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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


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Hodgkin Disease, Hodgkin Lymphoma

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Trial Information

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


Background:

- 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
transplant (ASCT).

- 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
refractory HL.

Objectives:

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.

Eligibility:

- 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.

Design:

- 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
design:

- 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
0).

- 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.

Inclusion Criteria


- INCLUSION CRITERIA:

2.1.1.1 All patients must have a pathologically confirmed diagnosis of classical Hodgkin's
lymphoma (HL) as outlined in the WHO Classification System of Lymphoid Tumours. Patients
with nodular lymphocyte-predominant HL (NLPHL) are not eligible.

2.1.1.2 Refractory or relapsed HL patients that are also candidates for ASCT.

2.1.1.3 At least one adverse prognostic factor: (1) initial relapse less than or equal to
12 months after primary chemotherapy, (2) staged as Ann Arbor Classification initial stage
III or IV disease, (3) chemotherapy resistant disease, (4) Failure to achieve a complete
response (CR) with cytoreductive chemotherapy or persistent positive (18)FDGPET imaging.

2.1.1.4 At least 10% of the cells obtained from lymph node, or extranodal sites must react
with anti-CD25 (anti-Tac) on immunofluorescent or immunoperoxidase staining. Because of
the high frequency of CD25 positivity of the infiltrating Tcells in HL tumors, patients
with CD25-positive infiltrating T cells will be eligible even if their Hodgkin's
(Reed-Sternberg) cells are CD25-negative.

2.1.1.5 Measurable disease as defined by the Cheson Response Criteria for Malignant
Lymphoma detailed in section 6.2 with at least one lesion greater than or equal to 1.0 cm
in longest diameter by CT scan.

2.1.1.6 Omission of cytotoxic chemotherapy or other systemic therapy of the malignancy for
greater than or equal to 4 weeks prior to entry into the trial. Patients must be greater
than or equal to 4 weeks since major surgery, radiotherapy, or biotherapy/targeted
therapies and recovered from the toxicity of prior treatment to less than or equal to CTC
grade 1, exclusive of grade 2 alopecia, fatigue, lymphopenia, CD4+ circulating T cells,
WBC or bilirubin.

2.1.1.7 Patients must be greater than or equal to 18-years old.

2.1.1.8 Patients must have a life expectancy of greater than 3 months.

2.1.1.9 Patients must have an ECOG performance status of less than or equal to 1.

2.1.1.10 The patient must have a granulocyte count of at least 1,500/microL and a platelet
count of greater than 100,000/microL.

2.1.1.11 Patients must have a creatinine of less than 2.0 mg/dL, or if the patient has a
serum creatinine greater than or equal to 2.0, a measured creatinine clearance (Ccr) must
be greater than 60 mL/min/1.73m(2).

2.1.1.12 Patients must have a serum alkaline phosphatase, ALT (SGOT), and AST (SGPT) less
than 3 times the upper limit of normal (ULN), unless due to liver or bone involvement by
HL. Under these circumstances, serum alkaline phosphatase, SGPT and SGOT must be less than
5 times ULN.

2.1.1.13 Patients must have a total serum bilirubin less than 2.5 times ULN.

2.1.1.14 Patients must have a cardiac ejection fraction greater than 45% on 2D
echocardiography or MUGA obtained within 28 days of study enrollment.

2.1.1.15 Lung diffusion capacity for carbon monoxide (DLCO) greater than 50%, or forced
expiratory volume at 1.0 seconds (FEV1.0) greater than 65% of predicted on pulmonary
function testing (PFT) obtained within 28 days of study enrollment.

2.1.1.16 Women of childbearing potential must have a negative serum Beta-HCG pregnancy
test at initial screening and within 3 days prior to registration.

2.1.1.17 The effects of (90)Y-daclizumab on the developing human fetus are unknown. Women
of child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, while receiving
treatment and for 4 months after undergoing ASCT. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately.

2.1.1.18 Patients receiving a stable dose (greater than 4 weeks) of corticosteroid therapy
equivalent to 20 mg of prednisone per day or less are eligible.

2.1.1.19 Patients must be able to understand and sign informed consent.

EXCLUSION CRITERIA:

2.1.2.1 Patients enrolled on another therapeutic study.

2.1.2.2 Patients that have received prior radioimmunotherapy.

2.1.2.3 Patients that have received a prior autologous or allogeneic stem cell transplant

2.1.2.4 Patients that have received prior radiation to the lung, excluding prior
mediastinal radiation.

2.1.2.5 Patients with greater than 25% involvement of the bone marrow with HL.

2.1.2.6 Patients with evidence of myelodysplasia, leukemia by morphology, immunostains
flow cytometry or abnormal cytogenetics on a bone- marrow aspirate or biopsy. The
diagnosis of myelodysplasia will be made by an independent investigator of the Laboratory
of Pathology, NCI taking into consideration the totality of the clinical, pathological,
flow cytometric and cytogenetic information described in Appendix E and present in a
particular individual's evaluation.

2.1.2.7 Patients with history of CNS involvement or active CNS involvement by malignancy.

2.1.2.8 Patients with an active second primary cancer will not be eligible. Patients
curatively treated for a second cancer greater than 5 years prior to enrollment without a
recurrence are eligible. Patients curatively treated for a second primary cancer within
the last 5 years with a less than or equal to 5% risk of recurrence are eligible. Patients
with a history of curatively treated basal cell carcinoma or intraepithelial neoplasia of
the uterine cervix will be allowed on study.

2.1.2.9 Patients with serum human anti-human antibody (HAHA) against daclizumab.

2.1.2.10 Patients with HIV infection (antibody positive with positive confirmatory
molecular test).

2.1.2.11 Patients who have chronic hepatitis B or hepatitis C.

2.1.2.12 Patients with an uncontrolled serious infection.

2.1.2.13 Pregnant or breastfeeding women.

2.1.2.14 Patients with significant medical comorbidities, including uncontrolled
hypertension (diastolic BP greater than 115 mmHg), unstable angina, congestive heart
failure (greater than NYHA class II), poorly controlled diabetes, severe chronic pulmonary
disease, coronary angioplasty or myocardial infarction within the last 6 months, or
uncontrolled atrial or ventricular cardiac arrhythmias.

2.1.2.15 Patients with a history of a psychiatric disorder that may interfere with the
understanding and compliance with this protocol and the required follow up.

2.1.2.16 Exclusion at the discretion of the PI or delegate if participation to the study
is deemed too risky (e.g. clinically significant pleural or pericardial effusion or
ascites with possibly increased radio-toxicity).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Assess safety and adverse events assoc with 90Y-daclizumab radioimmunotherapy (RIT) in combination w/BEAM and ASCT.

Principal Investigator

Thomas A Waldmann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

120003

NCT ID:

NCT01468311

Start Date:

October 2011

Completion Date:

September 2021

Related Keywords:

  • Hodgkin Disease
  • Hodgkin Lymphoma
  • Immunotherapy
  • Resistant Hodgkins Lymphoma
  • Auto Stem Cell Transplant
  • Combination Chemo and Radiolabeled Monoclonal Antibody
  • Hodgkin Lymphoma
  • Hodgkin Disease
  • Lymphoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892