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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06297941
• Other study ID #: REM-422-102
• Status: Recruiting
• Phase: Phase 1
• Start date: April 26, 2024
• Est. completion date: June 15, 2027

Study information

• Verified date: May 2024
• Source: Remix Therapeutics
• Contact: Barb Geiger, BSN
• Phone: 913-206-2798
• Email: bgeiger[@]remixtx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: June 15, 2027
• Est. primary completion date: March 15, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Be able to provide informed consent.

2. Be 18 or older at the time of informed consent.

3. Disease criteria:

Histologically confirmed diagnosis of either:

1. 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.

2. 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).

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5. Has agreed to undergo serial blood and bone marrow sampling.

6. 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.

7. Toxicities from prior therapy must be either stable or recovered to = Grade 1.

8. Participants must be able to swallow and retain oral medications.

9. Oxygen saturation > 92% on room air or up to 2 L/min supplemental oxygen by nasal cannula with = Grade 1 dyspnea.

10. People of childbearing potential (POCBP) must have a negative serum beta-human chorionic gonadotropin test result.

11. 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.

12. 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.

13. Adequate organ function and laboratory parameters

Exclusion Criteria:

1. Active central nervous system (CNS) leukemia or a confirmed diagnosis of CNS leukemia.

2. 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).

3. Has immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.

4. Known hypersensitivity or contraindication to any component of REM-422 or to drugs chemically related to REM-422 or its excipients.

5. 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).

6. Evidence of active HIV infection.

7. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

8. Primary immunodeficiency.

9. 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.

10. Live vaccine = 6 weeks prior to the start of REM-422.

11. Use of strong CYP3A inhibitors (except azole antifungals) or CYP3A inducers

12. 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.

13. Currently pregnant, have intentions to become pregnant during the study duration, or are currently lactating.

14. Has dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs.

15. Current use of prohibited medication = 1 week before starting REM-422.

16. Clinically significant cardiovascular disease:

17. 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.

18. History of organ transplant that requires use of immunosuppressive agents.

19. History or current autoimmune disease requiring systemic treatment (eg, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus).

20. Radiation therapy = 7 days prior to the start of REM-422.

21. 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.

22. Receiving any other investigational treatment for any indication = 3 weeks prior to enrollment.

23. Unwillingness or inability to follow protocol requirements.

24. 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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Acute Myeloid Leukemia Refractory
• Higher Risk Myelodysplastic Syndromes
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

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

Locations

Country	Name	City	State
United States	City of Hope	Duarte	California
United States	MD Anderson Cancer Center	Houston	Texas
United States	Memorial Sloan Kettering	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Remix Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency and severity of Treatment Emergent Adverse Events (TEAEs)	Frequency and severity of Treatment Emergent Adverse Events (TEAEs) will be evaluated according to the NCI-CTCAE version 5.0 and number of participants with Dose Limiting Toxicities will be assessed to determine Safety and Tolerability of REM-422 from the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Primary	Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)	Frequency and severity of Treatment Emergent Adverse Events (TEAEs) will be evaluated according to the NCI-CTCAE version 5.0 and the number of participants with Dose Limiting Toxicities will be assessed from the date of first dose of REM-422 until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months	Assessed at the end of Cycle 1 (each cycle is 28 days) for each participant for approximately 24 months
Secondary	AML: Rate of Complete Response (remission) (CR)	Rate of Complete Response (CR) will be measured based on Investigator assessment per the modified International Working Group (IWG) response criteria 2003 from the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Secondary	AML: Rate of CR with partial hematologic recovery (CRh)	Rate of Complete Response (CR) with partial hematologic recovery (CRh) will be measured based on Investigator assessment per the modified International Working Group (IWG) response criteria 2003 from the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Secondary	AML: Duration of CR	Duration of CR will be evaluated per the modified International Working Group (IWG) response criteria 2003 following treatment with REM-422 from the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Secondary	AML: Duration of CRh	Duration of CRh will be evaluated per the modified International Working Group (IWG) response criteria 2003 following treatment with REM-422 from the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Secondary	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	Duration of Overall Response Rate (ORR) will be evaluated per the modified International Working Group (IWG) response criteria 2003 following treatment with REM-422 from the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Secondary	AML: Duration of response (DOR)	Duration of Response (DoR) will be evaluated following treatment with REM-422 based on Investigator assessment for participants who achieve a response per IWG response criteria 2003, defined as the time from when response criteria are first met for CR, CRi, CRh, or PR until progressive disease (PD) per IWG response criteria 2003 is documented or death, whichever occurs first	24 months
Secondary	MDS: Rate of Compete Response (CR)	Rate of CR will be evaluated based on Investigator assessment per IWG 2023 response criteria following treatment with REM-422 for participants who achieve a Complete Response (CR), defined as the time from when criteria are first met for CR until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Secondary	MDS: Duration of Complete Response (CR)	Duration of CR will be evaluated per IWG 2023 response criteria following treatment with REM-422 based on Investigator assessment for participants who achieve a CR per IWG response criteria 2003, defined as the time from when response criteria are first met for CR until progressive disease (PD) per IWG response criteria 2003 is documented or death, whichever occurs first	24 months
Secondary	MDS: Overall Response Rate (ORR)	ORR will be evaluated per IWG 2023 response criteria based on Investigator assessment following treatment with REM-422 from the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.	24 months
Secondary	MDS: Duration of Response (DOR)	DOR will be evaluated following treatment with REM-422 based on Investigator assessment for participants who achieve a response per IWG 2023 response criteria, defined as the time from when criteria are first met for CR, CRi, CRh, or PR until PD per IWG 2023 or death, whichever occurs first	24 months
Secondary	Determine pharmacokinetic profile (Cmax) of REM-422	Measure Maximal concentration (Cmax) of REM-422	24 months
Secondary	Determine pharmacokinetic profile (Cmin) of REM-422	Measure Minimal concentration (Cmin) of REM-422	24 months
Secondary	Determine pharmacokinetic profile (Tmax) of REM-422	Measure Time to peak drug concentration (Tmax) of REM-422	24 months
Secondary	Determine pharmacokinetic profile (AUC) of REM-422	Measure Area Under the Curve (AUC) of REM-422	24 months