A Study of Roginolisib in Combination With Ruxolitinib in Patients With Myelofibrosis (MF) Who Are Unresponsive to JAK Inhibitors

Inclusion Criteria:

1. ≥18 years of age inclusive, at the time of signing the informed consent.

2. Capable of giving signed informed consent, which includes compliance with therequirements of this protocol.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

4. Diagnosis of MF, Post-Polycythaemia Vera Myelofibrosis MF (PPV-MF), orpost-essential thrombocythemia MF (PET-MF)

5. Dynamic International Prognostic Scoring System (DIPSS) risk category ofintermediate-1, intermediate-2, or high

6. 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 spleenreduction, such as a reduction of less than 25%, and spleen must be palpable ≥ 10 cmbelow the left costal margin on physical examination

7. Did not receive experimental drug therapy for MF or any other drug considered as aneffective treatment for MF (e.g., danazol, hydroxyurea, interferon products) withthe exception of ruxolitinib, within 3 months of starting study drug (except inconditions where other effective treatments for MF were completed 6 months prior tostarting ruxolitinib)

8. Independent of spleen size, active symptoms of MF at the screening visit, asdemonstrated by the presence of a Total Symptom Score (TSS) of ≥ 10 using theScreening Symptom Form.

9. Peripheral blast count < 10%

10. Act to avoid pregnancy or fathering children based on the criteria below:

11. Women of non-childbearing potential (i.e., surgically sterile with ahysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and atleast 50 years of age).

12. Women of childbearing potential who had a negative serum pregnancy test atscreening 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 atleast 99% effective in preventing pregnancy should be communicated to thepatient and their understanding confirmed.

13. Men who agree to take appropriate precautions to avoid fathering from screeningthrough safety follow-up, at least 1 month after the last dose of studytreatment. Permitted methods that are at least 99% effective in preventingpregnancy (see Appendix 3) should be communicated to the patient and theirunderstanding confirmed.

Exclusion Criteria:

1. Inability to swallow food or any condition of the upper gastrointestinal tract thatprecludes administration of oral medications.

2. History of a prior Grade 3 or 4 AE which did not respond to therapy or resolved withtreatment 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.

3. Active autoimmune process (e.g., rheumatoid arthritis, moderate or severe psoriasis,multiple sclerosis, inflammatory bowel disease, immune colitis) for which systemictreatment (i.e., use of disease-modifying agents, corticosteroids, orimmunosuppressive drugs) is required. Replacement therapy (e.g., thyroxine, insulin,or physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

4. History or presence of an abnormal ECG that, in the Investigator's opinion, isclinically meaningful. Screening QTc interval > 480 milliseconds is excluded (corrected by Fridericia). In the event that a single QTc is > 480 milliseconds, thepatient may enrol if the average QTc for the 3 ECGs is < 480 milliseconds. Forpatients with an intraventricular conduction delay (QRS interval > 120 msec), theJTc 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 bundlebranch block are excluded.

5. Clinically significant (i.e., active) cardiovascular disease: cerebral vascularaccident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 monthsprior to enrolment), unstable angina, congestive heart failure (≥ New York HeartAssociation Classification Class II), or serious cardiac arrhythmia requiringmedication.

6. Patients with active malignancy requiring concurrent intervention or previousmalignancies unless a complete remission was achieved at least 2 years prior tostudy entry and no additional therapy is required during the study period and thepatient is assessed at low risk of relapse by the investigator. Note: Patients witha slow progressing cancer (e.g. prostate) or an in situ cancers (e.g. cervicaldysplasia) are permitted.

7. Any serious or uncontrolled medical disorder or active infection that, in theopinion of the Investigator, may increase the risk associated with studyparticipation, study drug administration, or would impair the ability of the patientto receive protocol therapy.

8. Use of the following treatments within the time periods noted:

9. Erythropoiesis stimulating agent (ESA) within 4 weeks prior to start ofroginolisib.

10. Splenic irradiation within 3 months prior to start of roginolisib.

11. Major surgery within 2 weeks of the first dose of study drug (minimally invasiveprocedures such as bronchoscopy, bone marrow biopsy, insertion of a central venousaccess device, and insertion of a feeding tube are not considered major surgery andare not exclusionary)

12. Receiving an immune-suppressive based treatment for any reason (including chronicuse of systemic corticosteroid at doses > 10 mg/day prednisone equivalent) within 14days 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 briefcorticosteroid use for radiographic procedures or systemic corticosteroids ≤ 10 mgis permitted.

13. Have received a live vaccine within 30 days of planned start of study therapy whileon trial. Other type of vaccines, including SARS-Co2 vaccines, are allowed.

14. Known allergy or reaction to any component of either study drugs or formulationcomponents.

15. Currently breastfeeding.

16. Known alcohol or other substance abuse.

17. Laboratory and medical history parameters not within Protocol-defined range.

18. Absolute neutrophil count < 1.5 × 109/L.

19. Platelet count < 100 × 109/L.

20. Haemoglobin < 8 g/dL (transfusion is acceptable to meet this criterion).

21. Serum creatinine ≥ 1.5 × institutional ULN or measured or calculated creatinineclearance (glomerular filtration rate can also be used in place of creatinineor CrCl) < 50 mL/min for patients with creatinine levels > 1.5 × institutionalULN.

22. Aspartate aminotransferase (AST) or Alanine transaminase (ALT) ≥ 2.5 × ULN inthe absence of hepatic metastases or ≥ 5 × ULN with hepatic metastases atscreening.

23. Total bilirubin ≥ 1.2 × ULN are excluded unless direct bilirubin is ≤ ULN. Ifthere is no institutional ULN, then direct bilirubin must be < 40% of totalbilirubin to be eligible (except patients with Gilbert syndrome, who must havetotal bilirubin < 51.3 μmol/L).

24. International normalized ratio or prothrombin time (PT) > 1.5 × ULN.

25. Activated partial thromboplastin time (aPTT) > 1.5 × ULN.

26. Evidence of acute infection of hepatitis B virus (HBV), (for example: positivefor 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 aviral load < 400 copies/mL and a CD4+ count of ≥ 350 cells/uL) AND asymptomatic areeligible for the study

27. Presence of active or inactive 'latent' tuberculosis.