AML, CML, MDS
Conditions
Keywords
interleukin-7, immune based therapies, graft vs host disease, immune reconstitution, infection, lymphopenia, hematopoetic stem cell transplantation, bone marrow transplantation, peripheral blood stem cell transplant, immunosuppression
Brief summary
This is a phase I inter-patient dose escalation open labeled study assessing multiple doses of CYT107 in patients of at least 15 years of age, who are recipients of HLA matched ex vivo T cell depleted bone marrow or peripheral blood stem transplants. The dose escalation design is aimed at establishing the absence of significant toxicity and to define a biologically active dose in this patient population. At each dose level, eligible patients will receive 3 doses of CYT107 injected subcutaneously (under the skin of the arm, legs, or stomach) once a week for 3 weeks. Groups of three patients will be entered at each dose level of CYT107. Three dose levels are planned: 10 mcg/kg/week, 20 mcg/kg/week and 30 mcg/kg/week. Three patients must complete day 42 of the study at a dose level without a dose limiting toxicity (DLT) before there is escalation to the next dose level.
Detailed description
Rationale: Delayed and deficient reconstitution of T cells and their functions are a major obstacle to the success of a hematopoietic stem cell transplant (HSCT). CYT-107 may have potential clinical use after allogeneic HSCT to enhance lymphoid reconstitution which could have a number of beneficial effects including decreased morbidity and mortality from post-transplant infections. Our preliminary data with a previous generation IL-7, CYT 99 007, raise the possibility that IL-7 could have, in some cases, an anti-GVHD effect while keeping the anti-tumor effect of the allograft intact. Primary Objective: * To determine the safety and a recommended dose of CYT107 (r-hIL-7) in recipients of an HLA-matched related or unrelated ex vivo T-cell-depleted bone marrow (BM) or peripheral blood stem cell (PBSC) transplant after initial engraftment and hematopoietic reconstitution. * If toxicities are encountered, to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Secondary Objectives: * To define the pharmacokinetics of escalating doses of CYT107 in recipients of allogeneic transplants. To achieve preliminary characterization: * Of the effects of CYT107 treatment on engraftment and GVHD. * Of the effects of CYT107 on the recovery of T, NK and B cell populations and their functions in vitro. * Of a tolerable biologically active range of doses for CYT107 in recipients of allogeneic transplants. * Whether and to what degree administration of CYT107 might influence the risk of developing an EBV-lymphoproliferative disorder. * Of the effects of CYT107 treatment on leukemia relapse.
Interventions
DRUGCYT107 - Recombinant glycosylated human interleukin 7.
Patients will be treated with CYT107 60 to 210 days post transplantation, in 3 successive cohorts of 3 patients. Escalating doses of CYT107 will be given to successive cohorts. Patients will receive 1 dose of CYT107 by the subcutaneous route, once a week for 3 weeks. Dose level 1: 10 mcg/kg/dose for 3 doses; Dose level II: 20 mcg/kg/dose for 3 doses; Dose level III: 30 mcg/kg/dose for 3 doses. Only 1 treatment course for this initial study.
DRUGrhIL-7 (CYT107)
10, 20, or 30 mcg/kg once a week for 3 consecutive weeks via the subcutaneous route.
Sponsors
Cytheris, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able to read consent form and give informed consent. * At least 15 years old. * Histologically confirmed non-lymphoid hematological malignancy. * Recipient of T cell depleted bone marrow (BM) or peripheral blood stem cell (PBSC) transplant from a 6/6 HLA (A, B, DR by intermediate resolution) identical related or unrelated donor after myeloablative conditioning. * Received TCD HCT containing \< 1x105 CD3+ T cells/kg of recipient. * Patient included in at least one of the following categories: * AML in 2nd or greater complete remission. * High-risk AML (high-risk cytogenetics, undifferentiated leukemia, secondary AML, antecedent MDS) in 1st remission. * CML in 2nd or greater chronic phase, 2nd or greater accelerated phase. * MDS intermediate or high risk by IPSS criteria. * History of opportunistic infection (CMV viremia requiring anti-viral therapy, PCP pneumonia, mycobacterial infection, herpes zoster, viral respiratory infection (influenza, RSV, para-influenza), etc. * CD4+ T cell count \< 100 at 6 months post-transplant. * At high risk for opportunistic infection (e.g., history of treated invasive fungal infection prior to the transplantation, positive CMV serology in patient, or positive toxoplasmosis serology in donor and patient, etc.). * 60 - 210 days post transplant. * In remission at the time of initiation of CYT107. * Documented engraftment with sustained neutrophil counts of at least 1000/mcl and untransfused platelet counts \> 20 000/mcl for 3 consecutive lab values (the last one tested \<10 days before initiation of treatment) on 3 different days prior to treatment. Patients who have engrafted but require G-CSF for myelosuppressive antibiotics or antiviral medications are eligible if they require G-CSF no more than twice weekly and their ANC remains \>1000/mcl. * KPS \> 60%. * Adequate organ function: * Cardiac: No evidence of change in cardiac function by history, exam and/or EKG post-HCT. * Pulmonary: Absence of dyspnea or hypoxia (\< 90% of saturation by pulse oxymetry on room air). * Hepatic: Bilirubin \<= 1.5 X ULN, AST (SGOT) and /or ALT (SGPT) \<= 2.5 X ULN. PT/PTT \< 1.5 X ULN. * Renal: Calculated Creatinine clearance \> 60 mL/min/1.73 m2. \[Note: all transplant patients had an ejection fraction of \> 40% on their pre-transplant echocardiogram and a DLCO \> 50% of predicted (corrected for hemoglobin)\]
Exclusion criteria
* No evidence or history of acute GVHD or of chronic GVHD. * No recurrent leukemia post HCT. * No active uncontrolled viral, bacterial or fungal infection. * No documented HIV-1 or -2, HBV or HCV infection at any time before or after transplant (a positive hepatitis B serology indicative of a previous immunization is not an
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Toxicity of CYT107 in post-transplant patients with AML, CML and MDS using the NCI Common Toxicity Criteria version 3.0 with the BMT specific adverse event grading system. | Visits: 2 week screening period; treatment visits on days 0, 7, and 14; non-treatment visits on Days 1, 21, 28, 42, 56, and 77. |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetics and Pharmacodynamics | Study days 0, 1, 7, 14, 21, 28, 42, and 77. |
Countries
United States
Outcome results
None listed