Radiolabeled Monoclonal Antibody Therapy and Combination Chemotherapy Before Stem Cell Transplant in Treating Patients With Primary Refractory or Relapsed Hodgkin Lymphoma

Sponsor

City of Hope Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01476839

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

121.7

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I clinical trial studies the side effects and best dose of radiolabeled monoclonal antibody therapy when given together with combination chemotherapy before stem cell transplant and to see how well it works in treating patients with primary refractory (did not respond to treatment) or relapsed (returned after treatment) Hodgkin lymphoma. Radiolabeled monoclonal antibodies can find cancer cells and carry cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as carmustine, etoposide, cytarabine, and melphalan (BEAM), work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or stopping them from spreading. Giving radiolabeled monoclonal antibody therapy together with combination chemotherapy may kill more cancer cells

Condition or Disease	Intervention/Treatment	Phase
Recurrent Adult Hodgkin Lymphoma	Biological: basiliximab Drug: carmustine Drug: etoposide Drug: cytarabine Drug: melphalan Other: pharmacological study Other: laboratory biomarker analysis Procedure: autologous hematopoietic stem cell transplantation Biological: yttrium Y 90-labeled basiliximab	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To determine the safety and feasibility of the autologous hematopoietic cell transplantation (AHCT) regimen of yttrium Y-90 basiliximab/DOTA, given in combination with standard dose(s) of BEAM in patients with primary progressive or relapsed Hodgkin lymphoma (HL).
To determine the recommended phase II dose (RP2D) and characterize toxicities at each dose level - including time course.
To evaluate hematological recovery in terms of neutrophil and platelet engraftment time.
To estimate overall response rate (ORR: complete remission [CR] + partial remission [PR]), response duration, overall survival, progression-free survival, and the cumulative incidence of non-relapse mortality and relapse/progression.
To estimate the radiation doses to the whole body and normal organs through serial imaging studies.
To define biodistribution/extended pharmacokinetics of 111indium (In)-basiliximab/DOTA and 90Y- basiliximab/DOTA including terminal elimination, serum half-life (t1/2), and area under the curve (AUC).

OUTLINE: DOSIMETRY STUDY: Patients receive basiliximab intravenously (IV) and indium In 111 basiliximab IV on day -21. Patients undergo indium In 111 imaging scans daily. Patients with appropriate biodistribution continue on to treatment.

TREATMENT: Patients receive basiliximab IV and yttrium Y 90 basiliximab IV on day -14. Patients also receive BEAM chemotherapy comprising carmustine IV over 2 hours on days -7 and -6, etoposide IV over 4 hours twice daily (BID) and cytarabine IV over 2 hours BID on days -5 to -2, and melphalan IV on day -1. Patients undergo autologous hematopoietic progenitor cell infusion on day 0.

After completion of study treatment, patients are followed up at day 90-100, 180, 1 year, 1.5 years, and 2-5 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Yttrium-90 Labeled Anti-CD25 (a-Tac) Monoclonal Antibody Plus BEAM for Autologous Hematopoietic Cell Transplantation (AHCT) in Patients With Primary Refractory or Relapsed Hodgkin Lymphoma, the "a-Tac BEAM Regimen"

Actual Study Start Date :

Nov 9, 2012

Actual Primary Completion Date :

Jul 24, 2021

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (radiolabeled monoclonal antibody, chemotherapy) DOSIMETRY STUDY: Patients receive basiliximab IV and indium In 111 basiliximab IV on day -21. Patients undergo indium In 111 imaging scans daily. Patients with appropriate biodistribution continue on to treatment. TREATMENT: Patients receive basiliximab IV and yttrium Y 90 basiliximab IV on day -14. Patients also receive BEAM chemotherapy comprising carmustine IV over 2 hours on days -7 and -6, etoposide IV BID over 4 hours and cytarabine IV over 2 hours BID on days -5 to -2, and melphalan IV on day -1. Patients undergo autologous hematopoietic progenitor cell infusion on day 0.	Biological: basiliximab Given IV Other Names: SDZ-CHI-621 Simulect Drug: carmustine Given IV Other Names: BCNU BiCNU bis-chloronitrosourea Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213 Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: melphalan Given IV Other Names: Alkeran CB-3025 L-PAM L-phenylalanine mustard L-Sarcolysin Other: pharmacological study Correlative studies Other Names: pharmacological studies Other: laboratory biomarker analysis Correlative studies Procedure: autologous hematopoietic stem cell transplantation Undergo autologous hematopoietic progenitor cell infusion Biological: yttrium Y 90-labeled basiliximab Given IV Other Names: 90Y basiliximab

Arm

Intervention/Treatment

Experimental: Treatment (radiolabeled monoclonal antibody, chemotherapy)

DOSIMETRY STUDY: Patients receive basiliximab IV and indium In 111 basiliximab IV on day -21. Patients undergo indium In 111 imaging scans daily. Patients with appropriate biodistribution continue on to treatment. TREATMENT: Patients receive basiliximab IV and yttrium Y 90 basiliximab IV on day -14. Patients also receive BEAM chemotherapy comprising carmustine IV over 2 hours on days -7 and -6, etoposide IV BID over 4 hours and cytarabine IV over 2 hours BID on days -5 to -2, and melphalan IV on day -1. Patients undergo autologous hematopoietic progenitor cell infusion on day 0.

Biological: basiliximab

Given IV

Other Names:

SDZ-CHI-621

Simulect

Drug: carmustine

Given IV

Other Names:

BCNU

BiCNU

bis-chloronitrosourea

Drug: etoposide

Given IV

Other Names:

EPEG

VP-16

VP-16-213

Drug: cytarabine

Given IV

Other Names:

ARA-C

arabinofuranosylcytosine

arabinosylcytosine

Cytosar-U

cytosine arabinoside

Drug: melphalan

Given IV

Other Names:

Alkeran

CB-3025

L-PAM

L-phenylalanine mustard

L-Sarcolysin

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Other: laboratory biomarker analysis

Correlative studies

Procedure: autologous hematopoietic stem cell transplantation

Undergo autologous hematopoietic progenitor cell infusion

Biological: yttrium Y 90-labeled basiliximab

Given IV

Other Names:

90Y basiliximab

Outcome Measures

Primary Outcome Measures

RP2D of Yttrium-90 labeled basiliximab [Up to 18 months]
RP2D will generally be the highest maximum tolerated dose (MTD), but it may be less than the MTD based on a review of available data/cumulative toxicities. Additional pulmonary toxicity monitoring will be performed among enrolled/treated patients with prior brentuximab vedotin exposure for both portions of the study.
DLT [For 30 days post-transplant]
Toxicities will be recorded using two distinct grading systems: the modified Bearman Scale and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.0 scale. Observed toxicities will be summarized by type, severity, date of onset, duration (for neutropenia only), and attribution.

Secondary Outcome Measures

Best ORR [Up to 5 years]
Response will be evaluated using the revised Cheson criteria. Objective tumor response for all patients will be summarized for each dose level, and the number and percent responding combined across dose levels.
Biodistribution of basiliximab [Pre-basiliximab infusion; pre radiolabeled basiliximab infusion; 2 and 4-6 hours post radiolabeled basiliximab infusion; and then 1, 2, 3-4, 5, and 6 days post radiolabeled basiliximab infusion]
Serum basiliximab levels will be evaluated. T1/2 and alpha- and beta- phase will be estimated for each patient using compartmental and non-compartmental methods, with summary statistics tabulated. Exploratory models to predict tumor response, survival, and toxicities from serum data and patient characteristics will be performed to better understand the effect of treatment on patients.
Cumulative incidence of non-relapsed mortality (NRM) [From stem cell infusion to death from any cause other than disease relapse or progression, assessed up to 5 years]
Cumulative relapse incidence will be estimated treating non-relapse related death events as competing risks and conversely, NRM will be calculated controlling for relapse as a competing risk. Cumulative incidence of NRM and relapse-related mortality will be calculated using the method of Gooley et al. Cumulative incidence differences will be assessed by Gray's test.
Cumulative incidence of relapse/progression incidence [Up to 5 years]
Cumulative relapse incidence will be estimated treating non-relapse related death events as competing risks and conversely, NRM will be calculated controlling for relapse as a competing risk. Cumulative incidence of NRM and relapse-related mortality will be calculated using the method of Gooley et al. Cumulative incidence differences will be assessed by Gray's test.
Incidence of toxicity [Up to 100 days post-infusion]
Observed toxicities will be summarized by type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE v4.0 and nadir or maximum values for lab measures), dates of onset, duration, reversibility, and attribution.
Overall survival (OS) [Time from transplant to death from any cause, assessed up to 5 years]
OS will be estimated using the KM product-limit method; 95% CIs will be calculated using the logit transformation and the Greenwood variance estimate. OS will be estimated using two different start times (from radio-labeled therapeutic infusion and from stem cell infusion) to death from any cause.
Progression free survival (PFS) [Time from transplant to the first observation of disease progression or death from any cause, whichever occurs first, assessed at 5 years]
PFS will be estimated using the Kaplan-Meier (KM) product-limit method. 95% confidence intervals (CIs) will be calculated using the logit transformation and the Greenwood variance estimate. PFS will be estimated using two different start times (from radio-labeled therapeutic infusion and from stem cell infusion) to recurrence, progression, or death from any cause.
Response duration [Time from when criteria for response (CR or PR) are met to the first documentation of relapse or progression, assessed up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Pathology confirmation of HL with City of Hope (COH) pathology review
Hodgkin lymphoma that is:
PIF (primary induction failure): did not enter complete remission with first line of therapy; Note: a patient with PIF who responds to salvage therapy with a PR or CR is also eligible (and would be considered PIF-sensitive)
Early 1st relapse: initial CR of > 3 months and < 12 months after 1st line chemotherapy
1st relapsed HL in a patient who is not in CR after 2 cycles of salvage therapy
In 2nd or subsequent relapse (RL) whether in CR or not after salvage therapy
Relapse/persistent disease evidenced by a computed tomography and fluorodeoxyglucose (FDG)-positron emission tomography (PET), or bone marrow biopsy
Cardiac ejection fraction of >= 50% by echocardiogram or multi gated acquisition scan (MUGA)
Forced expiratory volume in one second (FEV1) > 65% of predicted measured, or diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted measured
Bilirubin =< 1.5 x normal
Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 2 x normal except in cases where abnormal liver function tests (LFTS) are due to involvement with HL
Serum creatinine of =< 1.5 mg/dL, and a measured creatinine clearance of >= 60 mL/min
Karnofsky status >= 70%
Life expectancy >= 6 months
Females must not be pregnant or breast feeding, and must use accepted birth control methods; males must use accepted birth control methods
Capability of providing informed consent
Patients will be enrolled after receiving at least two cycles of salvage cytoreductive chemotherapy and collection of at least 3.0 x 10^{6 CD34 cells/kg of autologous
hematopoietic progenitor cells (HPC-A) by apheresis; a minimum of 2 collection
procedures is required, unless collection on day #1 > 5.0 x 10}6 CD34 cells/kg; a maximum of 10 collections is allowed; bone marrow harvest to supplement apheresis is not allowed
Co-enrollment on Institutional Review Board (IRB) #98117, entitled Molecular Pathogenesis of Therapy-Related Leukemia
All pre-study and follow-up imaging studies preferably performed at City of Hope
Recovery from non-hematologic toxicities of salvage cytoreductive chemotherapy to =< grade 2 (Common Terminology Criteria for Adverse Events version 4 [CTCAE v4])
Body mass index (BMI) > 30% will be considered on a case-by-case basis by the radiation oncology principal investigator (PI)
While on this study, patients may not be treated with any other investigational agent for any purpose until relapse or progression

Exclusion Criteria:

Lymphocyte-predominant Hodgkin lymphoma
Prior high dose chemotherapy with autologous stem cell transplant, or prior allogeneic transplantation
Significant prior external beam dose-limiting radiation to a critical organ based on review of the prior radiation treatment records by the radiation oncology PI; patients who have had prior external beam radiation > 2000 cGy (at 180 to 200 cGy per day) to any portion of the lung will be ineligible; patients with ANY prior radiation to the heart are ineligible; patients with > 500 cGy to any portion of the kidney will be excluded from the study
Presence of antibody against basiliximab (only required for patients who have received prior antibody)
Myelodysplasia or any active malignancy other than HL, or < 5 years remission from any other prior malignancy, except adequately treated basal cell or squamous cell carcinoma
Active hepatitis B or C viral infection or hepatitis B surface antigen positive
Positive human immunodeficiency virus antibody
Patients with psychosocial circumstances or illnesses that preclude protocol participation (to be determined by PI)
Co-morbid illnesses that preclude protocol participation (to be determined by PI)
Any cytogenetic abnormality in the bone marrow that is known to be associated with or predictive of myelodysplasia is excluded. This includes, but is not limited to, del(5), del(7), del(11)
Persistent marrow involvement (> 10%) with HL after salvage cytoreductive therapy and before stem cell mobilization
Systemic chemotherapy or radiation within 4 weeks prior to the Y-90 dose of radioimmunotherapy (RIT), with the exception of single agent Cytoxan priming chemotherapy administered for mobilization
Bone marrow (BM) harvest required to reach adequate cell dose for transplant