A Multicenter, Open-Label Clinical Trial of RVU120 in Patients with Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia with or without NPM1 Mutation (RIVER-52)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ryvu Therapeutics S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Jan 2024 → 27 Aug 2025

Decision date (initial)

2024-09-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ryvu Therapeutics S.A.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Efficacy, Pharmacokinetic

To provide estimation of the anti-tumor activity of RVU120 monotherapy (preliminary in Part 1)

Secondary objectives 5

1. To evaluate the clinical benefit of RVU120 monotherapy
2. To further characterize the safety and tolerability profile of RVU120 monotherapy
3. To further characterize single and multiple dose PK of RVU120
4. Part 2 only: To evaluate the effect of RVU120 on patient-reported outcomes/health-related quality of life
5. To evaluate the depth of response to RVU120 monotherapy

Conditions and MedDRA coding

Relapsed or Refractory High-Risk Myelodysplastic Syndrome

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

IPD plan description

NA

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Written informed consent provided prior to any study-related procedure
2. Age ≥18 years at time of provision of informed consent.
3. Diagnosis of AML or MDS as follows: • Cohort 1: AML according to the 2022 World Health Organization (WHO) classification (Arber 2022) in the absence of a mutation in the NPM1 or DNMT3A gene • Cohort 2: AML according to the 2022 WHO classification (Arber 2022) with a mutation in the NPM1 gene regardless of any other co-occurring mutation • Cohort 3: AML according to the 2022 WHO classification (Arber 2022) in the absence of a mutation in the NPM1 gene and with a mutation in the DNMT3A gene • Cohort 4: MDS according to the 2022 WHO classification (Arber 2022) confirmed as high risk with IPSS-R >4.5 following the most recent line of treatment (Section 10.6).
4. Relapsed or refractory AML per the ELN 2022 (Döhner 2022) or relapsed or progressing HR-MDS per the International Working Group response criteria in MDS (Zeidan 2023). Participants with AML and <10% bone marrow cellularity may be enrolled where immunophenotyping of the bone marrow demonstrates this is due to underlying disease and not to potential myelotoxicity e.g., where >50% of cells have AML phenotype.
5. Failed at least 1 line of therapy and no available alternative therapeutic options likely to produce clinical benefit.
6. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2 (Section 10.7).
7. No other anti-cancer treatment received for 4 weeks or 5 half-lives, whichever is shorter, prior to first dose of study drug.
8. Must have recovered from the toxic effects of previous treatments to at least Grade 1, except for neurotoxicity (which should return at least to Grade 2 or baseline), or alopecia.
9. Clinical laboratory parameters as follows: a. peripheral white blood cell (WBC) count, no upper limit during Screening, but must be <30 x 109/L on Day 1 prior to first dose of study drug. b. platelet count >10,000 /μL Note: Platelet infusion permitted c. serum albumin ≥ 25 g/L (2.5 g/dL) d. normal coagulation (elevated international normalized ratio, prothrombin time or activated partial thromboplastin time [APTT] <1.3 x the upper limit of normal [ULN] acceptable) e. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN f. Direct bilirubin ≤1.5 x ULN g. creatinine clearance ≥30 mL/min (Cockcroft and Gault formula; Section 10.8).
10. Life expectancy of at least 12 weeks.
11. For women of childbearing potential (WOCBP), a negative pregnancy test must be confirmed during Screening and prior to first dose of ≤3 days prior to first dose of study drug. WOCBP must commit to using a highly effective method of contraception during study participation and until 28 weeks (approximately 6.5 months) after the last dose of study drug (Section 10.4) or For males, an effective barrier method of contraception must be used during study participation and until 28 weeks (approximately 6.5 months) after the last dose of study drug, if the participant is sexually active with a WOCBP (Section 10.4). Sexually active male participants are asked to advise their female partners of childbearing potential to also use highly effective contraception for the same time period.
12. Agree not to donate blood, eggs (ova) or sperm, during study participation and until 28 weeks (approximately 6.5 months) after the last dose of study drug (Section 10.4).
13. Investigator considers the participant to be suitable for participation in the clinical study by assessing that they: - understand the requirements of the clinical study and can give informed consent - can comply with study medication dosing requirements and all study-related procedures and evaluations - are not considered to be potentially unreliable and/or not cooperative.
14. Has received all Coronavirus disease-19 (COVID-19) vaccinations per relevant national guidelines.

Exclusion criteria 19

1. Active central nervous system leukemia
2. Diagnosis of acute promyelocytic leukemia, the M3 subtype of AML
3. Previous treatment with CDK8 and/or CDK19-targeted therapy
4. Major surgery within 28 days prior to first dose of study drug
5. Hematopoietic stem cell transplant within 120 days prior to first dose of study drug
6. Active, ≥Grade 2 acute graft versus host disease (GVHD), active moderate-to-severe chronic GVHD, or requirement for systemic immunosuppressive medications for GVHD
7. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection and acute inflammatory conditions (including pancreatitis).
8. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV).
9. Ongoing significant liver disease such as cirrhosis, drug-induced liver injury, active hepatitis, or chronic persistent hepatitis B and/or C: - positive serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection. Participants whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation. (https://www.cdc.gov/hepatitis/hbv/interpretationOfHepBSerologicResults.htm) - Acute or chronic hepatitis C virus (HCV) infection. Participants who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.
10. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RVU120 (e.g., active inflammatory bowel disease, ulcerative disease, malabsorption syndrome, short bowel syndrome, uncontrolled nausea, vomiting or diarrhea).
11. Ongoing drug-induced pneumonitis
12. Concurrent participation in another therapeutic clinical trial
13. Taking any medications, herbal supplements, or other substances that are known to be strong inhibitors or moderate/strong inducers or sensitive substrates of CYPXXX, within less than 5 half-lives prior to first dose of study drug (Section 10.9).
14. Significant cardiac dysfunction defined as myocardial infarction within 12 months of first dose of study drug, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias, poorly controlled angina (Section 10.10), or left ventricular ejection fraction <40% as per echocardiography or multiple gated acquisition (MUGA) scan.
15. Taking medications that are documented in their drug package insert to have a risk of causing prolonged Q wave to T wave interval (QT) corrected for heart rate (QTc) or Torsades de pointes within 5 half-lives prior to first dose of study drug.
16. History of ventricular arrhythmia, or QTc ≥470 ms (Bazett’s formula; Section 10.12).
17. Prior history of malignancies other than AML, unless the participant has been free of the disease for 5 years or more prior to Screening, or the following apply:  basal cell carcinoma of the skin  non-metastatic squamous cell carcinoma of the skin  carcinoma in situ of the cervix  carcinoma in situ of the breast  carcinoma in situ of the bladder  incidental histological finding of prostate cancer (Tumor/Node/Metastasis stage of T1a or T1b).
18. Pregnant or breast-feeding
19. Any other prior or current medical condition, intercurrent illness, surgical history, physical or electrocardiogram (ECG) findings, laboratory abnormalities, or extenuating circumstance (e.g., alcohol or drug addiction) that, in the Investigator’s and Sponsor's opinion, could jeopardize participant safety or interfere with the objectives of the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of CR

Secondary endpoints 5

1. Overall response rate (ORR) including clinical benefit beyond CR • Duration of response (DoR) • Transfusion independence and/or hematological improvement • 1-year progression-free survival (PFS) • 1-year relapse-free survival (RFS) • 1-year overall survival (OS) • Percentage of participants bridged to hematopoietic stem cell transplantation (HSCT)
2. Incidence and severity of AE
3. PK of RVU120 including, data permitting, Cmax, tmax, AUCtau, AUCinf ax, AUC, and t½
4. Part 2 only: Changes in patient-reported outcomes as assessed by changes in summary scores of the HM-PRO and QOL-E
5. Rate of measurable residual disease (MRD) negativity

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ryvu Therapeutics S.A.

Sponsor organisation

Ryvu Therapeutics S.A.

Address

Ul. Leona Henryka Sternbacha 2

City

Cracow

Postcode

30-394

Country

Poland

Scientific contact point

Organisation

Ryvu Therapeutics S.A.

Contact name

Renata Dudziak

Public contact point

Organisation

Ryvu Therapeutics S.A.

Contact name

Kamil Sitarz

Third parties 7

Locations

4 EU/EEA countries · 44 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications