ATIOM: Allogeneic Hematopoietic Cell Transplantation With Pegylated Interferon Alfa-2a for Primary and Secondary Myelofibrosis
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment: All Patients A 3+3 dose de-escalation design will be used to determine the recommended phase 2 dose,while ensuring the safety and tolerability of the treatment. In this trial, the dose determined to be the maximum tolerated dose will be the recommended phase 2 dose and will be utilized in the cohort expansion. |
Drug: Pegylated interferon alpha2a
PegINFa will be given once every 2 weeks by subcutaneous administration in the abdomen or thigh.
|
Outcome Measures
Primary Outcome Measures
- Rate of dose-limiting toxicities (DLTs) during the DLT evaluation period [Start of treatment to 86 days after treatment initiation]
To identify the Recommended Phase 2 Dose (RP2D) of pegylated interferon alfa-2a in subjects undergoing allogeneic hematopoietic cell transplantation for primary or secondary myelofibrosis
Secondary Outcome Measures
- Assess the safety of pegylated interferon alfa-2a in the study population. [3 years]
Frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE version 5.0), seriousness, duration, and relationship to study treatment.
- Assess the tolerability of pegylated interferon alfa-2a in the study population. [3 years]
Frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE version 5.0), seriousness, duration, and relationship to study treatment.
- Assess the rate of treatment-related mortality in the study population. [3 years]
Rate of treatment-related mortality which is defined as any death attributed to complications from study therapy in the absence of myelofibrosis relapse or progression.
- Assess leukemia-free survival (LFS) in the study population. [3 years]
Rate of Leukemia-free survival (LFS) as defined from the day of allogeneic hematopoietic cell transplantation to the time documented disease relapse/progression (date of bone marrow blast count of 20% or greater or date of first peripheral blast count of 20% or greater that was subsequently confirmed to sustain for at least 8 weeks), initiation of non-protocol MF therapy, loss to follow-up, study end, or death from any cause, whichever comes first.
- Assess the incidence of acute graft versus host disease (GVHD) in the study population [3 years]
Cumulative incidence of Glucksberg grade II, III, and IV acute GVHD.
Eligibility Criteria
Criteria
Inclusion Criteria:
Pre-Transplant Inclusion Criteria (Step 1)
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Male or female subject aged ≥ 18 years.
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Diagnosis of primary or secondary myelofibrosis.
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Eligible to undergo a myeloablative or reduced intensity conditioning regimen (MAC or RIC)
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Eligible to undergo a standard of care bone marrow biopsy with aspirate as part of his or her routine pre-transplant work-up.
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Peripheral blood stem cell (PBSC) graft
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10/10 HLA matched related or matched unrelated donor
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ECOG performance status ≤ 2.
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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:
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Women < 50 years of age:
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Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
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Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
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Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
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Women ≥ 50 years of age:
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Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
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Had radiation-induced menopause with last menses >1 year ago; or
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Had chemotherapy-induced menopause with last menses >1 year ago; or
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Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
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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)
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Male or female subject aged ≥ 18 years.
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Diagnosis of primary or secondary myelofibrosis.
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Have undergone a myeloablative or reduced-intensity conditioning regimen (MAC or RIC) within 50-80 days prior to start of study therapy.
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Peripheral blood stem cell (PBSC) graft
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10/10 HLA matched related or matched unrelated donor
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ECOG Performance Status ≤ 2.
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Adequate organ function as defined as:
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Hepatic:
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Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)
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AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
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Renal:
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Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:
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TSH and T4 within normal limits or adequately controlled thyroid function.
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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:
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Women < 50 years of age:
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Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
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Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
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Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
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Women ≥ 50 years of age:
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Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
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Had radiation-induced menopause with last menses >1 year ago; or
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Had chemotherapy-induced menopause with last menses >1 year ago; or
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Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
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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.
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Male subjects must agree to use a condom during intercourse for the duration of study therapy as described in Section 5.4.1.
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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.
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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)
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Receiving other investigational agents concurrently
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Prior systemic anti-cancer therapy or any investigational therapy within five half-lives prior to starting study treatment.
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Prior radiotherapy within 6 weeks prior to the first dose of study treatment.
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Major surgery within 6 weeks prior to starting study drug or patients who have not fully recovered from major surgery.
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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).
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Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
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Graft-versus-host disease:
---Acute or chronic
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Cardiovascular disorders:
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Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
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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.
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QTc prolongation defined as a QTcF > 500 ms.
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Known congenital long QT.
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Left ventricular ejection fraction < 55%.
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Uncontrolled hypertension defined as ≥ 140/90 as assessed from the mean of three consecutive blood pressure measurements taken over 10 minutes.
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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.)
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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.
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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.
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Autoimmune hepatitis or decompensated hepatic disease
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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.
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Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3).
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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.
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History of neuropsychiatric disease, autoimmune disease, or pancreatitis.
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Presence of active interstitial lung disease or pneumonitis, bronchiolitis obliterans, pulmonary hypertension, ulcerative and hemorrhagic/ischemic colitis, and ophthalmologic disorders.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Huntsman Cancer Institute at the University of Utah | Salt Lake City | Utah | United States | 84112 |
Sponsors and Collaborators
- University of Utah
Investigators
- Principal Investigator: Sagar Patel, MD, Huntsman Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HCI149616