygen saturation > 92% on room air or up to 2 L/min supplemental oxygen by nasal cannula with ≤ Grade 1 dyspnea.
• People of childbearing potential (POCBP) must have a negative serum beta-human chorionic gonadotropin test result.
• POCBP must agree to use acceptable, effective methods of contraception and not donate ova from screening until 6 months after discontinuation of REM-422. Women who have undergone surgical or ablative sterilization or who have been postmenopausal for ≥ 2 years are not considered to be of childbearing potential.
• Men must agree to use acceptable, effective methods of contraception and must agree not to donate sperm from the start of receiving REM-422 until 6 months after discontinuation of REM-422.
• Adequate organ function and laboratory parameters

Exclusion criteria

• Active central nervous system (CNS) leukemia or a confirmed diagnosis of CNS leukemia.
• Has undergone hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of REM-422 or is receiving immunosuppressive therapy post HSCT at the time of screening, or has GVHD requiring systemic treatment (topical steroids for ongoing skin GVHD is permitted).
• Has immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.
• Known hypersensitivity or contraindication to any component of REM-422 or to drugs chemically related to REM-422 or its excipients.
• Clinically significant active infection. Note: Patients with simple urinary tract infection or uncomplicated bacterial pharyngitis responding to active treatment are permitted. Note: Patients receiving intravenous (IV) antibiotics ≤ 7 days prior to enrollment are excluded (prophylactic antibiotics, antivirals, or antifungals are permitted).
• Evidence of active HIV infection.
• Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Primary immunodeficiency.
• Current or expected need for daily systemic corticosteroid therapy ≥ 10 mg of prednisone equivalent.

Note: Patients who are receiving topical or inhaled corticosteroids with minimal systemic absorption are eligible for enrollment and may continue with minimal corticosteroid use as long as they are on a stable dose.

• Live vaccine ≤ 6 weeks prior to the start of REM-422.
• Use of strong CYP3A inhibitors (except azole antifungals) or CYP3A inducers
• Drugs that reduce gastric acidity, such as H2-receptor antagonists (eg, ranitidine, famotidine) and proton pump inhibitors (eg, omeprazole, esomeprazole) within 7 days prior to the initiation of REM-422 administration or during the study.
• Currently pregnant, have intentions to become pregnant during the study duration, or are currently lactating.
• Has dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs.
• Current use of prohibited medication ≤ 1 week before starting REM-422.
• Clinically significant cardiovascular disease:
• Has undergone major surgery (opening a mesenchymal barrier such as the pleural cavity, peritoneum, or meninges or surgical procedures requiring general anesthesia) < 4 weeks prior to enrollment.
• History of organ transplant that requires use of immunosuppressive agents.
• History or current autoimmune disease requiring systemic treatment (eg, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus).
• Radiation therapy ≤ 7 days prior to the start of REM-422.
• Concurrent or previous other malignancy ≤ 2 years of enrollment, except curatively treated malignancies including basal or squamous cell skin cancer, breast cancer, prostate intraepithelial neoplasm, and carcinoma in situ of the cervix.
• Receiving any other investigational treatment for any indication ≤ 3 weeks prior to enrollment.
• Unwillingness or inability to follow protocol requirements.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of REM-422 or interpretation of the participant's safety or study results.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 5 centers

• City of Hope — Duarte
• Moffitt Cancer Center — Tampa
• Massachusetts General Hospital — Boston
• Memorial Sloan Kettering — New York
• MD Anderson Cancer Center — Houston

France · 4 centers

• Centre Hospitalier Universitaire (CHU) de Bordeaux — Bordeaux
• AP-HP - Hôpital Saint-Louis — Paris
• IUCT-Oncopole — Toulouse
• Institut de Cancerologie Gustave-Roussy — Villejuif

Identifiers

NCT: NCT06297941 · REM-422-102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗