Clinical trial NCT01468311: Yttrium-90-labeled Daclizumab With Chemotherapy and Stem Cell Transplant for Hodgkin's Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Hodgkin Disease
Hodgkin Lymphoma
Keywords: Immunotherapy
Resistant Hodgkins Lymphoma
Auto Stem Cell Transplant
Combination Chemo and Radiolabeled Monoclonal Antibody
Hodgkin Lymphoma
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-11-09
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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....

Detailed description: 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.

Eligibility 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 World Health Organization (WHO) Classification System of Lymphoid Tumours. Patients with nodular lymphocyte-predominant Hodgkin's lymphoma (HL) (NLPHL) are not eligible.

2.1.1.2 Refractory or relapsed HL patients that are also candidates for auto stem cell transplant (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) fluorodeoxyglucose positron emission tomography (FDGPET) imaging.

2.1.1.4 At least 10% of the cells obtained from lymph node, or extranodal sites must react with anti-cluster of differentiation 25 (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 computed tomography (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, cluster of differentiation 4 (CD4)+ circulating T cells, white blood cell (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 Eastern Cooperative Oncology Group (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, alanine aminotransferase (ALT) serum glutamic oxaloacetic transaminase (SGOT), and aspartate aminotransferase (AST) serum glutamic pyruvic transaminase (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 multi-gated acquisition scan (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-human chorionic gonadotropin (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 who have relapsed from their initial Adriamycin, bleomycin, vinblastine, dacarbazine) ABVD or similar standard treatment regimen and have not received any other chemotherapy or salvage systemic treatment.

2.1.2.2 Patients that have received prior radioimmunotherapy.

2.1.2.2. Patients enrolled on another therapeutic study.

2.1.2.3 Patients that have received prior radioimmunotherapy.

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

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

radiation.

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

2.1.2.7 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, National Cancer Institute (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.

2.1.2.8 Patients with history of central nervous system (CNS) involvement or active CNS involvement by malignancy.

2.1.2.9 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.

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

2.1.2.11 Patients with human immunodeficiency virus (HIV) infection (antibody positive with positive confirmatory molecular test).

2.1.2.2 Patients who have chronic hepatitis B or hepatitis C.

2.1.2.13 Patients with an uncontrolled serious infection.

2.1.2.14 Pregnant or breastfeeding women.

2.1.2.15 Patients with significant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure (BP) greater than 115 mmHg), unstable angina, congestive heart failure (greater than New York Heart Association (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.

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

2.1.2.17 Exclusion at the discretion of the principal investigator (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).

Primary outcomes:
measure: 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
timeFrame: Day 100 post autologous stem cell transplant
measure: Number of Participants With Adverse Events
timeFrame: 30 months
measure: Number of Participants With A Dose Limiting Toxicity
timeFrame: 30 months
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Response is evaluated at day 100 post autologous stem cell transplant, then 1-4 times yearly for 5 years
measure: Complete Response Rate
timeFrame: 20 months post autologous stem cell transplant
measure: Disease Free Survival (DFS)
timeFrame: DFS is evaluated at day 100 post autologous stem cell transplant, then 1-4 times yearly for 5 years
measure: Overall Survival
timeFrame: OS is evaluated at day 100 post autologous stem cell transplant, then 1-4 times yearly for 5 years
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Kevin C Conlon, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 Nov 19;327(21):1478-84. doi: 10.1056/NEJM199211193272102.
citation: Moskowitz CH, Nimer SD, Zelenetz AD, Trippett T, Hedrick EE, Filippa DA, Louie D, Gonzales M, Walits J, Coady-Lyons N, Qin J, Frank R, Bertino JR, Goy A, Noy A, O'Brien JP, Straus D, Portlock CS, Yahalom J. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001 Feb 1;97(3):616-23. doi: 10.1182/blood.v97.3.616.
citation: Josting A, Engert A, Diehl V, Canellos GP. Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin's disease. Ann Oncol. 2002;13 Suppl 1:112-6. doi: 10.1093/annonc/13.s1.112. No abstract available.