Overview

This is a single site, open-label, dose de-escalation, Phase 1 study of pegylated interferon alfa-2a administered after alloHCT in subjects with primary or secondary myelofibrosis. Part 1 of the study will assess the rate of dose-limiting toxicities (DLTs) during the DLT evaluation period and identify the Recommended Phase 2 Dose (RP2D). Once the RP2D is identified, 6 additional patients will be enrolled in the expansion cohort.

Eligibility

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.