Clinical trial testing an investigational drug RVU120 for myelofibrosis (myeloproliferative neoplasm, MPN)

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

19 Sep 2024 → ongoing

Decision date (initial)

2024-08-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-511688-27-00

WHO UTN

U1111-1304-0495

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Safety, Pharmacokinetic

To evaluate the anti-cancer activity of RVU120 when given as monotherapy or in combination with RUX

Secondary objectives 4

1. To further evaluate the anti-tumor activity and/or clinical benefit of RVU120 when given as monotherapy or in combination with RUX
2. To evaluate the safety of RVU120 when given as monotherapy or in combination with RUX
3. To evaluate the pharmacokinetics (PK) of RVU120 given as monotherapy or in combination with RUX
4. To assess changes in symptom burden as assessed by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0

Conditions and MedDRA coding

Myelofibrosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age ≥18 years at time of provision of informed consent.
2. Diagnosis of primary or secondary MF according to the revised World Health Organization (WHO) criteria (Arber 2022).
3. Intermediate or high-risk disease according to the DIPSS for MF.
4. Participants in Cohort 1: Resistant or refractory to prior JAK inhibitor treatment or ineligible for JAK inhibitor treatment in the opinion of the investigator. Participants in Cohort 2: Suboptimal response to JAK inhibitor treatment. Note: a suboptimal response to JAK inhibitor treatment is defined as spleen size increase by palpation >25% after the first 3 months of treatment with a JAK inhibitor or persistent splenomegaly (spleen volume of >450 cm3) after at least 6 months of JAK inhibitor treatment and presence of 1 symptom score ≥5 or 2 symptom scores ≥3, new or persistent red blood cell (RBC) transfusion dependence. Participants in Cohort 3 (optional cohort): naïve to previous treatment with JAK inhibitor.
5. Measurable splenomegaly as demonstrated by: • palpable spleen measuring ≥5 cm below the left costal margin. The edge of the spleen should be measured from the mid-clavicular line on the left side of the abdomen to the point of greatest splenic protrusion or • spleen volume of ≥450 cm3 measured by MRI or CT.
6. Active symptoms of MF as demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale) on at least one of the symptoms or a score of 3 or greater on at least 2 of the following symptoms: night sweats, itchiness, abdominal discomfort, pain under ribs on left side, early satiety, bone or muscle pain, and inactivity.
7. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
8. Adequate hematologic function defined as the following: a. absolute neutrophil count (ANC) ≥1.0 × 109/L (without growth factor support) b. PLT count ≥50 × 109/L (Cohort 2 and Cohort 3 only).
9. Adequate renal function defined as calculated or measured creatinine clearance (CrCl) of ≥30 mL/minute using the formula of Cockcroft and Gault .
10. Adequate liver function defined as the following: a. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) b. alkaline phosphatase (ALP) ≤2 × ULN (ALP ≤5 × ULN for participants with isozymes specific to bone) c. bilirubin <2 × ULN or bilirubin ≤3 × ULN if due to Gilbert’s disease.
11. For WOCBP, a negative pregnancy test must be confirmed during Screening and ≤3 days prior to Cycle 1 Day 1. 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 13.1) 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 13.1). 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 13.1).
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 and are not considered to be potentially unreliable and/or not cooperative.

Exclusion criteria 15

1. Peripheral blood blast count of ≥10% or bone marrow blast count of ≥10%.
2. Prior history of hematopoietic stem cell transplant.
3. Participation in any other study in which receipt of an investigational new drug occurred within 4 weeks prior to Cycle 1 Day 1.
4. Active known second malignancy with the exception of any of the following: a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b. Adequately treated Stage I cancer from which the participant is currently in remission and has been in remission for ≥2 years c. Low-risk prostate cancer with a Gleason score <7 and a prostate-specific antigen (PSA) level <10 ng/mL d. Any other cancer from which the participant has been disease-free for ≥3 years.
5. Known or suspected allergy to RVU120 or RUX.
6. 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).
7. Major surgical procedure or significant traumatic injury within 28 days before Cycle 1 Day 1, or anticipation of need for major surgical procedure during the course of the study. Placement of a vascular access device or minor surgery is permitted within 14 days before Cycle 1 Day 1 (provided that the wound has healed).
8. Ongoing systemic infection requiring antibiotic, antiviral, or antifungal treatment. Note: prophylactic treatment is allowed.
9. Significant cardiac dysfunction defined as myocardial infarction within 12 months of Cycle 1 Day 1, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias, poorly controlled angina (Section 17), or left ventricular ejection fraction (LVEF) <40% as per echocardiography or multiple gated acquisition (MUGA) scan.
10. Taking any medications, herbal supplements, or other substances (including smoking) that are known to be strong inhibitors or moderate/strong inducers or sensitive substrates of CYP1A2, within less than 5 half-lives prior to Cycle 1 Day 1 (Section 16). Note: Any exception should be discussed with the Medical Monitor.
11. History of ventricular arrhythmia, or QTc ≥470 ms (Bazett’s formula; Section 18).
12. Known active human immunodeficiency virus (HIV) infection defined as any of the following: a. CD4+ T-cell count of less than 350 cells/µL at Screening b. AIDS‑defining opportunistic infection within the past 12 months c. 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 d. on ART or prophylactic antimicrobials that are expected to cause significant drug-drug interactions or overlapping toxicities with study treatment (HIV testing is not required unless mandated locally).
13. Current active liver disease from any cause including hepatitis A (hepatitis A virus IgM positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV RNA). Participants with HCV with undetectable virus after treatment are eligible. A prior history of HBV is acceptable if quantitative PCR for HBV DNA is negative.
14. Pregnant or lactating females.
15. Any other prior or current medical or psychiatric 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 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. The proportion of participants achieving Spleen Volume Reduction (SVR) of ≥35% after 24 weeks of commencing study treatment by magnetic resonance imaging (MRI) or computed tomography (CT) scan

Secondary endpoints 10

1. The proportion of participants achieving ≥1 Grade bone marrow fibrosis improvement after 24 weeks of commencing study treatment
2. Duration of Spleen Response assessed as time from initial SVR of ≥35% by MRI/CT until disease progression or death, whichever occurs first
3. Leukemic transformation as evidenced by bone marrow blast counts of at least 20%, or peripheral blast counts of at least 20% lasting 2 weeks
4. Hematologic (clinical) improvement as defined by International Working Group (IWG) Consensus Criteria 2006
5. Progression-Free Survival
6. Overall Survival
7. Incidence and severity of adverse events (AEs)
8. PK of RVU120 including Cmax, tmax, AUCtau, and AUCinf, and t½
9. The proportion of participants achieving at least a 50% reduction in Total Symptom Score (TSS) after 24 weeks of commencing study treatment
10. For all participants, assessment of the absolute change in TSS from baseline

Investigational products

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

Test 14

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

Rostislav Kuklik, Medical Director

Public contact point

Organisation

Ryvu Therapeutics S.A.

Contact name

Kamil Sitarz

Third parties 8

Locations

2 EU/EEA countries · 19 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 16 files

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

Application history

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