Phase I/II Trial of Yttrium-90-labeled Daclizumab (Anti-CD25) Radioimmunotherapy With High-dose BEAM Chemotherapy and Autologous Hematopoietic Stem Cell Rescue in Recurrent and Refractory Hodgkin's Lymphoma
- Although Hodgkin's lymphoma (HL) is considered a highly treatable cancer, patients with
relapsed and chemotherapy refractory disease represent a major therapeutic challenge.
- Only 30-65% of relapsed patients will achieve long-term disease free survival with the
current standard of care high-dose chemotherapy with autologous hematopoietic stem cell
- The malignant Reed-Sternberg cells of HL and the surrounding benign T cell
infiltrates often express CD25, the high affinity interleukin-2 receptor (IL-2R alpha).
- In study NCI-97-C-0110, we treated 30 patients with CD25-expressing relapsed or
refractory HL with radioimmunotherapy (RIT) using (90)Y-labeled daclizumab (anti-CD25),
and achieved a 63% response rate including 12 complete responses with few serious
adverse events other than MDS in 4 patients.
- We propose integrating (90)Y-labeled daclizumab RIT into the induction regimen of ASCT
in an effort to improve the response and disease-free survival in relapsed and
Phase I Primary Objectives:
- To assess the safety and adverse events associated with (90)Y-daclizumab (humanized
anti-CD25) radioimmunotherapy (RIT) in combination with high-dose BEAM (carmustine,
etoposide, cytarabine, [Ara-C, cytosine arabinoside] and melphalan) chemotherapy and
autologous hematopoietic stem cell transplantation (ASCT) in patients with relapsed or
refractory Hodgkin's lymphoma (HL) with adverse prognostic factors.
- To determine the maximum tolerated dose in mCi of (90)Y-daclizumab RIT in combination
with high-dose BEAM chemotherapy and ASCT in patients with relapsed or refractory HL.
Phase II Primary Objectives:
- To assess the frequency of the failure to engraft, myelodysplastic syndrome (MDS),
secondary leukemia for the development of abnormal bone-marrow cytogenetics in
refractory or relapsed HL patients treated with (90)Y-daclizumab RIT in combination
with high-dose BEAM chemotherapy and ASCT.
- To estimate the response rate (the number of complete and partial responses) in
patients with refractory or relapsed HD to (90)Y-daclizumab RIT administered in
combination with high-dose BEAM chemotherapy and ASCT.
- Patients must have a confirmed diagnosis of relapsed or refractory HL with at least 10%
of malignant Reed-Sternberg cells or infiltrating T-cells expressing CD25 (IL-2R
alpha). A. Patients must have at least one of the following: (1) had an initial relapse
less than 12 months after achieving a CR with primary chemotherapy for HL; (2) were
Staged at III/IV at diagnosis; (3) exhibited chemotherapy resistant disease or (4) did
not achieve a CR with cytoreductive chemotherapy prior to a planned transplant. B.
Patient must have a lesion of at least 1.0 cm in its greatest diameter. C. Patients
with lymphocyte predominant HL are excluded. D. Patients with pre-existing MDS or
marrow cytogenic abnormalities will not be eligible to participate.
- Omission of cytotoxic chemotherapy or other systemic therapy of HL for at least 4 weeks
prior to entry into the trial.
- No prior ASCT or allogeneic stem cell transplant.
- A single institution non-randomized open-label phase I/II trial.
- Patients will undergo peripheral blood stem cell (PBSC) mobilization with
granulocyte-colony stimulating factor (G-CSF, filgrastim) and Plerixafor followed by
apheresis to collect a target dose of 4 times 10(6) CD34 plus cells/kg (minimal dose of
2 times 10(6) CD34 plus cells/kg) of actual body weight.
- Phase I study will be carried out using a standard 3 plus 3 cohort dose-escalation
- Dose level 1: Patients will receive a single dose of 15 mCi (90)Y-daclizumab RIT
(day -15) followed by high-dose BEAM chemotherapy (beginning Day -6) and ASCT (Day
- Dose levels 2-7: Patients will receive two doses of (90)Y-daclizumab RIT 6 weeks
apart (Day -56 and -15) followed by high-dose BEAM chemotherapy (beginning day -6)
and ASCT (Day 0). The first dose of (90)Y-daclizumab will be fixed at 15 mCi. The
second dose will be escalated in 15 mCi increments from 15 mCi until maximum
tolerated dose, not to exceed 90 mCi.
- Phase II: All patients will receive two doses of (90)Y-daclizumab (Day -56 and -15)
followed by high-dose BEAM chemotherapy (beginning Day -6) and ASCT (Day 0). The first
dose of RIT will be 15 mCi. The second dose will be the maximum tolerated dose as
determined from phase I.
- (111)In-daclizumab (5 mCi) imaging will be performed concurrently with each
(90)Y-daclizumab RIT and at day 100 after ASCT.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Assess safety and adverse events assoc with 90Y-daclizumab radioimmunotherapy (RIT) in combination w/BEAM and ASCT.
Thomas A Waldmann, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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