A Multicenter, Open-Label, Dose-Finding Clinical Trial to Assess the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of RVU120 in Combination with Venetoclax in Participants with Acute Myeloid Leukemia Who Failed Prior Therapy with Venetoclax and a Hypomethylating Agent (RIVER-81)

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

5 Jan 2024 → ongoing

Decision date (initial)

2024-03-29

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: Efficacy, Pharmacokinetic, Pharmacodynamic, Safety

Part 1 only: To determine the RD of RVU120 plus Ven to be administered in AML patients failing prior Ven + HMA
Part 2 and 3: To evaluate the anti-leukemic activity of RVU120 when given in combination with Ven, including measurable residual disease (MRD) response were applicable, in AML patients failing prior Ven + HMA

Secondary objectives 4

1. All parts: To determine the safety and tolerability of RVU120 when given in combination with Ven, in AML patients failing prior Ven + HMA
2. All parts: To evaluate further efficacy endpoints of RVU120 when given in combination with Ven, in AML patients failing prior Ven + HMA
3. Part 1: To characterize single and multiple dose PK of RVU120 when given in combination with Ven
4. Part 2 and 3: To evaluate the effect of RVU120 when given in combination with Ven, on patient-reported outcomes/health-related quality of life (HRQOL)

Conditions and MedDRA coding

Acute Myeloid Leukemia

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 16

1. Written informed consent provided prior to any study-related procedure.
2. Age ≥18 years at time of provision of informed consent.
3. AML diagnosis according to the 2022 World Health Organization (WHO) classification (Arber 2022).
4. Relapsed or refractory AML per the ELN 2022 (Döhner 2022) - Participants with <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 first-line treatment with Ven + HMA specified as any of the following: - Participants who do not achieve at least morphologic leukemia-free state (MLFS) or partial remission (PR), or are progressing after at least 2 cycles of Ven + HMA - Participants who do not achieve CR, CRh, or CRi, after 4 cycles of Ven + HMA - Participants relapsing any time after treatment with Ven + HMA.
6. No alternative, approved therapeutic options likely to produce clinical benefit.
7. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2 (Section 10.6).
8. Life expectancy of at least 12 weeks.
9. No other anti-cancer treatment received for 14 days or 5 half-lives, whichever is shorter, prior to first dose of study drug.
10. 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.
11. Clinical laboratory parameters as follows: - Peripheral WBC count, no upper limit at Screening, but must be <25 x10^9/L on Day 1 prior to first dose of study drug (see acceptable methods of cytoreduction above) - Platelet count >10,000/μL at the time of first study drug administration (platelet infusion is permitted) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3X the upper limit of normal (ULN) - Direct bilirubin ≤1.5X ULN - Creatinine clearance ≥50 mL/min (Cockcroft and Gault formula; Section 10.7).
12. Adequate cardiac function confirmed by left ventricular ejection fraction ≥40% as per echocardiography.
13. 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 RVU120 (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 RVU120, if the participant is sexually active with a WOCBP (Section 10.4).
14. 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 RVU120 (Section 10.4).
15. 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.
16. Has received all Coronavirus disease-19 (COVID-19) vaccinations per institutional standards.

Exclusion criteria 19

1. 1. Active central nervous system (CNS) leukemia.
2. 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).
3. 11. Ongoing drug-induced pneumonitis.
4. 12. Concurrent participation in another investigational clinical trial.
5. 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 10.8)
6. 14. Taking medications, over-the-counter medications, foods or herbal supplements that are known to be strong or moderate inhibitors of CYP3A or P-gp, within less than 5 half-lives prior to first dose of study drug. Note: Azole antifungals used in clinical practice for prophylaxis or maintenance are allowed (following the Ven prescribing information), except during Cycle 1 for participants enrolled to Part 1.
7. 15. 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 10.9) or left ventricular ejection fraction (LVEF) <40% as per echocardiography or multiple gated acquisition (MUGA) scan.
8. 16. History of ventricular arrhythmia, or QTc ≥470 ms (Fridericia’s formula; Section 10.10).
9. 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). Note: Any exception should be discussed with the Medical Monitor.
10. 18. Pregnant or breastfeeding.
11. 2. Diagnosis of acute promyelocytic leukemia (APL), the M3 subtype of AML.
12. 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- or the Sponsor’s opinion, could jeopardize participant safety or interfere with the objectives of the study.
13. 3. Previous treatment with CDK8 and/or CDK19-targeted therapy.
14. 4. Major surgery within 28 days prior to first dose of study drug.
15. 5. Hematopoietic stem cell transplant within 120 days prior to first dose of study drug.
16. 6. Active, ≥Grade 2 acute graft versus host disease (GVHD), active moderate-to-severe chronic GVHD, or requirement for systemic immunosuppressive medications for GVHD.
17. 7. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection and acute inflammatory conditions (including pancreatitis).
18. 8. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV) infection defined as any of the following: •CD4+ T-cell count of less than 350 cells/µL at Screening •AIDS‑defining opportunistic infection within the past 12 months •On established antiretroviral therapy (ART) for less than 4 weeks or presenting with a viral load of more than 400 copies/mL prior to Screening •On ART or prophylactic antimicrobials that are expected to cause significant drug-drug interactions or overlapping toxicities with study treatment. Note: HIV testing is not required unless mandated locally.
19. 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 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 HCV infection. Participants who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part 1: Incidence and severity of AE, including events qualifying as DLTs
2. Part 2 and 3: CCR rate, including CR, CRh, CRi, with and without MRD (according to ELN 2022 [Döhner 2022])

Secondary endpoints 4

1. All parts: Incidence and severity of AE
2. All parts: Transfusion independence, DoR, PFS, RFS, EFS, Overall survival, Percentage of participants bridged to HSCT
3. Part 1: PK of RVU120 including Cmax, tmax, AUCtau, and AUCinf, and t½
4. Part 2 and 3: Changes in patient-reported outcomes as assessed by changes in summary scores of the HM-PRO

Investigational products

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

Test 5

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

Chadi Saba

Public contact point

Organisation

Ryvu Therapeutics S.A.

Contact name

Kamil Sitarz

Third parties 6

Locations

4 EU/EEA countries · 39 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 28 files

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

Application history

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