MORAb-004 in Treating Young Patients With Recurrent or Refractory Solid Tumors or Lymphoma

Study of the TEM-1 Antibody, MORAb-004 (IND# 103821), in Children With Recurrent or Refractory Solid Tumors

This phase I trial studies the side effects and best dose of MORAb-004 in treating young patients with recurrent or refractory solid tumors or lymphoma. Monoclonal antibodies, such as MORAb-004, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of MORAb-004 (anti-endosialin/TEM1 monoclonal antibody MORAb-004) administered as an intravenous infusion every week to children with refractory solid tumors.

II. To define and describe the toxicities of MORAb-004 administered on this schedule.

III. To characterize the pharmacokinetics of MORAb-004 in children with refractory cancer.

IV. To monitor for the development of human anti-human antibody (HAHA) in children receiving MORAb-004.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of MORAb-004 within the confines of a phase 1 study.

II. To examine tumor endothelial marker-1 (TEM-1) and PDGFRB levels in tissue and plasma samples as potential biomarkers of MORAb-004 activity.

III. To correlate baseline expression of TEM-1 and PDGFRB (in issue and plasma)with clinical parameters including disease response in an exploratory manner.

OUTLINE: This is a dose escalation study.

Patients receive anti-endosialin/TEM1 monoclonal antibody MORAb-004 intravenously (IV) on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

• Patients with relapsed or refractory solid tumors or lymphoma, excluding central nervous system (CNS) tumors, are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse; (patients with primary CNS tumors, known CNS metastases, or a prior history of CNS metastases are not eligible)

• Patients must have either measurable or evaluable disease

• Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life

• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy

• At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)

• At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair

• At least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair

• At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines

• At least 3 half-lives of the antibody after the last dose of a monoclonal antibody

• At least 14 days after local palliative radiotherapy (XRT) (small port); at least 150 days must have elapsed if prior total-body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation

• No evidence of active graft vs. host disease and at least 56 days must have elapsed after transplant or stem cell infusion

• For patients with solid tumors without known bone marrow involvement:

• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

• For patients with known bone marrow metastatic disease:

• ANC >= 750/mm^3

• Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

• Patients with known bone marrow metastatic disease will not be evaluable for hematologic toxicity; these patients must not be known to be refractory to red cell or platelet transfusion; at least 5 of every cohort of 6 patients with a solid tumor or lymphoma must be evaluable for hematologic toxicity; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

  • =< 0.6 mg/dL for patients age 1 to < 2 years
  • =< 0.8 mg/dL for patients age 2 to < 6 years
  • =< 1 mg/dL for patients age 6 to 10 2 years
  • =< 1.2 mg/dL for patients age 10 to < 13 years
  • =< 1.4 mg/dL for female patients age >= 13 years
  • =< 1.5 mg/dL for male patients age 13 to < 16 years
  • =< 1.7 mg/dL for male patients age >= 16 years

• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

• Serum albumin >= 2 g/dL

• Activated partial thromboplastin time (aPTT) and prothrombin time (PT) =< 1.5 x ULN

• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

• Tissue blocks or slides must be sent per Section 8.5. If tissue blocks or slides are unavailable, the study chair must be notified prior to enrollment.

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method

• Patients receiving chronic systemic corticosteroids are not eligible

• Patients who are currently receiving another investigation drug are not eligible

• Patients who are currently receiving other anti-cancer agents are not eligible

• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial

• Patients who have known human immunodeficiency virus (HIV), viral hepatitis, or an uncontrolled infection are not eligible

• Patients with primary CNS tumors are excluded

• Patients with prior history of or known metastatic CNS disease involvement are excluded; (Note: CNS imaging for patients without a known history of CNS disease is only required if clinically indicated)

• Patients who have had or are planning to have the following invasive procedures are not eligible:

  • Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to enrollment
  • Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 3 days prior to enrollment for external lines (e.g. Hickman or Broviac) and at least 7 days prior to enrollment for subcutaneous port
  • Core biopsy within 7 days prior to enrollment
  • Fine needle aspirate within 7 days prior to enrollment

• Patients who have received prior solid organ transplantation are not eligible

• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

• Patients with history of clinically significant bleeding risk (including evidence of active bleeding: intratumoral hemorrhage by current imaging, or bleeding diathesis; bleeding/coagulation disorder; active fracture; non-healing wound; and active gastric ulcer) are not eligible