Safety Study of IL-7 in Recipients of a Hemopoietic Stem Cell Transplant Peripheral Blood Stem Cell Transplant

A Phase I Study of CYT107 (Recombinant Glycosylated Human IL-7) in Recipients of HLA Matched Ex Vivo T Cell Depleted Bone Marrow or Peripheral Blood Stem Cell Transplant

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.

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.

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 exclusion criteria).
• Not be receiving systemic corticosteroid, anti-mitotic agent or other immunosuppressive treatment.
• Not receiving Growth Hormone or gonadotropin agonists/ antagonists.
• Not receiving any cytokine support other than G-CSF post-HCT.
• Not receiving concurrent treatment with another investigational drug and/or biological agent.
• Not receiving anticoagulant therapy.
• No uncontrolled hypertension.
• No history of lymphoid malignancy (e.g. Hodgkin disease, non Hodgkin lymphoma, Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia) or acute biphenotypic leukemia.
• No peripheral lymphadenopathy (any lymph node > 1 cm).
• No history of EBV associated lymphoproliferation.
• No EBV viremia equal to or greater than 500 copies EBV DNA/mL of blood by quantitative PCR.
• No history of autoimmune disease nor a HCT donor with a history of an autoimmune disease.
• Fertile patients must use effective birth control. Not pregnant or nursing. Negative pregnancy test within 2 weeks of study treatment.
• QTc prolongation (QTc > 470 ms) or prior history of significant arrhythmia or ECG abnormalities.
• No active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
• Any past or current psychiatric illness that, in the opinion of the investigator, would interfere with adherence to study requirements or the ability and willingness to give written informed consent.