Itacitinib and Alemtuzumab in Treating Patients With T-Cell Prolymphocytic Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of itacitinib in combination with alemtuzumab in patients with T-cell prolymphocytic leukemia (T-PLL).

SECONDARY OBJECTIVES:

I. To evaluate the event free survival (EFS) in patients (pts) with T-PLL treated with itacitinib in combination with alemtuzumab.

II. To evaluate response complete remission (CR), complete remission without blood count recovery (CRi), or partial remission (PR) (CR/CRi or PR) of itacitinib in combination with alemtuzumab in patients with T-PLL.

III. To explore the single-agent activity of itacitinib in pts with T-PLL. IV. To assess the time to response, response duration, and overall survival (OS) in pts with T-PLL treated with the combination of itacitinib and alemtuzumab.

EXPLORATORY OBJECTIVES:

I. To explore the effect of itacitinib on STAT5 phosphorylation in pts with T-PLL II. To explore the association of pretreatment somatic mutations and the dynamics of STAT5 phosphorylation with response.

OUTLINE: This is a dose-escalation study of alemtuzumab.

CYCLE 1: Patients receive itacitinib orally (PO) once daily (QD) on days 1-28 and alemtuzumab intravenously (IV) over 2 hours on days 15, 17, 19, 21, 23, 25, and 27 in the absence of disease progression of unacceptable toxicity.

CYCLE 2 AND BEYOND: Patients receive itacitinib PO QD on day 1-28 and alemtuzumab IV over 2 hours on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who achieve a response (CR/CRi or PR) may receive itacitinib for up to 8 additional cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

• Alemtuzumab (Biological), also known as Anti-CD52 Monoclonal Antibody, Campath, Campath-1H, LDP-03, Lemtrada, MabCampath, Monoclonal Antibody Campath-1H: Given IV
• Itacitinib (Drug), also known as INCB 039110, INCB-039110, INCB039110: Given PO

Primary outcomes

• Incidence of adverse events (AEs) [Up to 2 years]: The severity of the toxicities will be graded according to the latest version of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). The number and percent of subjects with treatment-emergent adverse events will be summarized according to intensity and drug relationship, and categorized by System Organ Class and preferred term by dose level/Part. All reported AEs that occur after signing informed consent will be included in the analysis of all reported AEs. Exposure to study drug and reasons for discontinuation of study drug will be tabulated. Data will be summarized using descriptive statistics. Continuous variables will be summarized using the number of observations, mean, standard deviation, coefficient of variation, median, and range as appropriate. Categorical values will be summarized using the number of observations and percentages as appropriate.

Secondary outcomes

• Response rate (complete remission[CR], complete remission without blood count recovery [CRi], or partial remission [PR]) [Up to 2 years]: The response rate (CR/CRi or PR) will be estimated for all patients along with the 95% confidence interval. Patients with missing or no response assessments will be classified as non-responders. The association between response and patient and clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test. The response rate will be compared between different subgroups (e.g. mutation types) by Fisher exact test.
• Duration of response (DOR) [From the first documented onset of PR or CR/CRi to the date of progressive disease/relapse or death due to underlying disease, assessed up to 2 years]: Listed and summarized by the Kaplan-Meier estimator.
• Time to response [Up to 2 years]: Listed and summarized by the Kaplan-Meier estimator. Time to response is defined as the time from treatment start till response (CR/CRi/PR) or last follow-up.
• Overall survival [From treatment till death or last follow-up, assessed up to 2 years]: Listed and summarized by the Kaplan-Meier estimator.
• Event-free survival [From start of treatment to the date of event defined as the first documented progressive disease/relapse, or death due to any cause, whichever comes first, assessed up to 2 years]: Listed and summarized by the Kaplan-Meier estimator. Logrank test will be used to compare the time-to-event difference between different subgroups.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with a diagnosis of T-cell prolymphocytic leukemia (T-PLL) will be eligible (both treatment naïve and relapsed patients are eligible).
* Age >/= 18 years.
* Patients must not have had chemotherapy or antibody therapy for 7 days prior to starting ITACITINIB. However, patients with rapidly proliferative disease may receive hydroxyurea or decadron until 24 hours prior to starting therapy on this protocol.
* Adequate organ function as defined below: liver function (bilirubin </=2mg/dL, AST and ALT </=3 x ULN or </=5 x ULN if related to leukemic involvement); kidney function (estimated creatinine clearance > 50); known cardiac ejection fraction of > or = 45% within the past 3 months; and platelet count </=30,000.
* ECOG performance status of </= 2.
* A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial.
* Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol.

Exclusion Criteria:

* Patients with a diagnosis of T-cell prolymphocytic leukemia (T-PLL) will be eligible (both treatment naïve and relapsed patients are eligible).
* Age >/= 18 years.
* Patients must not have had chemotherapy or antibody therapy for 7 days prior to starting ITACITINIB. However, patients with rapidly proliferative disease may receive hydroxyurea or decadron until 24 hours prior to starting therapy on this protocol.
* Adequate organ function as defined below: liver function (bilirubin </=2mg/dL, AST and ALT </=3 x ULN or </=5 x ULN if related to leukemic involvement); kidney function (estimated creatinine clearance > 50); known cardiac ejection fraction of > or = 45% within the past 3 months; and platelet count </=30,000.
* ECOG performance status of </= 2.
* A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial.
* Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol.

• Results publication: Kadia TM, Jain A, Rausch CR, Bataller A, Ravandi F, Jabbour E, Qiao W, Borthakur G, Short N, Montalban-Bravo G, Quesada AE, Burger J, Ferrajoli A, Wierda W, Hosing C, Kantarjian H. Phase 1B pilot study of itacitinib with alemtuzumab in patients with T-cell prolymphocytic leukemia. Blood Neoplasia. 2025 Oct 24;3(1):100175. doi: 10.1016/j.bneo.2025.100175. eCollection 2026 Feb. PMID 41536780

• Tapan M Kadia, Principal investigator, M.D. Anderson Cancer Center