A Safety Study in Patients With Chronic Lymphocytic Leukemia
A Safety Study in Patients With Chronic Lymphocytic Leukemia
This is an open-label, dose-escalation study to determine the tolerability, safety profile,
 and antitumor activity of SGN-40 in patients with CLL. All patients will receive dose
 escalation during the first two weeks regardless of cohort designation.
A minimum of three patients will be entered into each dose-level cohort for five weeks.
 Escalation to the next cohort will occur when three patients have received at least one
 infusion at the highest scheduled dose level, and at least one patient has completed the
 entire five week dosing schedule. Cohorts will be enrolled at a maximal dose level of 3, 4,
 6, or 8 mg/kg/week. Initial therapy will last for 5 weeks. Responding patients will receive
 additional infusions every two weeks x 4 at the maximal dose for each specific cohort.
Inclusion Criteria:

 1. Patients must have a histologic diagnosis of CLL as defined by the WHO criteria and
 exhibit active disease requiring treatment as per the NCI working group on CLL.

 2. Patients must have a fresh tumor specimen available (peripheral blood or bone marrow)
 for flow cytometry evaluation (e.g. CD40, CD38, CD20, CD19, and CD5).For the phase 2
 portion of the study, CD40 expression on malignant cells must be confirmed prior to
 registration.

 3. Patients must have relapsed after receiving at least one fludarabine containing
 regimen or an equivalent purine analog.

 At study start patients must be at least 8 weeks or 5 plasma half-lives (whichever is
 greater) from prior chemotherapy/radiation/investigational agents, 8 weeks from prior
 antibody therapy and 6 months from autologous stem cell transplant.

 4. Patients must have an ECOG performance status ≤ 2 and a life expectancy > 3 months.

 5. Patients must have the following required baseline laboratory data:

 -  Platelet count ≥ 50,000/mm3 (may be maintained by transfusion)

 -  Hemoglobin ≥ 7.5 g/dL (may be maintained by transfusions or growth factors)

 -  Absolute neutrophil count ≥ 1,000/mm3 (may be maintained by growth factors)

 -  ALT/AST ≤ 2.0 times ULN

 -  Total bilirubin ≤ 2.0 times ULN (unless related to hemolysis)

 -  Creatinine < 2.0 times ULN

 6. Females of childbearing potential must have a negative B-hCG pregnancy test result
 within 3 days prior to the first dose and must agree to use an effective contraceptive
 method during the course of the study and for 6 months following the last dose of
 study drug.

 7. If a deep venous thrombosis or other vascular event has required medical or surgical
 intervention in the past year, patients must either: a) be on a stable dose of
 anticoagulant therapy (i.e., Coumadin and/or Heparin) for at least three weeks or b)
 have completed anticoagulant therapy at least three months prior to registration with
 radiographic confirmation that thrombosis is resolved. Prophylactic anticoagulant
 therapy for indwelling catheters is acceptable.

 8. Patients must be at least 18 years of age.

 9. Patients must be available for periodic blood sampling, study-related assessments, and
 management of toxicity at the treating institution.

 10. Patients must give written informed consent. A copy of the signed informed consent
 form will be retained by the treating institution.

 Exclusion Criteria:

 1. Patients who have been treated previously with any anti-CD40 antibody.

 2. Patients with a documented history within 6 months of registration of a cerebral
 vascular event (stroke or TIA), unstable angina, or myocardial infarction.

 3. Patients with active CNS or leptomeningeal disease.

 4. Patients who have received allogeneic stem cell transplant.

 5. Patients who have had major surgery within four weeks prior to enrollment.

 6. Patients with a known hypersensitivity to recombinant proteins or any excipient
 contained in the drug formulation.

 7. Patients with a history of another primary malignancy that has not been in remission
 for at least 5 years (non-melanoma skin cancer and cervical carcinoma in situ on
 biopsy or a squamous intraepithelial lesion on PAP smear are exempt from the five year
 limit).

 8. Patients with any systemic viral, bacterial, or fungal infection that has required
 antibiotic therapy within four weeks prior to enrollment. Prophylactic antibiotics and
 antiviral therapy are permitted prior to registration and are required during the
 study period (e.g. Bactrim, acyclovir).

 9. Patients with known HIV, hepatitis B (by surface antigen expression), or active
 hepatitis C infection.

 10. Patients on systemic steroids who have not been on a stable daily dose during the four
 weeks immediately prior to first dose of SGN-40. Maximum steroid dose is 10 mg
 prednisone per day or equivalent.

 11. Patients with a history of migraines or severe headaches requiring medical therapy
 (other than occasional acetaminophen, aspirin, or non-steroidal anti-inflammatory
 drugs) within 12 months of enrollment.

 12. Patients who are pregnant or breastfeeding.

 13. Patients with any serious underlying medical condition that would impair their ability
 to receive or tolerate the planned treatment.

 14. Patients with dementia or altered mental status that would preclude the understanding
 and/or rendering of informed consent.