Phase IIa Study of Addition of Itacitinib With Tacrolimus/Sirolimus Regimen for GVHD Prophylaxis in Fludarabine and Melphalan Non-Myeloablative Conditioning Hematopoietic Cell Transplantation for Acute Leukemias, MDS or MF
Overview
- Phase
- Phase 2
- Intervention
- Fludarabine
- Conditions
- Acute Leukemia
- Sponsor
- City of Hope Medical Center
- Enrollment
- 59
- Locations
- 1
- Primary Endpoint
- Graft-versus-host Disease Free Relapse Free (GRFS) at 1 Year
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This phase IIa trial studies the side effects of itacitinib when given together with standard treatment (tacrolimus and sirolimus), and to see how well it works in preventing graft-versus-host-disease (GVHD) in patients with acute leukemia, myelodysplastic syndrome or myelofibrosis who are undergoing reduced intensity conditioning donor stem cell transplantation. GVHD is a common complication after donor stem cell transplantation, resulting from donor immune cells recognizing recipients' cells and attacking them. Adding itacitinib to tacrolimus and sirolimus may reduce the risk GVHD and ultimately improve overall outcome and survival after donor stem cell transplantation.
Detailed Description
PRIMARY OBJECTIVE: I. Following a patient safety lead-in, estimate graft-versus-host disease free relapse free (GRFS) survival at 1- year post allogeneic stem cell transplantation (alloHCT). SECONDARY OBJECTIVES: I. Estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and non-relapse mortality (NRM) at 100-days post-transplant. II. Estimate the cumulative incidence of chronic GVHD at 1- and 2-years post-transplant. III. Estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years post-transplant. IV. Estimate rate of infection and development of second malignancies including lymphoproliferative disorders at 1- and 2-years post-transplant. V. Assess patients' quality of life (QOL) at day 100 and 1 year post alloHCT. EXPLORATORY OBJECTIVES: I. Characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by cell count and flow cytometry of lymphocyte subsets. II. Characterize changes in aGVHD biomarkers (Reg-3alpha, TNF-RI, and ST2) and a composite biomarker panel (IL2Ralpha, TNF-R1, IL-8, and hepatocyte growth factor), JAK-regulated pro-inflammatory cytokines (i.e., IL-6, TNFalpha, CRP, Beta2 Microglobulin, and IFNgamma) and STAT3 phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade. OUTLINE: REDUCED INTENSITY CONDITIONING (RIC): Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT): Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib orally (PO) once daily (QD) beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus intravenously (IV) or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years post- transplantation.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Documented informed consent of the participant and/or legally authorized representative
- •Assent, when appropriate, will be obtained per institutional guidelines
- •Agreement to allow the use of archival tissue from diagnostic tumor biopsies
- •If unavailable, exceptions may be granted with study principal investigator (PI) approval
- •Performance status: Karnofsky \>= 70%
- •Patients with neoplastic hematologic disorders with indication of allogeneic transplant according to the standard guidelines as follows:
- •Acute leukemia (AL) in first complete response (CR1) or subsequent complete response (CR) or active disease with bone marrow (BM) blast of \< 5%
- •Myelodysplastic syndrome (MDS) with intermediate-2 or high risk per International Prognostic Scoring System (IPSS) or
- •Myelofibrosis; primary or secondary if intermediate-2 or high risk per Dynamic International Prognostic Scoring System (DIPPS)
- •All candidates for this study must have a matched related donor (MRD) who is willing to donate BM or peripheral blood stem cells or an 8/8 allele matched unrelated donor (MUD)
Exclusion Criteria
- •Chemotherapy, radiation therapy, biological therapy, and/or immunotherapy within 21 days prior to day 1 of protocol therapy
- •Note: Conditioning regimen within 21 days prior to day 1 of protocol therapy is not considered as an exclusion criterion
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
- •Psychological issues, no appropriate caregivers identified, or non-compliant to medication
- •Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of the attending physician)
- •Active diarrhea due to inflammatory bowel disease or malabsorption syndrome
- •Clinically significant uncontrolled illness
- •Active, uncontrolled systemic infection (bacterial, viral, or fungal) requiring antibiotics
- •Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
- •Diagnosis of Gilbert's disease
Arms & Interventions
Treatment (itacitinib adipate, tacrolimus, sirolimus)
RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.
Intervention: Fludarabine
Treatment (itacitinib adipate, tacrolimus, sirolimus)
RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.
Intervention: Itacitinib Adipate
Treatment (itacitinib adipate, tacrolimus, sirolimus)
RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.
Intervention: Melphalan
Treatment (itacitinib adipate, tacrolimus, sirolimus)
RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Treatment (itacitinib adipate, tacrolimus, sirolimus)
RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.
Intervention: Questionnaire Administration
Treatment (itacitinib adipate, tacrolimus, sirolimus)
RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.
Intervention: Sirolimus
Treatment (itacitinib adipate, tacrolimus, sirolimus)
RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.
Intervention: Tacrolimus
Outcomes
Primary Outcomes
Graft-versus-host Disease Free Relapse Free (GRFS) at 1 Year
Time Frame: From the date of transplantation to the first time of observing following events: grade 3-4 acute graft versus host disease (GVHD), chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first, assessed at 1 year post transplant.
GRFS is defined as time from the date of transplantation to the first time of observing following events: grade 3-4 acute graft versus host disease (GVHD), chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first. Kaplan-Meier curve will be generated for GRFS.
Secondary Outcomes
- Cumulative Incidence of Grade II-IV Acute GVHD(From day 0 (date of stem cell infusion) through 100 days post-transplant)
- Progression Free Survival (PFS)(From the date of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, whichever occurs first, assessed at 1 year post transplant)