Protocol Number: 08-C-0123

Title:

A Phase 1, Single Center, Dose Escalation Study of CAT-8015 in Children, Adolescents, and Young Adults with Refractory CD22+ Acute Lymphoblastic Leukemia (pALL) or Non-Hodgkin's Lymphoma (NHL)

Number:

08-C-0123

Summary:

Background:

-CAT-8015 is composed of a toxin and an antibody that combines with a protein called CD22 that is found on the surface of cancer cells. The drug is designed for the antibody to target the CD22 protein on the cancer cell and for the toxin to kill the cell.

-In animal studies, CAT-8015 has killed leukemia cells with the CD22 protein on their surface and decreased tumors in mice.

Objectives:

-To determine the highest safe dose of CAT-8015 in children and young adults.

-To learn how CAT-8015 is broken down in the body.

-To determine if CAT-8015 is effective in treating acute lymphocytic leukemia (ALL) and non-Hodgkin's lymphoma (NHL), including lymphoblastic lymphoma, Burkitt's lymphoma or large cell lymphoma.

Eligibility:

-Patients between 6 months and 25 years of age with ALL or NHL whose disease has not been cured by at least one course of standard chemotherapy and one salvage regimen.

-Patients' cancer cells must have the CD22 protein on their surface.

Design:

-In this dose escalation study, the first group of three to six patients receives the smallest study dose of CAT-8015. Subsequent small groups receive higher doses of the drug as long as the preceding group has not experienced unacceptable side effects. When the highest safe dose is determined, new patients enrolled in the study receive that dose.

-Patients receive CAT-8015 in 21-day treatment cycles. The drug is given through a vein in a 30-minute infusion on days 1, 3, 5, 7, 9 and 11 of each cycle.

-Patients with ALL also receive chemotherapy directly into the spinal fluid to lessen the risk that the disease will spread to the spine.

-Patients may receive up to 6 cycles of the treatment as long as their disease does not worsen and they do not develop severe side effects or make antibodies to the drug. They are followed up to 2 years after stopping treatment.

-Before each new cycle, patients have a physical examination, check of vital signs, blood draw, urine sample collection and disease evaluation. The evaluation may include CT or PET scan, bone marrow aspirate and/or biopsy, spinal tap and additional blood tests.

-When treatment ends, patients are seen in the clinic for followup at months 1, 3, 6, 12, 15, 18, 21 and 24. They are asked about their health and activity level and have a physical examination, blood tests and disease evaluation as detailed above.

-Patients have a final visit 3 months after the study ends or when they leave the study if they withdraw before it ends. This visit includes blood tests, vital signs and weight check, determination of activity level, electrocardiogram and pregnancy test for women who can become pregnant.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Subjects must meet all of the following criteria to be eligible to participate in the study:

Histologically confirmed diagnosis of acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) including lymphoblastic lymphoma, Burkitt's lymphoma, and large cell lymphoma.

Measurable or evaluable disease.

Evidence of CD22-positive malignancy by one of the following criteria:

- Greater than or equal to30% of malignant cells from a disease site CD22+ by FACS analysis or;

- Greater than or equal to 15 % of malignant cells from a disease site CD22+ by IHC.

Stage of disease:

- Patients must have relapsed or refractory disease and have received at least one standard chemotherapy and one salvage regimen.

- In the view of the PI and the primary oncologist, there must be no available alternative curative therapies and patients must either be ineligible for a hematopoietic stem cell transplant (BMT), have refused BMT, or have disease activity that prohibits the time required to identify a suitable stem cell donor.

- Relapse after prior autologous or allogeneic BMT is allowed. In the event of relapse after prior allogeneic BMT, the patient must be at least day +100 post-transplant and have no evidence of ongoing active graft-vs-host disease.

- Recovered from the acute toxic effects of all prior therapy before entry.

Performance status:

- Patients greater than or equal to12 years of age: ECOG score of 0, 1, 2, or 3.

- Patients less than 12 years of age: Lansky scale greater than or equal to 40%.

- Patients who are unable to walk because of paralysis, but who are up in a wheel chair will be considered ambulatory for the purpose of calculating the performance score.

Ability to give informed consent. For patients less than 18 years old their legal guardian must give informed consent. Pediatric patients will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 7 years of age.

Must be between the ages of greater than or equal to 6 months and less than 25 years.

Female and male patients with childbearing potential and their sexual partners must agree to use an approved method of contraception during the study.

EXCLUSION CRITERIA:

Subjects meeting any of the following criteria are not eligible for participation in the study:

Isolated testicular ALL.

Hepatic function:

- Inadequate liver function defined as total bilirubin greater than 2.0 mg/dl OR transaminases greater than 5 times the upper limit of normal (ALT and AST) based on age- and laboratory specific normal ranges.

Renal function:

- With greater than age-adjusted normal serum creatinine (see below) AND a creatinine clearance less than 60 mL/min/1.73 m(2).

Maximum Serum Creatinine (mg/dl)

- If age is less than or equal to 5, Maximum Serum Creatinine 0.8 mg/dl

- If age is 5, or less than or equal to10, Maximum Serum Creatinine 1.0 mg/dl

- If age is 10, or less than or equal to 15, Maximum Serum Creatinine 1.2 mg/dl

- If age is greater than 15, Maximum Serum Creatinine 1.5 mg/dl

Hematologic function:

For non-leukemic patients only, the ANC less than 1000/cmm, or platelet count less than 50,000/cmm, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy).

A patient will not be excluded because of pancytopenia greater than or equal to Grade 3 if it is due to disease, based on the results of bone marrow studies.

Central Nervous System (CNS) involvement by tumor (History of CNS involvement is not an exclusion criterion); CNS leukemia or lymphoma as manifested by any of the following:

- CSF WBC greater than 5/microliter and confirmation of CSF blasts.

- Cranial neuropathies deemed secondary to underlying malignancy.

- Radiologically detected CNS lymphoma.

Pregnant or breast-feeding females

Prior treatment with CAT-3888 (BL22) or any pseudomonas-exotoxin-containing compound.

Recent prior therapy:

- Systemic chemotherapy less than or equal to 2 weeks (6 weeks for nitrosoureas) and radiation therapy at less than or equal to 3 weeks prior to starting study drug.

Exceptions:

a. There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such.

b. Patients receiving corticosteroids or hydroxyurea are allowed provided there has been no increase in dose for at least 2 weeks prior to starting study drug.

c. For radiation therapy: the volume of bone marrow treated is less than 10% and also the patient has measurable disease outside the radiation port.

- Other investigational agents currently or within 30 days prior to entry.

- Less than or equal to 1 month prior monoclonal antibody therapy (e.g.rituximab).

HIV positive serology (due to increased risk of severe infection and unknown interaction of CAT-8015 with antiretroviral drugs).

Active hepatitis B or C infection as defined by seropositive for hepatitis B (HBsAg) or hepatitis C and elevated liver transaminases.

Uncontrolled, symptomatic, intercurrent illness including but not limited to: infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements.

Second malignancy other than non-basal cell carcinoma of the skin or in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and patient is in remission.

Special Instructions:

Currently Not Provided

Keywords:

Immunotoxin

Pediatric

Acute Lymphoblastic Leukemia

Non-Hodgkin's Lymphoma (NHL)

CD22+ Hematologic Malignancies

Recruitment Keyword(s):

Acute Lymphoblastic Leukemia

ALL

Non-Hodgkin Lymphoma

NHL

Childhood Acute Lymphoblastic Leukemia

Condition(s):

Acute Lymphoblastic Leukemia (ALL)

Non-Hodgkin's Lymphoma (NHL)

B-Precursor Acute Lymphoblastic Leukemia

Childhood Acute Lymphoblastic Leukemia

B-Lineage Non-Hodgkin's Lymphoma

Investigational Drug(s):

CAT-8015

Investigational Device(s):

None

Intervention(s):

Drug: CAT 8015

Drug: Anti-Cancer Agent

Drug: CAT-8015

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Law CL, Aruffo A, Chandran KA, Doty RT, Clark EA. Ig domains 1 and 2 of murine CD22 constitute the ligand-binding domain and bind multiple sialylated ligands expressed on B and T cells. J Immunol. 1995 Oct 1; 155(7):3368-76.

Tedder TF, Tuscano J, Sato S, Kehrl JH. CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Annu Rev Immunol. 1997;15:481-504. Review.

Tedder TF, Sato S, Poe JC, Fujimoto M. CD19 and CD22 regulate a B lymphocyte signal transduction pathway that contributes to autoimmunity. Keio J Med. 2000 Mar; 49(1):1-13.

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