AlloHCT With PegINFa for Myelofibrosis

Official title

Allogeneic Hematopoietic Cell Transplantation With Pegylated Interferon Alfa-2a for Primary and Secondary Myelofibrosis (ATIOM)

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.

Interventions

• Drug Pegylated interferon alpha2a
  PegINFa will be given once every 2 weeks by subcutaneous administration in the abdomen or thigh.

Primary outcome measures

• Rate of dose-limiting toxicities (DLTs) during the DLT evaluation period [Time frame: Start of treatment to 86 days after treatment initiation]

Secondary outcome measures (6)

• Assess the safety of pegylated interferon alfa-2a in the study population. [Time frame: 3 years]
• Assess the tolerability of pegylated interferon alfa-2a in the study population. [Time frame: 3 years]
• Assess the rate of treatment-related mortality in the study population. [Time frame: 3 years]
• Assess Objective Response Rate (ORR) in the study population. [Time frame: 3 Years]
• Assess leukemia-free survival (LFS) in the study population. [Time frame: 3 years]
• Assess the incidence of acute and/or chronic graft versus host disease (GVHD) in the study population [Time frame: 3 years]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Huntsman Cancer Institute at the University of Utah — Salt Lake City

Publications

• Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol. 1999 May;61(1):10-5. doi: 10.1002/(sici)1096-8652(199905)61:13.0.co;2-i. PMID 10331505
• Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018 Dec;93(12):1551-1560. doi: 10.1002/ajh.25230. Epub 2018 Oct 26. PMID 30039550
• Ballen KK, Shrestha S, Sobocinski KA, Zhang MJ, Bashey A, Bolwell BJ, Cervantes F, Devine SM, Gale RP, Gupta V, Hahn TE, Hogan WJ, Kroger N, Litzow MR, Marks DI, Maziarz RT, McCarthy PL, Schiller G, Schouten HC, Roy V, Wiernik PH, Horowitz MM, Giralt SA, Arora M. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2010 Mar;16(3):358-67. doi: 10.1016/j.bbmt.2009.10.025. Epub PMID 19879949
• Patriarca F, Bacigalupo A, Sperotto A, Isola M, Soldano F, Bruno B, van Lint MT, Iori AP, Santarone S, Porretto F, Pioltelli P, Visani G, Iacopino P, Fanin R, Bosi A; GITMO. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica. 2008 Oct;93(10):1514-22. doi: 10.3324/haematol.12828. Epub 2 PMID 18728030
• Gupta V, Malone AK, Hari PN, Ahn KW, Hu ZH, Gale RP, Ballen KK, Hamadani M, Olavarria E, Gerds AT, Waller EK, Costa LJ, Antin JH, Kamble RT, van Besien KM, Savani BN, Schouten HC, Szer J, Cahn JY, de Lima MJ, Wirk B, Aljurf MD, Popat U, Bejanyan N, Litzow MR, Norkin M, Lewis ID, Hale GA, Woolfrey AE, Miller AM, Ustun C, Jagasia MH, Lill M, Maziarz RT, Cortes J, Kalaycio ME, Saber W. Reduced-intens PMID 24161923
• Slot S, Smits K, van de Donk NW, Witte BI, Raymakers R, Janssen JJ, Broers AE, Te Boekhorst PA, Zweegman S. Effect of conditioning regimens on graft failure in myelofibrosis: a retrospective analysis. Bone Marrow Transplant. 2015 Nov;50(11):1424-31. doi: 10.1038/bmt.2015.172. Epub 2015 Aug 3. PMID 26237165
• Chhabra S, Narra RK, Wu R, Szabo A, George G, Michaelis LC, D'Souza A, Dhakal B, Drobyski WR, Fenske TS, Jerkins JH, Pasquini MC, Rizzo RD, Saber W, Shah NN, Shaw BE, Hamadani M, Hari PN. Fludarabine/Busulfan Conditioning-Based Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis: Role of Ruxolitinib in Improving Survival Outcomes. Biol Blood Marrow Transplant. 2020 May;26(5):893-901. d PMID 31982543
• Guardiola P, Anderson JE, Bandini G, Cervantes F, Runde V, Arcese W, Bacigalupo A, Przepiorka D, O'Donnell MR, Polchi P, Buzyn A, Sutton L, Cazals-Hatem D, Sale G, de Witte T, Deeg HJ, Gluckman E. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Societe Francaise de Greffe de Moelle, Gruppo Italiano per il Trapianto del M PMID 10216077

Identifiers

NCT: NCT05535764 · HCI149616

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗