Radiolabeled Monoclonal Antibody and Combination Chemotherapy Before Stem Cell Transplant in Treating Patients With High-Risk Lymphoid Malignancies

Sponsor
Fred Hutchinson Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT01921387
Collaborator
National Cancer Institute (NCI) (NIH)
20
1
1
81.5
0.2

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and the best dose of radiolabeled monoclonal antibody when given together with combination chemotherapy before stem cell transplant and to see how well it works in treating patients with high-risk lymphoid malignancies. Radiolabeled monoclonal antibodies, such as yttrium Y 90 anti-CD45 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving chemotherapy before a stem transplant stops the growth of cancer cells by stopping them from dividing or killing them. Stem cells collected from the patient's blood are then returned to the patient to replace the blood-forming cells that were destroyed by the radiolabeled monoclonal antibody and chemotherapy.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To estimate the maximum-tolerated dose (MTD) of 90Y-BC8-DOTA (yttrium Y 90 anti-CD45 monoclonal antibody BC8) (anti-cluster of differentiation [CD] 45) that can be delivered prior to myeloablative carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy and autologous stem cell transplant (ASCT) for patients with high-risk B-non-Hodgkin lymphoma (NHL), T-NHL, and Hodgkin lymphoma (HL).

  2. To evaluate the efficacy of 90Y-BC8-DOTA when administered at the estimated MTD prior to BEAM chemotherapy and ASCT for patients with high-risk B-NHL, T-NHL, and HL compared to historical controls treated with BEAM alone.

SECONDARY OBJECTIVES:
  1. To describe the toxicity observed from the addition of 90Y-BC8-DOTA to BEAM.

  2. To optimize the protein dose (Ab) to deliver a favorable biodistribution in the majority of patients.

  3. To describe response rates and overall survival of patients with high-risk B-NHL, T-NHL, and HL following administration of 90Y-BC8-DOTA plus BEAM prior to ASCT.

  4. To describe the impact of rituximab concentrations, B-cell depletion, and disease burden on CD45 targeting.

  5. To assess the correlation of lymphoma biomarkers with outcomes.

  6. To evaluate the effects of nodal-targeted irradiation by 90Y-BC8-DOTA on immune reconstitution following ASCT.

OUTLINE: This is a phase I, dose-escalation study of yttrium Y 90 anti-CD45 monoclonal antibody BC8 followed by a phase II study.

Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 intravenously (IV) on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours twice daily (BID) on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous peripheral blood stem cell (PBSC) transplant on day 0.

After completion of study treatment, patients are followed up at 3, 6, and 12 months and then annually thereafter.

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Study Evaluating Escalating Doses of 90Y-BC8-DOTA (Anti-CD45) Antibody Followed by BEAM Chemotherapy and Autologous Stem Cell Transplantation for High-Risk Lymphoid Malignancies
Actual Study Start Date :
Oct 9, 2013
Actual Primary Completion Date :
Jul 26, 2017
Actual Study Completion Date :
Jul 26, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)

Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0.

Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous PBSC transplant
Other Names:
  • autologous stem cell transplantation
  • Drug: Carmustine
    Given IV
    Other Names:
  • BCNU
  • Becenum
  • Becenun
  • BiCNU
  • Bis(chloroethyl) Nitrosourea
  • Bis-Chloronitrosourea
  • Carmubris
  • Carmustin
  • Carmustinum
  • FDA 0345
  • Gliadel
  • N,N'-Bis(2-chloroethyl)-N-nitrosourea
  • Nitrourean
  • Nitrumon
  • SK 27702
  • SRI 1720
  • WR-139021
  • Drug: Cytarabine
    Given IV
    Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453
  • Drug: Etoposide
    Given IV
    Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Drug: Melphalan
    Given IV
    Other Names:
  • Alanine Nitrogen Mustard
  • CB-3025
  • L-PAM
  • L-Phenylalanine Mustard
  • L-sarcolysin
  • L-Sarcolysin Phenylalanine mustard
  • L-Sarcolysine
  • Melphalanum
  • Phenylalanine Mustard
  • Phenylalanine nitrogen mustard
  • Sarcoclorin
  • Sarkolysin
  • WR-19813
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Undergo autologous PBSC transplant
    Other Names:
  • PBPC transplantation
  • PBSCT
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplant
  • Peripheral Stem Cell Transplantation
  • Radiation: Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8
    Given IV
    Other Names:
  • 90Y Anti-CD45 MoAb BC8
  • Outcome Measures

    Primary Outcome Measures

    1. Maximum-tolerated Dose (MTD) of Yttrium-90-BC8-DOTA [Within 30 days post-transplant]

      Single patients will be treated at escalating doses in 2-Gy increments (Table 4) until a DLT is observed. Once a DLT is observed, the second stage will begin at the next lower dose level and patients will be treated in cohorts of 4.

    2. Progression-free Survival Following Autologous Stem Cell Transplant (ASCT) [1 year]

      Estimate the 1 year progression-free survival (PFS) rate after ASCT

    Secondary Outcome Measures

    1. Estimated Dose to Tumor Sites Based on the Tumor to Normal Organ Ratios Derived From Dosimetry Estimates Coupled With the Absorbed Dose to Normal Organs Based on the Administered Activity of Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8 [Up to 5 years]

      Will be evaluated among all patients and among those treated at the estimated MTD.

    2. The Lowest Antibody (Yttrium 90-BC8-DOTA) Dose (mg/kg) That is Consistent With a Favorable Biodistribution Rate >= 80% in Lymphoma Patients [Up to 5 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have a histologically confirmed diagnosis of B-NHL, T-NHL, or HL; only patients with classical HL must have documented histologic demonstration of CD45+ cells adjacent to the Reed Sternberg cells; patients must have received at least one prior standard systemic therapy with documented recurrent or refractory disease; patients with mantle cell lymphoma (MCL), T-NHL, or other high-risk malignancies may be enrolled/transplanted in complete remission (CR)/first partial remission (PR1)

    • Creatinine < 2.0

    • Bilirubin < 1.5 mg/dL

    • All patients eligible for therapeutic study must have a minimum of >= 2 x10^6 CD34/kg autologous hematopoietic stem cells harvested and cryopreserved

    • Patients must have an expected survival of > 60 days and must be free of major infection

    Exclusion Criteria:
    • Circulating human anti-mouse antibody (HAMA), to be determined before each infusion

    • Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled therapy dose with the exception of rituximab

    • Inability to understand or give an informed consent

    • Lymphoma involving the central nervous system

    • Other serious medical conditions considered to represent contraindications to ASCT (e.g., abnormally decreased cardiac ejection fraction, diffusion capacity of carbon monoxide [DLCO] < 50% predicted, etc.)

    • Known human immunodeficiency virus (HIV) seropositivity

    • Pregnancy or breast feeding

    • Prior autologous or allogeneic bone marrow or stem cell transplant

    • Prior radiation therapy (RT) > 20 gray (Gy) to a critical organ within 1 year of enrollment

    • Southwestern Oncology Group (SWOG) performance status >= 2.0

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Fred Hutch/University of Washington Cancer Consortium Seattle Washington United States 98109

    Sponsors and Collaborators

    • Fred Hutchinson Cancer Center
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Ajay Gopal, Fred Hutch/University of Washington Cancer Consortium

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Ajay Gopal, Principal Investigator, Fred Hutchinson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT01921387
    Other Study ID Numbers:
    • 2728.00
    • NCI-2013-01378
    • 2728.00
    • P01CA044991
    • P30CA015704
    First Posted:
    Aug 13, 2013
    Last Update Posted:
    Aug 4, 2020
    Last Verified:
    Jul 1, 2020

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Arm/Group Description Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant Carmustine: Given IV Cytarabine: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies Melphalan: Given IV Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSC transplant Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8: Given IV
    Period Title: Overall Study
    STARTED 20
    COMPLETED 19
    NOT COMPLETED 1

    Baseline Characteristics

    Arm/Group Title Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Arm/Group Description Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant Carmustine: Given IV Cytarabine: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies Melphalan: Given IV Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSC transplant Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8: Given IV
    Overall Participants 20
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    16
    80%
    >=65 years
    4
    20%
    Sex: Female, Male (Count of Participants)
    Female
    8
    40%
    Male
    12
    60%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    5%
    Not Hispanic or Latino
    19
    95%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    17
    85%
    More than one race
    3
    15%
    Unknown or Not Reported
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Maximum-tolerated Dose (MTD) of Yttrium-90-BC8-DOTA
    Description Single patients will be treated at escalating doses in 2-Gy increments (Table 4) until a DLT is observed. Once a DLT is observed, the second stage will begin at the next lower dose level and patients will be treated in cohorts of 4.
    Time Frame Within 30 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Arm/Group Description Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant Carmustine: Given IV Cytarabine: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies Melphalan: Given IV Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSC transplant Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8: Given IV
    Measure Participants 19
    Number [Gy - MTD]
    34
    2. Primary Outcome
    Title Progression-free Survival Following Autologous Stem Cell Transplant (ASCT)
    Description Estimate the 1 year progression-free survival (PFS) rate after ASCT
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Arm/Group Description Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant Carmustine: Given IV Cytarabine: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies Melphalan: Given IV Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSC transplant Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8: Given IV
    Measure Participants 19
    Count of Participants [Participants]
    12
    60%
    3. Secondary Outcome
    Title Estimated Dose to Tumor Sites Based on the Tumor to Normal Organ Ratios Derived From Dosimetry Estimates Coupled With the Absorbed Dose to Normal Organs Based on the Administered Activity of Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8
    Description Will be evaluated among all patients and among those treated at the estimated MTD.
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Arm/Group Description Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant Carmustine: Given IV Cytarabine: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies Melphalan: Given IV Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSC transplant Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8: Given IV
    Measure Participants 19
    Number [mCi]
    52.8
    4. Secondary Outcome
    Title The Lowest Antibody (Yttrium 90-BC8-DOTA) Dose (mg/kg) That is Consistent With a Favorable Biodistribution Rate >= 80% in Lymphoma Patients
    Description
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Arm/Group Description Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant Carmustine: Given IV Cytarabine: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies Melphalan: Given IV Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSC transplant Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8: Given IV
    Measure Participants 19
    Number [mg/kg]
    0.75

    Adverse Events

    Time Frame AEs are monitored and recorded from the time of first exposure to the investigational agent (i.e., the start of the 111In-DOTA-BC8 infusion) through day +30 post-transplant or through discharge prior to that date from the SCCA system to care of the patient's primary physician; Beyond day 30 after transplant/discharge from the transplant service until day 100, only SAEs and grade 4 and 5 toxicities will be collected.
    Adverse Event Reporting Description
    Arm/Group Title Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Arm/Group Description Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant Carmustine: Given IV Cytarabine: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies Melphalan: Given IV Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSC transplant Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8: Given IV
    All Cause Mortality
    Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Affected / at Risk (%) # Events
    Total 5/20 (25%)
    Serious Adverse Events
    Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Affected / at Risk (%) # Events
    Total 20/20 (100%)
    Blood and lymphatic system disorders
    Febrile neutropenia 13/20 (65%) 13
    Cardiac disorders
    Chest pain 1/20 (5%) 1
    Gastrointestinal disorders
    Diarrhea 1/20 (5%) 1
    Mucositis 15/20 (75%) 15
    Nausea 2/20 (10%) 2
    Vomiting 1/20 (5%) 1
    General disorders
    Fever 3/20 (15%) 3
    Immune system disorders
    Allergic reaction 3/20 (15%) 3
    Anaphylaxis 1/20 (5%) 1
    Engraftment syndrome 1/20 (5%) 1
    Serum sickness 2/20 (10%) 2
    Infections and infestations
    Blood infection 2/20 (10%) 2
    Sinusitis 1/20 (5%) 1
    Metabolism and nutrition disorders
    Anorexia 5/20 (25%) 5
    Hyponatremia 1/20 (5%) 1
    Hypophosphatemia 2/20 (10%) 2
    Musculoskeletal and connective tissue disorders
    Pain in extremity 1/20 (5%) 1
    Nervous system disorders
    Headache 1/20 (5%) 1
    Peripheral neuropathy 1/20 (5%) 1
    Syncope 2/20 (10%) 2
    Respiratory, thoracic and mediastinal disorders
    Cough 1/20 (5%) 1
    Dyspnea 1/20 (5%) 1
    Hypoxia 2/20 (10%) 2
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 3/20 (15%) 3
    Pruritus 1/20 (5%) 1
    Vascular disorders
    Hypotension 2/20 (10%) 2
    Other (Not Including Serious) Adverse Events
    Treatment (90Y-BC8-DOTA, Chemotherapy, PBSC)
    Affected / at Risk (%) # Events
    Total 0/20 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Ajay Kumar Gopal, MD, Director of Clinical Research
    Organization Seattle Cancer Care Alliance
    Phone (206) 606-2037
    Email agopal@uw.edu.org
    Responsible Party:
    Ajay Gopal, Principal Investigator, Fred Hutchinson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT01921387
    Other Study ID Numbers:
    • 2728.00
    • NCI-2013-01378
    • 2728.00
    • P01CA044991
    • P30CA015704
    First Posted:
    Aug 13, 2013
    Last Update Posted:
    Aug 4, 2020
    Last Verified:
    Jul 1, 2020