Other Inclusion Criteria:

Ruxolitinib Run-in Period

1. Adults ≥ 18 years of age able to provide informed consent.
2. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by the treating physician according to the World Health Organization (WHO) criteria (Appendix 2).
3. IPSS risk category of Intermediate-1, Intermediate-2, or High.
4. Spleen measuring ≥ 450 cm3 by MRI or CT scan (central review).
5. MF symptoms as defined by a baseline TSS of ≥ 10. Baseline TSS will be calculated as a 7-day average per MFSAF v4.0.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
7. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of ruxolitinib monotherapy):
   1. Hematologic:
      1. Absolute neutrophil count (ANC) ≥ 1.5 × 109 /L in the absence of myeloid growth factors during the prior 28 days.
      2. Platelet count ≥ 100 × 109 /L.
      3. White blood cell count ≤ 50 × 109 /L.
   2. Hepatic:
      1. Total serum bilirubin within normal limits. If total bilirubin is > upper limit of normal (ULN), subjects are eligible if direct bilirubin ≤ 2.0 ULN, unless documented Gilbert’s Syndrome.
      2. Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2.5 ULN.
   3. Renal: estimated creatinine clearance ≥ 30 mL/min by the Cockcroft Gault equation.
8. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for one month and one week, and male subjects must continue to use a highly effective method of contraception for three months and one week. A woman is considered of childbearing potential (ie, fertile) following menarche and until becoming post-menopausal unless permanently sterile (see Appendix 9.)

Randomized Period

1. PMF, post-PV MF, or post-ET MF that is TP53WT as assessed by central testing.
2. ECOG performance status of 0 to 2.
3. Treatment with ruxolitinib monotherapy for ≥ 18 weeks but < 25 weeks (as described in Section 3.1), and on a stable dose of ruxolitinib in the 8 consecutive weeks prior to study treatment.
   1. A stable dose is defined as a ruxolitinib dose that did not require a treatment hold or dose adjustment.
   2. Subjects must be taking a stable dose of ruxolitinib of ≥ 5 mg BID.
4. Suboptimal response to standard of care ruxolitinib monotherapy, defined as SVR of > 0% but < 35% and TSS reduction of > 0% but < 50%, assessed from the start of the run-in period baseline to the end of the run-in period.
5. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 14 days prior to the first dose of study treatment):
   1. Hematologic:
      1. ANC ≥ 1.5 × 109 /L in the absence of myeloid growth factors during the prior 28 days.
         
      2. Platelet count ≥ 100 × 109 /L.
         
      3. Hepatic:
         1. AST/SGOT and ALT/SGPT ≤ 2.5 ULN.
         2. Total serum bilirubin within normal limits. If total bilirubin is > ULN, subjects are eligible if direct bilirubin ≤ 2.0 ULN, unless documented Gilbert’s Syndrome.
         3. Renal: estimated creatinine clearance ≥ 30 mL/min by the Cockcroft Gault equation.
6. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for one month and one week, and male subjects must continue to use a highly effective method of contraception for three months and one week. A woman is considered of childbearing potential (ie, fertile) following menarche and until becoming post-menopausal unless permanently sterile (see Appendix 9).

Other Exclusion Criteria:

Ruxolitinib Run-in Period

1. Participation in another interventional clinical trial within four weeks prior to the first dose of ruxolitinib monotherapy (participation in observational studies is permitted).
2. Prior therapy with any JAK inhibitor.
3. Prior therapy with BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors; prior p53-directed therapy. Subjects must have discontinued all drugs (including hydroxyurea) used to treat underlying MF ≥ 28 days prior to first dose of ruxolitinib monotherapy. Erythroid growth factors, danazol (or equivalent androgen), or prednisone (or equivalent corticosteroid) are permitted if the subject is on a stable dose for at least two months prior to starting ruxolitinib.
4. Prior splenectomy.
5. Splenic irradiation within three months prior to the first dose of ruxolitinib monotherapy.
6. Non-spleen-directed radiation therapy for MF or major surgery or planned major surgery within 28 days prior to the first dose of ruxolitinib monotherapy.
7. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation. Subjects who are eligible for stem cell transplant but refuse transplant are not excluded.
8. Peripheral blood or bone marrow blast count ≥ 10% at any time within 28 days prior to the first dose of ruxolitinib monotherapy.
9. Women who are pregnant or breastfeeding.
10. History of solid organ transplant.
11. Known infection with human immunodeficiency virus (HIV).
12. Known active hepatitis B or C infection.
13. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before enrollment. Subjects with acute infections requiring systemic antibiotic use should delay enrollment until the course of antibiotic therapy has been completed.
14. Subjects with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or subjects with psychiatric illness/social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority.
15. Active or chronic bleeding within 28 days prior to the first dose of ruxolitinib monotherapy.
16. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of ruxolitinib monotherapy.
17. Other malignancy within the last three years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial/non-invasive transitional cell bladder carcinoma.
18. Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0).
19. History of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease conditions that may hamper compliance and / or absorption of the study treatment.
20. History of severe hypersensitivity reaction to any component of navtemadlin or ruxolitinib, any of their excipients, or to required prophylaxis.

Other Exclusion Criteria:

Ruxolitinib Run-in Period

1. Participation in another interventional clinical trial within four weeks prior to the first dose of ruxolitinib monotherapy (participation in observational studies is permitted).
2. Prior therapy with any JAK inhibitor.
3. Prior therapy with BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors; prior p53-directed therapy. Subjects must have discontinued all drugs (including hydroxyurea) used to treat underlying MF ≥ 28 days prior to first dose of ruxolitinib monotherapy. Erythroid growth factors, danazol (or equivalent androgen), or prednisone (or equivalent corticosteroid) are permitted if the subject is on a stable dose for at least two months prior to starting ruxolitinib.
4. Prior splenectomy.
5. Splenic irradiation within three months prior to the first dose of ruxolitinib monotherapy.
6. Non-spleen-directed radiation therapy for MF or major surgery or planned major surgery within 28 days prior to the first dose of ruxolitinib monotherapy.
7. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation. Subjects who are eligible for stem cell transplant but refuse transplant are not excluded.
8. Peripheral blood or bone marrow blast count ≥ 10% at any time within 28 days prior to the first dose of ruxolitinib monotherapy.
9. Women who are pregnant or breastfeeding.
10. History of solid organ transplant.
11. Known infection with human immunodeficiency virus (HIV).
12. Known active hepatitis B or C infection.
13. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before enrollment. Subjects with acute infections requiring systemic antibiotic use should delay enrollment until the course of antibiotic therapy has been completed.
14. Subjects with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or subjects with psychiatric illness/social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority.
15. Active or chronic bleeding within 28 days prior to the first dose of ruxolitinib monotherapy.
16. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of ruxolitinib monotherapy.
17. Other malignancy within the last three years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial/non-invasive transitional cell bladder carcinoma.
18. Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0).
19. History of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease conditions that may hamper compliance and / or absorption of the study treatment.
20. History of severe hypersensitivity reaction to any component of navtemadlin or ruxolitinib, any of their excipients, or to required prophylaxis.
21. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within six months prior to first dose of ruxolitinib monotherapy.
22. Subjects with indwelling surgical drains (eg, peritoneal, CNS, or pleural).
23. Subjects with symptomatic ascites or requiring paracentesis.
24. Subjects with any open wound or ulcer.

Randomized Period

1. White blood cell count that meets both of the following criteria:
   1. Increases by two-fold (ie, doubles) or more during therapy with ruxolitinib monotherapy (comparing baseline prior to the run-in period vs pre-randomization) and
   2. Exceeds 50 × 109 /L at pre-randomization.
2. Active treatment with BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors, or p53-directed therapy.
3. Splenic irradiation within three months prior to the first dose of study treatment.
4. Non-spleen-directed radiation therapy for MF or major surgery or planned major surgery within 28 days prior to the first dose of study treatment.
5. Eligible for allogeneic stem cell transplantation. Subjects who are eligible for stem cell transplant but refuse transplant are not excluded.
6. Peripheral blood or bone marrow blast count ≥ 10% at any time within 28 days prior to the first dose of study treatment.
7. Women who are pregnant or breastfeeding.
8. History of solid organ transplant.
9. Known infection with HIV.
10. Known active hepatitis B or C infection.
11. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before screening/randomization. Subjects with acute infections requiring systemic antibiotic use should delay screening/randomization until the course of antibiotic therapy has been completed.
12. Subjects with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or subjects with psychiatric illness/social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority.
13. Active or chronic bleeding within 28 days prior to the first dose of study treatment.
14. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment.
15. Subjects with indwelling surgical drains (eg, peritoneal, CNS, or pleural).
16. Subjects with symptomatic ascites or requiring paracentesis.
17. Any concurrent disease, or condition that would make the subject unsuitable for participation in the study.

Subjects with any open wound or ulcer