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Daclizumab

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Yttrium-90-labeled Daclizumab + BCNU, etoposide, cytarabine and melphalan (BEAM) + Auto stem cell transplant (ASCT)

Auto stem cell transplant (ASCT) is given after 90Y-daclizumab

Auto stem cell transplant

BCNU, etoposide, cytarabine and melphalan (BEAM) chemotherapy are given after 90Y-daclizumab

BEAM

111In-daclizumab will be administered to patients with each therapeutic infusion of 90Y-daclizumab in order to define the distribution of radiolabeled daclizumab, and to allow visualization by scans.

111In-daclizumab

90Y-daclizumab administered with a fixed dose of pentetate calcium trisodium (Ca-DTPA) followed by BEAM Chemo and Auto stem cell transplant

90Y-daclizumab

Kevin C Conlon, M.D.

Background:

* Hodgkins lymphoma (HL) is a highly treatable cancer. However, if HL does not respond to chemotherapy or returns after chemotherapy, further treatments often are not successful.
* Some HL cells have a molecule called cluster of differentiation 25 (CD25) on the surface. Daclizumab is a drug that can detect CD25 on cells. In a treatment study for HL that did not respond to chemotherapy, daclizumab plus a radioactive atom called Yttrium 90 helped kill these HL cells. Researchers want to combine this 90Y daclizumab with high-dose chemotherapy and stem cell transplant. This treatment may be more effective than the daclizumab alone.

Objectives:

- To see if yttrium-90 daclizumab, high-dose chemotherapy, and stem cell transplants can treat HL that has not responded to earlier treatments.

Eligibility:

- Individuals at least 18 years of age who have Hodgkins lymphoma that has not responded to chemotherapy.

Design:

* Participants will be screened with a physical exam and medical history. They will also have blood and urine tests.
* Participants will have filgrastim and plerixafor to move stem cells into the blood. Stem cells will be collected with apheresis.
* Four weeks after stem cells are collected, participants will have the 90Y daclizumab and normal daclizumab to treat the HL. Chemotherapy will start 9 days after the first treatment.
* Most participants will have a second dose of 90Y daclizumab 6 weeks after the first dose.
* After each daclizumab treatment, participants will have several imaging studies of the chest and abdomen. Blood samples will also be collected.
* On the day after the last day of chemotherapy, participants will receive the stem cells collected earlier. Filgrastim injections will help stimulate stem cell growth....

Background:

* Although Hodgkins 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 complete response (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 myelodysplastic syndrome (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 x 106 cluster of differentiation 34 (CD34) cells/kg (minimal dose of 2 x 106 CD34+ cells/kg) of actual body weight.
* Phase I study will be carried out using a standard 3 + 3 cohort dose-escalation design:

  * Dose level 1: Patients will receive a single dose of 15 mCi 90Y-daclizumab RIT (day -15 2 days) followed by high-dose BEAM chemotherapy (beginning Day -6) and ASCT (Day 0).
  * Dose levels 2-7: Patients will receive two doses of 90Y-daclizumab RIT 6 weeks apart (Day -56 and -15 2 days) followed by high-dose BEAM chemotherapy (beginning day -6) and ASCT (Day 0). The first dose of 90Y-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 90Y-daclizumab (Day -56 and -15 2 days) 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.

  111In-daclizumab (5 mCi) imaging may be performed concurrently with each 90Ydaclizumab RIT and at day 100 after ASCT.

Yttrium-90-labeled Daclizumab With Chemotherapy and Stem Cell Transplant for Hodgkin's Lymphoma

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

The MTD is defined as the dose level below the dose at which 2 out of 2 to 6 patients at a given dose level develop dose limiting toxicity (DLT). A DLT is defined as patients who develop either a Common Terminology Criteria in Adverse Events (CTCAE) v4.0 grade 3 or greater non-hematologic toxicity, with the exception of fatigue, of more than 5 days duration possibly, probably or definitely related to the infusion of 90Y-daclizumab prior to the start of BEAM chemotherapy (Day - 6) will have developed by definition a dose-limiting toxicity (DLT).

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Patients who develop either a Common Terminology Criteria in Adverse Events (CTCAE) v4.0 grade 3 or greater non-hematologic toxicity, with the exception of fatigue, of more than 5 days duration possibly, probably or definitely related to the infusion of 90Y-daclizumab prior to the start of Carmustine, Etoposide, Cytarabine, \[Ara-C, Cytosine Arabinoside\] and Melphalan (BEAM) chemotherapy (Day - 6) will have developed by definition a dose-limiting toxicity (DLT).

Overall response rate is defined as the number of complete and partial responses in patients with refractory or relapsed Hodgkin's disease. Response is assessed by the Revised Response Criteria for Malignant Lymphoma. Complete response requires all of the following: complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy. A post treatment residual mass is permitted as long as it is positron emission tomography negative. Partial response requires all of the following: at least a 50% reduction in the sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses. These nodes or masses should be selected according to all of the following: they should be clearly measurable in at least two perpendicular dimensions; if possible they should be from disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.

Complete response rate is defined as the time it takes a participant to achieve a complete response. Response is assessed by the Revised Response Criteria for Malignant Lymphoma. Complete response requires all of the following: complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy. A post treatment residual mass is permitted as long as it is positron emission tomography (PET) negative. If a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on computed tomography (CT) to normal size (\<1.5 cm in their greatest transverse diameter for nodes \>1.5 cm before therapy); Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis before treatment must have decreased to \<1.0 cm in their short axis after treatment.

DFS is defined as the amount of time participants remain disease free.

Overall survival is defined as the time from the date of registration to the date of death due to any cause or if no death occurs to the last documented information on the patient.

National Cancer Institute (NCI)

Principal Investigator

Yttrium-90-labeled Daclizumab + BCNU, etoposide, cytarabine and melphalan (BEAM) + Auto stem cell transplant (ASCT)

Auto stem cell transplant: Auto stem cell transplant (ASCT) is given after 90Y-daclizumab

BEAM: BCNU, etoposide, cytarabine and melphalan (BEAM) chemotherapy are given after 90Y-daclizumab

111In-daclizumab: 111In-daclizumab will be administered to patients with each therapeutic infusion of 90Y-daclizumab in order to define the distribution of radiolabeled daclizumab, and to allow visualization by scans.

90Y-daclizumab: 90Y-daclizumab administered with a fixed dose of pentetate calcium trisodium (Ca-DTPA) followed by BEAM Chemo and Auto stem cell transplant

Yttrium-90-labeled Daclizumab + Chemotherapy

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Ethnicity, customized

Race/Ethnicity, Customized

United States

Region of Enrollment

Dr. Kevin C. Conlon

MTD was not determined due to low enrollment into the study.

Maximum Tolerated Dose (MTD) of 90Y-daclizumab With Carmustine, Etoposide, Cytarabine, [Ara-C, Cytosine Arabinoside] and Melphalan (BEAM) and Auto Stem Cell Transplant (ASCT): Phase I Portion

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Yttrium-90-labeled Daclizumab With Chemotherapy and Stem Cell Transplant for Hodgkin's Lymphoma	NCT01468311	Hodgkin Disease Hodgkin Lymphom...	Auto stem cell ... BEAM 111In-daclizuma... 90Y-daclizumab	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Yttrium-90-labeled Daclizumab With Chemotherapy and Stem Cell Transplant for Hodgkin's Lymphoma	NCT01468311	Hodgkin Disease Hodgkin Lymphom...	Auto stem cell ... BEAM 111In-daclizuma... 90Y-daclizumab	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

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