Clinical Study of WT2725 in Patients With Advanced Malignancies

Part 1 Inclusion Criteria:

• Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0, 1, or 2
• Patient must have one of the following histologically or cytologically documented measurable (may be measureable by tumor markers only, such as quantitative RT-PCR for WT1 transcript for AML, or CA-125 for ovarian carcinoma) advanced stage malignancies: non-small cell lung, ovarian, glioblastoma, and AML (not including acute promyelocytic leukemia), known to overexpress the WT1 protein.
• Patient must qualify with a study specific HLA typing assay.
• Haematological parameters:
• Absolute neutrophil count (ANC) ≥ 1,000/μl
• Platelet count ≥ 10.0x10(to the 4th power)/μl (≥ 5.0 x 10(to 4th power)/μl after stem cell transplant)
• Hemoglobin ≥ 9.0 g/dL
• Absolute lymphocyte count (ALC) ≥ 1,000/μl (≥ 500/μl after stem cell transplant) Note: After completion of dose escalation, patients with AML are not required to meet these hematologic criteria.
• Biochemical Parameters:
• serum creatinine of ≤ 1.5x upper limit of normal (ULN) for the reference lab.
• total bilirubin of ≤ 2.0 mg/dl (≤ 3.0 mg/dl for patients with known Gilbert's syndrome)
• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the ULN for the reference lab
• Patient must have access to archival tumor tissue sample or agree to undergo biopsy after study eligibility has been confirmed to obtain fresh sample for evaluation of WT1 expression. In place of archival tumor tissue samples, subjects with AML should have available a bone marrow aspirate and/or, bone marrow biopsy, with PCR for WT1 transcript performed before the first dose of study drug.

Note: The archived tumor tissue sample does not need to be delivered to the clinical site prior to enrollment of the patient, however its availability should be confirmed through provision of the accession number or other identification number.

Patient Inclusion Criteria - Part 2:

• Patient or his or her legal representatives must give written informed consent and privacy authorization prior to participation in the study.
• Patient must be willing and able to comply with the study procedures and visit schedules and must be able to follow verbal and written instructions.
• Patient must be ≥ 18 years of age.
• Women of childbearing potential and men with female sexual partners of childbearing potential must agree to abstain from sexual intercourse or use a double barrier method to determine if a woman is of childbearing potential (http://www.nccn.org/professionals/physician_gls/f_guidelines.asp).
• Patient must have an ECOG Performance Score of 0, 1, or 2 (refer to Appendix II).
• Patient has a life expectancy of at least 4 months.
• Patient must have histologically or cytologically documented measurable (may be measurable by tumor markers only, such as quantitative RT-PCR for WT1 transcript for AML) advanced stage glioblastoma or AML (not including acute promyelocytic leukemia), known to overexpress the WT1 protein. Note: Determination of WT1 expression will not be assessed prior to patient enrollment.
• Patient must have an advanced stage malignancy defined as meeting at least one of the following criteria:
• progressed or recurred despite standard therapy
• no standard therapy exists
• patient is intolerant of standard therapy
• patient is not a candidate for standard therapy
• Patient must be HLA-A*0201+ and/or HLA-A*0206+
• Patient with glioblastoma must have adequate bone marrow and immune reserve, as documented by:
• ANC ≥ 1000/μl (≥ 500/μl after stem cell transplant)
• Platelet count ≥ 10.0 x 1(to the 4th power)/μl (≥ 5.0 x 10(to the 4th power)/μl after stem cell transplant)
• Hemoglobin ≥ 9.0 g/dL
• ALC ≥ 900/μl (Note: Patients with AML are not required to meet these hematologic criteria).
• Patient must have adequate renal function documented by a serum creatinine of ≤ 1.5 times the ULN for the reference lab.
• Patient must have adequate hepatic function documented by a total bilirubin of ≤ 2.0 mg/dl (≤ 3.0 mg/dl for patients with known Gilbert's syndrome) and ALT and AST ≤ 3 times the ULN for the reference lab.
• Patient must have access to archival tumor tissue sample or agree to undergo biopsy after study eligibility has been confirmed to obtain fresh sample for evaluation of WT1 expression. In place of archival tumor tissue samples, patients with AML should have available a bone marrow aspirate and/or bone marrow biopsy with PCR for WT1 transcript performed before the first dose of study drug.

Note: The archived tumor tissue sample does not need to be delivered to the clinical site prior to enrollment of the patient, however its availability should be confirmed through provision of the accession number or other identification number.

• Patients with AML must be willing to undergo bone marrow aspiration/biopsy during treatment if there are no other indicators of measureable disease.

Part 1 Exclusion Criteria:

• Patient with an extensively disseminated primary glioblastoma.
• Patient with symptomatic brain metastases, ie, not neurologically stable or requiring treatment with corticosteroids, or central nervous system (CNS) leukemia.
• Patient with an infection requiring treatment with systemic antibiotics or antiviral medication or has completed treatment for such an infection within 4 days prior to planned initial dose of WT2725.
• Patient requiring systemic, pharmacologic doses of corticosteroids (equivalent to > 60 mg hydrocortisone/day or 2 mg dexamethasone/day). Replacement doses (equivalent to ≤ 5 mg prednisone/day), and topical, ophthalmic, and inhalation steroids are permitted as needed.
• Patient has a positive test for Hepatitis B surface antigen, Hepatitis C antibody, human immunodeficiency virus (HIV)-1, or HIV-2 antibody, or has a history of a positive result.
• Patient has received any of the following treatments within the specified timeframe prior to dosing:
• endocrine therapy, immunotherapy, transfusion, hematopoietic factors within 14 days prior to planned first dose of study drug (Note: After completion of dose escalation, patients with AML are not required to meet these hematologic criteria, eg. transfusions and hematopoietic growth factors.)
• chemotherapy including molecular-targeting therapy within 21 days (for molecular-targeted agents that are not associated with myelosuppression or immunosuppression, the minimum interval is 5 half-lives if that is less than 21 days)
• surgery, radiation, or immunosuppressants within 28 days
• investigational drug within 28 days
• mitomycin-C or nitrosoureas within 42 days
• Patient with an unresolved ≥ Grade 2 AE from a previous antineoplastic treatment, excluding alopecia.
• Pregnant or lactating women
• Patient with an autoimmune condition
• Patients with serious unstable medical illness
• Patient with pleural effusion, ascites, or pericardial fluid requiring drainage.
• Patient is a staff member of the sponsor or clinical site and is involved in the conduct of the study or the relative of such a staff member.

Patient Exclusion Criteria - Part 2:

• Patient has an extensively disseminated primary glioblastoma.
• Patient has symptomatic brain metastases, ie, presence of neurological symptoms or requiring treatment with corticosteroids, or CNS leukemia.
• Patient has an infection and has had a body temperature of > 38.3˚C within 48 hours prior to planned first dose of study drug.
• Patient requires systemic, pharmacologic doses of corticosteroids (equivalent to > 60 mg hydrocortisone/day or 2 mg dexamethasone/day). Replacement doses (equivalent to ≤ 5 mg prednisone/day), and topical, ophthalmic, and inhalation steroids are permitted as needed.
• Patient has a positive test for Hepatitis B surface antigen, Hepatitis C antibody, HIV-1, or HIV-2 antibody, or has a history of a positive result.
• Patient has received any of the following treatments within the specified timeframe:
• endocrine therapy, immunotherapy, transfusion, or hematopoietic factors within 14 days prior to planned first dose of study drug (Note: Patients with AML are not required to meet these hematologic criteria, eg, transfusions and hematopoietic growth factors.),
• chemotherapy including molecular-targeting therapy within 21 days prior to planned first dose of study drug (for molecular-targeted agents that are notis 5 half-lives if that is less than 21 days),
• surgery, radiation, or immunosuppressants within 28 days prior to planned first dose of study drug,
• investigational drug within the 28 days prior to planned first dose of study drug, or
• mitomycin-C or nitrosoureas within 42 days prior to planned first dose of study drug.

Note: Patients receiving LHRH agonists or antagonists or antiestrogens or aromatase inhibitors started and at a stable dose for at least 90 days prior to planned first dose of study drug are eligible. Patients are permitted one 28 day cycle of concurrent treatment with hydroxyurea during the study.

• Patient has an unresolved ≥ Grade 2 AE from a previous antineoplastic treatment, excluding alopecia.
• Woman who is pregnant or lactating or has a positive pregnancy test at screening. If a woman has a positive pregnancy test, further evaluation may be conducted to rule out ongoing pregnancy to allow the patient to be eligible.
• Patient has an autoimmune condition, including, but not limited to, multiple sclerosis, Grave's disease, vasculitis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, myasthenia gravis, ankylosing spondylitis, Wegener's granulomatosis, ulcerative colitis, Crohn's disease, psoriasis requiring systemic therapy, pemphigus, temporal arteritis, dermatomyositis, Sjögren's syndrome, Goodpasture's syndrome, interstitial pneumonitis, interstitial nephritis, or Henoch-Schönlein purpura.
• Patient has in the opinion of the investigator any intercurrent conditions that could preclude their participation in the study, pose an undue medical hazard, or that could interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (NYHA Class III or IV; refer to Appendix III), unstable angina, cardiac arrhythmia requiring treatment, recent (within the prior 6 months) myocardial infarction, acute coronary syndrome or stroke, severe obstructive pulmonary disease, hypertension requiring more than2 medications for adequate control, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 12 months.
• Patient has pleural effusion, ascites, or pericardial fluid requiring drainage. Note: Patient who had drain removal ≥ 14 days prior to planned first dose of study drug and has no sign of worsening is eligible.
• Patient has any other medical, psychiatric, or social condition, including substance abuse that in the opinion of the investigator would preclude participation in the study.
• Patient has had previous treatment with the study drug or other WT1-related vaccine therapy.
• Patient has a known hypersensitivity to any of the components of the study drug.
• Patient is a staff member of the sponsor or clinical site and is involved in the conduct of the study or the relative of such a staff member