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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01476839
First received: November 18, 2011
Last updated: April 10, 2014
Last verified: April 2014
  Purpose

This phase I/II 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 or relapsed 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 or by stopping them from dividing. Giving radiolabeled monoclonal antibody therapy together with combination chemotherapy may kill more cancer cells


Condition Intervention 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
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II 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"

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • RP2D of Yttrium-90 labeled basiliximab (phase I) [ Time Frame: Up to 18 months ] [ Designated as safety issue: Yes ]
    RP2D is defined as the highest Yttrium-90 labeled basiliximab dose tested in which fewer than 33% of patients experience dose limiting toxicity (DLT) attributable to study treatment, among those evaluable for toxicity. Additional pulmonary toxicity monitoring will be performed among enrolled/treated patients with prior brentuximab vedotin exposure for both portions of the study.

  • DLT (phase I) [ Time Frame: For 30 days post-transplant ] [ Designated as safety issue: Yes ]
    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 (CTCASE) 4.0 scale. Observed toxicities will be summarized by type, severity, date of onset, duration, reversibility, and attribution.

  • Anti-tumor activity of the regimen, as assessed by PFS (phase II) [ Time Frame: Time from transplant to the first observation of disease progression or death from any cause, whichever occurs first, assessed at 2 years ] [ Designated as safety issue: No ]
    Progression Free Survival (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. Estimated from radiolabeled therapeutic infusion and from stem cell infusion.


Secondary Outcome Measures:
  • ORR (phase I) [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
    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/analyses of basiliximab (phase I) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Overall survival (phase II) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Estimated using the KM product-limit method; 95% CIs will be calculated using the logit transformation and the Greenwood variance estimate. Estimated using two different start times (from radiolabeled therapeutic infusion and from stem cell infusion) to death from any cause.

  • ORR: CR + PR (phase II) [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
    Evaluated using the Cheson Revised Response Criteria for Malignant Lymphoma.

  • Response duration (phase II) [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
    Defined as time from when criteria for response (CR or PR) are met, for which the event is the first documentation of relapse or progression.

  • Toxicities and complications (phase II) [ Time Frame: Up to 100 days post-infusion ] [ Designated as safety issue: Yes ]
    For both the phase I and phase II studies, 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), dated of onset, duration, reversibility, and attribution.


Estimated Enrollment: 64
Study Start Date: November 2012
Estimated Primary Completion Date: January 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 90Y basiliximab

Detailed Description:

PRIMARY OBJECTIVES:

I. 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).

(Phase I) II. To determine the recommended phase II dose (RP2D) and characterize toxicities at each dose level -including time course.

(Phase I) III. To evaluate hematological recovery in terms of neutrophil and platelet engraftment time.

(Phase I) IV. To estimate the radiation doses to the whole body and normal organs through serial imaging studies.

(Phase I) V. 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).

(Phase I) VI. Using the RP2D defined in the Phase I study, to determine anti-tumor activity of anti (a)Tac-BEAM as assessed by progression-free survival (PFS).

(Phase II) VII. To determine the overall response rate (ORR: complete remission [CR] + partial remission [PR]) and response duration.

(Phase II) VIII. To estimate the overall survival, and non-relapse mortality (NRM) at 100-days and 1-year.

(Phase II) IX. To summarize toxicities by organ and severity, evaluating short and long-term complications, including, delayed engraftment, infection, and myelodysplasia.

(Phase II) X. To descriptively compare the outcomes of patients treated on this protocol to a comparable patient population treated with conventional BEAM for relapsed and refractory HL.

(Phase II) 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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathology confirmation of HL with City of Hope (COH) pathology review; the COH Department of Pathology will stain the biopsy tissue for CD25 and will semiquantitatively score the expression of CD25 on the HL cells (neoplastic cells) and surrounding lymphocytes, since this may correlate with the response to treatment
  • Hodgkin Lymphoma that is:

    • Primary Induction Failure-resistant (PIF res): Never in complete remission but with stable or progressive disease on treatment (primary refractory = PIF res)
    • Primary Induction Failure-sensitive (PIF sen)/first partial remission (PR1) : Never in complete remission, but with partial remission on treatment
    • 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 RL whether in CR or not after salvage therapy
  • Relapse/persistent disease evidenced by a computed tomography and fluorodeoxyglucose-positron emission tomography (FDG-PET), or bone marrow biopsy
  • Cardiac Ejection Fraction of > 50% by echocardiogram or 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 glutamic 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; 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, Dr. Bhatia, Principal Investigator
  • 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 (CTCAE v4)
  • Body mass index (BMI) > 30% will be considered on a case-by-case basis by the Radiation Oncology Principal Investigator (P.I.)
  • 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 radiation to the lung will be excluded from the study, although mediastinal irradiation will be permitted if minimal lung is in the treatment volume; patients with > 500 cGy to the kidney will be excluded from the study
  • Presence of antibody against basiliximab
  • 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 P.I.)
  • Co-morbid illnesses that preclude protocol participation (to be determined by PI)
  • Abnormal marrow cytogenetics at any time, excluding proven constitutional cytogenetic variants
  • 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)
  • Bone marrow (BM) harvest required to reach adequate cell dose for transplant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01476839

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Eileen P. Smith    800-826-4673    esmith@coh.org   
Principal Investigator: Eileen P. Smith         
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Eileen Smith City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01476839     History of Changes
Other Study ID Numbers: 08179, NCI-2011-03334, P01CA030206
Study First Received: November 18, 2011
Last Updated: April 10, 2014
Health Authority: United States: Federal Government
United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hodgkin Disease
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies
Antibodies, Monoclonal
Cytarabine
Melphalan
Basiliximab
Carmustine
Etoposide phosphate
Etoposide
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on July 20, 2014