A Phase I/II clinical trial using a fractionated dosing regimen of 90Y-epratuzumab
(anti-CD22) has showed encouraging responses in follicular and aggressive NHL with an ability
to administer safely 2 injections of 20 mCi/m2 spaced 1 week apart. The investigators propose
to combine this active 90Y-epratuzumab treatment with a regimen of veltuzumab that was also
found active in Phase I/II trials.
The goal of this study is to determine the safety and efficacy of 90Y-epratuzumab when used
in combination with veltuzumab. The primary objective is to determine the response rate of
this combination treatment. Secondary objectives are to assess safety, pharmacokinetics and
targeting of 90Y-epratuzumab . Veltuzumab blood levels and anti-antibody responses will also
be monitored at various times.
The treatment regimen consists of 2 elements. The first element is represented by one courses
of veltuzumab (4 weekly injections of 200 mg/m2). 90Y-epratuzumab will be given as 2
injections at escalating doses 1 week apart and administered starting one week following the
4th veltuzumab injection.
After confirming eligibility and undergoing baseline assessments, the treatment starts with
an imaging study using 111In-epratuzumab (5-mCi 111In-DOTA-epratuzumab co-infused with a
total of 1.5 mg/kg unlabeled epratuzumab). Blood samples (~7 samples, 5 mL each) for
pharmacokinetic analysis will be collected over 5-7 days, and patients will be imaged on 4
separate occasions (e.g., the day of injection (Day 0), Day 1, Day 3, 4, or 5, and day 6 or
7).
The patient will then initiate veltuzumab treatments starting 7 days after the
111In-epratuzumab injection. Veltuzumab is given in 4 weekly doses, each 200 mg/m2. A single
blood sample will be taken before each veltuzumab dose to assess residual veltuzumab
concentrations in the serum, and then at 1 h later to determine peak values. Patients will
receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30
minutes. Patients will also receive 111In-epratuzumab immediately following the unlabeled
epratuzumab. Blood samples will be collected at the same intervals as after the first
111In-epratuzumab. Only 2 imaging sessions will be required, on Day 1 and then again on day 6
or 7 (these days should match those obtained after the first 111In-epratuzumab injection).
The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection.
Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused
over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be
escalated by patient cohort starting at 2x15 mCi/m2 and, at 2x 20 mCi/m2, and 2x 25 mCi/m2..
Blood samples will be collected at the same intervals as after each
111In-epratuzumab.Patients will also receive 111In-epratuzumab immediately following the
unlabeled epratuzumab and immediately before the 90Y-epratuzumab injection. Blood samples
will be collected at the same intervals as after the first 111In-epratuzumab. Only 2 imaging
sessions will be required, on Day 1 and then again on day 6 or 7 (these days should match
those obtained after the first 111In-epratuzumab injection).
The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first
90Y-epratuzumab dose. CBC will be checked prior to administration of this second dose to
ensure blood counts continue to meet criteria for treatment as specified in inclusion
criteria. Blood samples will again be collected over the same period as the first injection,
but no imaging studies are required.
Patients are closely monitored during all infusions, and then at intervals over a 12-weeks
post-treatment evaluation period, with evaluation procedures including vital signs, physical
examination, CT (chest, abdomen, pelvis, other regions of involvement), CBC, serum
chemistries, serum immunoglobulins, urinalysis, peripheral blood B-cell levels
(immunophenotyping based on CD19), and serum samples for HAHA (veltuzumab and epratuzumab
ELISA to be analyzed by Immunomedics). Follow-up evaluations then continue every 3 months for
up to 5 years or until progression occurs or until resolution of treatment-related toxicity.
Inclusion Criteria:
- Male or female, >18 years old
- Histological diagnosis of CD20+ Follicular lymphoma by WHO lymphoma criteria.
- FLIPI intermediate or high risk (2-5 risk factors)
- No prior systemic treatment for NHL
- Measurable disease by CT, with at least one lesion >1.5 cm in one dimension
- Life expectancy of at least 6 months
- ECOG performance status > = 2
- Patients must have normal organ and marrow function as defined below:
- ANC > = 1,500/uL
- platelets > = 100,000/uL
- total bilirubin < = 1.5 x upper limit of normal
- AST(SGOT)/ALT(SGPT) < = 2.5 X upper limit of normal
- creatinine < = 1.5 x upper limit of normal
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Pregnant or lactating women. Women of childbearing potential are required to have a
negative pregnancy test
- Women of childbearing potential and fertile men who are not practicing or who are
unwilling to practice birth control while enrolled in the study until at least 12
weeks after the last weekly veltuzumab infusion.
- Primary CNS lymphoma, HIV lymphoma or transformed lymphoma, or presence of symptomatic
CNS metastases or carcinomatous meningitis.
- Bulky disease by CT, defined as any single mass >10 cm in its greatest diameter
- Disease status eligible for potentially curative external beam radiation (stage 1 or
contiguous stage 2 at sites appropriate for radiotherapy)
- Bone marrow involvement ≥25%; patients with CLL
- Pleural effusion with positive cytology for lymphoma
- Patients known to be HIV positive or hepatitis B positive
- Corticosteroid use within 2 weeks, unless 20 mg/day or less at stable dose.
- Prior malignancy with less than a 1-year disease-free interval, excluding non-melanoma
skin cancers and carcinoma in situ of the cervix.
- Other concurrent medical or psychiatric conditions that, in the Investigator's
opinion, may be likely to confound study interpretation or prevent completion of study
procedures and follow-up examinations
