AlloHCT With PegINFa for Myelofibrosis

Inclusion criteria

Pre-Transplant Inclusion Criteria (Step 1)

• Male or female subject aged ≥ 18 years.
• Diagnosis of primary or secondary myelofibrosis.
• Eligible to undergo a myeloablative or reduced intensity conditioning regimen (MAC or RIC)
• Eligible to undergo a standard of care bone marrow biopsy with aspirate as part of his or her routine pre-transplant work-up.
• Peripheral blood stem cell (PBSC) graft
• 10/10 HLA matched related or matched unrelated donor
• ECOG performance status ≤ 2.
• For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

• Women < 50 years of age:

• Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
• Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
• Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women ≥ 50 years of age:

• Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
• Had radiation-induced menopause with last menses >1 year ago; or
• Had chemotherapy-induced menopause with last menses >1 year ago; or
• Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
• Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception as described in Section 5.4.1.

Treatment Inclusion Criteria (Step 2)

• Male or female subject aged ≥ 18 years.
• Diagnosis of primary or secondary myelofibrosis.
• Have undergone a myeloablative or reduced-intensity conditioning regimen (MAC or RIC) and be 50-80 days from Day 0 of transplant at initiation of study therapy.
• Peripheral blood stem cell (PBSC) graft
• 10/10 HLA matched related or matched unrelated donor
• ECOG Performance Status ≤ 2.
• Adequate organ function as defined as:

• Hepatic:

• Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
• Renal:

---Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:

• TSH and T4 within normal limits or adequately controlled thyroid function.
• For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

• Women < 50 years of age:

• Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
• Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
• Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women ≥ 50 years of age:

• Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
• Had radiation-induced menopause with last menses >1 year ago; or
• Had chemotherapy-induced menopause with last menses >1 year ago; or
• Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
• Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception as described in Section 5.4.1.
• Male subjects must agree to use a condom during intercourse for the duration of study therapy as described in Section 5.4.1.
• Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior cancer therapy, unless considered clinically not significant by the treating investigator.
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion criteria

Exclusion criteria

(Step 2)

• Receiving other investigational agents concurrently
• Prior systemic anti-cancer therapy or any investigational therapy within five half-lives prior to starting study treatment.
• Prior radiotherapy within 6 weeks prior to the first dose of study treatment.
• Major surgery within 6 weeks prior to starting study drug or patients who have not fully recovered from major surgery.
• The diagnosis of another malignancy within ≤ 2 years before study enrollment, except for those considered to be adequately treated with no evidence of disease or symptoms and/or will not require therapy during the study duration (i.e., basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, or low-grade prostate cancer with Gleason Score ≤ 6).
• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

• Graft-versus-host disease:

---Acute or chronic

• Cardiovascular disorders:

• Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before the first dose.
• QTc prolongation defined as a QTcF > 500 ms.
• Known congenital long QT.
• Left ventricular ejection fraction < 55%.
• Uncontrolled hypertension defined as ≥ 140/90 as assessed from the mean of three consecutive blood pressure measurements taken over 10 minutes.
• Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• Active infection including HIV, tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice) or hepatitis C.

--Note: Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.

• Autoimmune hepatitis or decompensated hepatic disease
• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
• Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3).
• Subjects taking prohibited medications as described in Section 6.5.1. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.
• History of neuropsychiatric disease, autoimmune disease, or pancreatitis.
• Presence of active interstitial lung disease or pneumonitis, bronchiolitis obliterans, pulmonary hypertension, ulcerative and hemorrhagic/ischemic colitis, and ophthalmologic disorders.