ROGINOLISIB for Myelofibrosis (refractory to JAK inhibitors)

Inclusion criteria

• {"criterion_text":"- ≥18 years of age inclusive, at the time of signing the informed consent.\n- Act to avoid pregnancy or fathering children based on the criteria below:a.\tWomen of non-childbearing potential (i.e., surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age). b.\tWomen of childbearing potential who had a negative serum pregnancy test at screening and who agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up, at least 1 month after the last dose of study treatment. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the patient and their understanding confirmed. c.\tMen who agree to take appropriate precautions to avoid fathering from screening through safety follow-up, at least 1 month after the last dose of study treatment. Permitted methods that are at least 99% effective in preventing pregnancy (see protocol Appendix 3) should be communicated to the patient and their understanding confirmed.\n- Capable of giving signed informed consent, which includes compliance with the requirements of this protocol.\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.\n- Diagnosis of MF, Post-Polycythaemia Vera Myelofibrosis MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF)\n- Dynamic International Prognostic Scoring System (DIPSS) risk category of intermediate-1, intermediate-2, or high\n- Treated with ruxolitinib for ≥ 3 months with a stable dose ≥ 10 mg for a minimum of 8 weeks prior to Day 1. Furthermore, patients must show an unsatisfactory spleen reduction, such as a reduction of less than 25%, and spleen must be palpable ≥ 10 cm below the left costal margin on physical examination.\n- Did not receive experimental drug therapy for MF or any other drug considered as an effective treatment for MF (e.g., danazol, hydroxyurea, interferon products) with the exception of ruxolitinib, within 3 months of starting study drug (except in conditions where other effective treatments for MF were completed 6 months prior to starting ruxolitinib)\n- Independent of spleen size, active symptoms of MF at the screening visit, as demonstrated by the presence of a Total Symptom Score (TSS) of ≥ 10 using the Screening Symptom Form.\n- Peripheral blast count < 10%"}

Exclusion criteria

• {"criterion_text":"- Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications.\n- Receiving an immune-suppressive based treatment for any reason (including chronic use of systemic corticosteroid at doses > 10 mg/day prednisone equivalent) within 14 days prior to the first dose of study treatment. Use of inhaled or topical steroids (including but not limited to creams or intra-articular injection) or brief corticosteroid use for radiographic procedures or systemic corticosteroids ≤ 10 mg is permitted.\n- Have received a live vaccine within 30 days of planned start of study therapy while on trial. Other type of vaccines, including SARS-Co2 vaccines, are allowed.\n- Known allergy or reaction to any component of either study drugs or formulation components.\n- Currently breastfeeding.\n- Known alcohol or other substance abuse.\n- Laboratory and medical history parameters not within Protocol-defined range. a. Absolute neutrophil count < 1.5 × 109/L. b. Platelet count < 100 × 109/L. c. Haemoglobin < 8 g/dL (transfusion is acceptable to meet this criterion). d. Serum creatinine ≥ 1.5 × institutional ULN or measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine or CrCl) < 50 mL/min for patients with creatinine levels > 1.5 × institutional ULN. e. Aspartate aminotransferase (AST) or Alanine transaminase (ALT) ≥ 2.5 × ULN in the absence of hepatic metastases or ≥ 5 × ULN with hepatic metastases at screening. f. Total bilirubin ≥ 1.2 × ULN are excluded unless direct bilirubin is ≤ ULN. If there is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin to be eligible (except patients with Gilbert syndrome, who must have total bilirubin < 51.3 μmol/L). g. International normalized ratio or prothrombin time (PT) > 1.5 × ULN. h. Activated partial thromboplastin time (aPTT) > 1.5 × ULN. i. Evidence of acute infection of hepatitis B virus (HBV), (for example: positive for HBsAg, anti-HBc, IgM anti-HBc and negative for anti-HBs), hepatitis C virus (HCV) (for example: HCV antibody reactive; HCV RNA detected) and HIV. Patients who are on stable antiviral therapy, in good clinical control (ie for HIV a viral load < 400 copie/ml and a CD4+ count of > 350 cells/uL) and asymptomatic are eligible for the study.\n- Presence of active or inactive ‘latent’ tuberculosis.\n- History of a prior Grade 3 or 4 AE which did not respond to therapy or resolved with treatment interruptions and returned to at least Grade 1, other than fatigue. Note: Patients with ≤ Grade 2 neuropathy or alopecia are an exception and may enrol\n- Active autoimmune process (e.g., rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, immune colitis) for which systemic treatment (i.e., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) is required. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.\n- History or presence of an abnormal ECG that, in the Investigator's opinion, is clinically meaningful. Screening QTc interval > 480 milliseconds is excluded (corrected by Fridericia). In the event that a single QTc is > 480 milliseconds, the patient may enrol if the average QTc for the 3 ECGs is < 480 milliseconds. For patients with an intraventricular conduction delay (QRS interval > 120 msec), the JTc interval may be used in place of the QTc with Sponsor approval. The JTc must be < 340 milliseconds if JTc is used in place of the QTc. Patients with left bundle branch block are excluded.\n- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.\n- Patients with active malignancy requiring concurrent intervention or previous malignancies unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required during the study period and the patient is assessed at low risk of relapse by the investigator. Note: Patients with a slow progressing cancer (e.g. prostate) or an in situ cancers (e.g. cervical dysplasia) are permitted.\n- Any serious or uncontrolled medical disorder or active infection that, in the opinion of the Investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patient to receive protocol therapy.\n- Use of the following treatments within the time periods noted: a. Erythropoiesis stimulating agent (ESA) within 4 weeks prior to start of rogilonisib. b. Splenic irradiation within 3 months prior to start of rogilonisib.\n- Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, bone marrow biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary)"}

Primary endpoints

• {"endpoint_text":"- Safety measured by AEs, 12-lead ECG, serum chemistry and haematology laboratory parameters, vital signs, physical examinations","definition_or_measurement_approach":"Safety assessed by adverse events (AEs), 12-lead ECG, serum chemistry and haematology laboratory parameters, vital signs and physical examinations"}

Secondary endpoints

• {"endpoint_text":"- Changes in peripheral blood Tregs from baseline at Week 12 and continued reduction over time\n- Splenic response rate (SRR) of ≥15%, ≥25% and ≥35% reduction in spleen volume at 12 and 24 weeks compared to baseline, as assessed by MRI/CT\n- Duration of spleen response as determined every 12 weeks\n- Proportion of patients with transfusion independence at 12 and 24 weeks where applicable\n- Overall Survival (OS) defined as the time from the date of the first dose of study treatment until death from any cause\n- Proportion of patients who have any reduction in Total Symptom Score (TSS) at 12 and 24 weeks compared to baseline as measured by Myelofibrosis Symptom Assessment Form (MFSAF)\n- Proportion of patients who have a reduction of ≥25% and ≥50% in TSS at 12 and 24 weeks compared to baseline as measured by Myelofibrosis Symptom Assessment Form (MFSAF)\n- Mean change in TSS as measured by Myelofibrosis Symptom Assessment Form (MFSAF) from baseline at 12 and 24 weeks\n- Time to the first ≥50% reduction compared to baseline in TSS as measured by Myelofibrosis Symptom Assessment Form (MFSAF)\n- Duration of TSS response as measured by MFSAF (e.g., duration of TSS ≥25% and ≥50%)\n- Concentration of roginolisib at pre-dose and steady state levels (including Area under the curve [AUC], population PK)","definition_or_measurement_approach":"Endpoints include biomarker (Treg) change measured in peripheral blood at Week 12 and over time; splenic volume reductions at 12 and 24 weeks assessed by MRI/CT; duration assessed every 12 weeks; transfusion independence proportion at 12 and 24 weeks; OS measured from first dose to death; TSS reductions measured by MFSAF at 12 and 24 weeks (including ≥25% and ≥50% thresholds, mean change, time to first ≥50%, and duration); PK measures including pre-dose and steady-state concentrations and AUC/population PK"}

Italy

Earliest CTIS Part Ii Submission Date

14-12-2024

Latest Decision Or Authorization Date

09-04-2026

Processing Time Days

481

Number Of Sites

10

Number Of Participants

13

Spain

Earliest CTIS Part Ii Submission Date

05-12-2024

Latest Decision Or Authorization Date

28-04-2026

Processing Time Days

509

Number Of Sites

4

Number Of Participants

14

Primary sponsor

Full Name

iOnctura SA

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Third parties

• {"country":"France","full_name":"Oracle France","duties_or_roles":"eCRF","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Propharma Group The Netherlands B.V.","duties_or_roles":"Pharmacovigilance Provider","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Aptuit (Verona) S.r.l.","duties_or_roles":"Samples analysis (PK)","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Catalent Germany Schorndorf GmbH","duties_or_roles":"IMP storage, IMP labelling & packaging & kit production, QP certification, IMP release, IMP distribution to sites in EU. IMP return from sites in EU and IMP destruction","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Firalis","duties_or_roles":"Proteomic analysis, CD34+ and Bioanlaysis for Roginolisib","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Veeva Systems Inc.","duties_or_roles":"eTMF/CTMS Provider","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"eCOA & Central ECG","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Teiko Bio Inc.","duties_or_roles":"Sample analysis (T-reg)","organisation_type":"Pharmaceutical company"}