Study of REM-422 in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma

Study Overview
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Brief Summary
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The goal of this study is to determine the safety and antitumor effects of REM-422, a MYB mRNA degrader, in people with advanced Adenoid Cystic Carcinoma (ACC)

Detailed Description
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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 recurrent or metastatic ACC. 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 recurrent or metastatic ACC. 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.

Official Title
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A Phase 1, Multicenter, Open-label Study of REM-422, a MYB mRNA Degrader, in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma

Conditions
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Adenoid Cystic Carcinoma, Metastatic Adenoid Cystic Carcinoma, Recurrent Adenoid Cystic Carcinoma

Intervention / Treatment
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* Drug: REM-422


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be able to provide informed consent. Be 18 or older at the time of informed consent. Disease criteria: Histologically confirmed ACC, any site of origin. Have locally advanced or metastatic ACC. Dose Escalation phase ONLY: Evidence of radiographic progression and/or signs and symptoms associated with their disease (eg, pain, dyspnea, reduced performance status). Participants who have stable disease while being treated with another agent that is not tolerated are eligible after the appropriate washout period. Dose Expansion phase ONLY: Measurable disease at the time of enrollment. At least 1 measurable lesion according to RECIST v1.1 criteria. Participants must have radiographic evidence of disease progression by RECIST v1.1 criteria ≤ 6 months prior to study enrollment. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Be able to provide during Screening a tissue specimen of either a fresh biopsy of a non-target lesion or an archival tumor sample obtained within the last 6 months or longer if there has been no systemic interval therapy since the last biopsy. A formalin-fixed paraffin-embedded block can be submitted or a minimum of 15 freshly sectioned unstained slides. At least 3 weeks since prior systemic non-investigational therapy at the time of start of REM- 422. Toxicities from prior therapy must be stable or recovered to ≤ Grade 1. Note: Stable chronic and clinically non-significant conditions (≤ Grade 2) that are not expected to resolve are exceptions (eg, neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies, etc.), and patients with these conditions may enroll. 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. Participants of childbearing potential (POCBP) must have a negative serum beta-human chorionic gonadotropin test result. Participants Of Child Bearing Potential must agree to use acceptable, effective methods of contraception as outlined in Appendix 1 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 bone marrow, organ function and laboratory parameters Exclusion Criteria: 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. Simple urinary tract infection, uncomplicated bacterial pharyngitis responding to active treatment are permitted. Participants receiving intravenous antibiotics ≤ 7 days prior to enrollment are excluded (prophylactic antibiotics, antivirals or antifungals are permitted). Evidence of active HIV infection. Evidence of currently 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. Topical or inhaled corticosteroids with minimal systemic absorption may enroll and continue minimal corticosteroids if the participant is on a stable dose. Live vaccine ≤ 6 weeks prior to the start of REM-422. Use of strong CYP3A inhibitors or CYP3A inducers Drugs that reduce gastric acidity, such as H2-receptor antagonists (eg, ranitidine, famotidine) and proton pump inhibitors (e.g., omeprazole, esomeprazole) within 7 days prior to the initiation of REM-422 administration or during the study Pregnancy or participants planning to become pregnant during the duration of the study, or lactation. Participants with malabsorption syndrome, a disease significantly affecting gastrointestinal function, or resection of the stomach or bowel. Current use of prohibited medication ≤ 1 week before starting REM-422. Clinically significant cardiovascular disease: Participants who have undergone major surgery (opening a mesenchymal barrier such as the pleural cavity, peritoneum, 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 (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 (other than adenoid cystic carcinoma, hematologic malignancies, or primary central nervous system [CNS] malignancies) ≤ 2 years of enrollment, except curatively treated malignancies including basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix. Participants 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REM-422<br>Dose Escalation: Participants will receive escalating doses of REM-422 to determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)-422, oral capsule administered once daily Dose Expansion: Participants will receive REM-422 at the identified RP2D Treatment will continue until disease progression, therapy intolerance, or participant withdrawal Safety evaluation will continue until 30 days of last administration of REM-422 | Drug: REM-422<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 18 months | 
| 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 | Assessed at the end of Cycle 1 for each participant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR will be evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1 following treatment with REM-422 | 18 months | 
| Median Progression Free Survival (mPFS) | PFS will be evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1 following treatment with REM-422 | 18 months | 
| Duration of Response (DoR) | DoR will be evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1 following treatment with REM-422 | 18 months | 
| Time to Response (mTTR) | TTR will be evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1 following treatment with REM-422 | 18 months | 
| Disease Control Rate (DCR) | DCR will be evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1 following treatment with REM-422 | 18 months | 
| Median Overall Survival (mOS) | mOS will be evaluated after treatment with REM-422 | 18 months | 
| Determine pharmacokinetic profile (Cmax) of REM-422 | Measure Maximal concentration (Cmax) of REM-422 | 18 months | 
| Determine pharmacokinetic profile (Cmin) of REM-422 | Measure Minimal concentration (Cmin) of REM-422 | 18 months | 
| Determine pharmacokinetic profile (Tmax) of REM-422 | Measure Time to peak drug concentration (Tmax) of REM-422 | 18 months | 
| Determine pharmacokinetic profile (AUC) of REM-422 | Measure Area Under the Curve (AUC) of REM-422 | 18 months |