Combination Chemotherapy Followed by Radiation Therapy in Treating Young Patients With Newly Diagnosed Hodgkin's Lymphoma

Sponsor
Children's Oncology Group (Other)
Overall Status
Completed
CT.gov ID
NCT00302003
Collaborator
National Cancer Institute (NCI) (NIH)
287
Enrollment
1
Location
1
Arm
160.9
Duration (Months)
1.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase III trial is studying how well combination chemotherapy works when given before radiation therapy and/or additional chemotherapy in treating young patients with newly diagnosed Hodgkin's lymphoma. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. Giving more than one drug (combination chemotherapy) and giving them together with radiation therapy may kill more cancer cells.

Detailed Description

OBJECTIVES:
  1. Investigate the paradigm of response-based therapy for low-risk Hodgkin's lymphoma by eliminating involved-field radiotherapy (IFRT) in patients who achieve a complete remission (CR) after initial chemotherapy.

  2. Investigate whether 3 courses of doxorubicin hydrochloride, vincristine, prednisone, and cyclophosphamide (AV-PC) for the treatment of low-risk Hodgkin's lymphoma is sufficient to induce CR in at least 80% of patients.

  3. Investigate whether patients who experience a low-risk relapse after initial treatment with chemotherapy alone can be successfully treated with a salvage regimen comprising ifosfamide and vinorelbine ditartrate with dexamethasone, etoposide phosphate, cisplatin, and cytarabine (IV/DECA) and IFRT.

  4. Maintain the overall survival for patients with low-risk Hodgkin's lymphoma at or above 97%.

  5. Determine the prognostic significance of very early response as measured by fludeoxyglucose-positron emission tomography (FDG-PET) or gallium after the first course of chemotherapy.

  6. Evaluate the prognostic significance of elevation of erythrocyte sedimentation rate and C-reactive protein at the time of diagnosis in patients with low-risk Hodgkin's lymphoma on CR rate and relapse rate after chemotherapy alone.

  7. Determine the frequency and severity of late effects of therapy, including thyroid dysfunction, infertility, cardiotoxicity, and second malignant neoplasms.

OUTLINE: This is a multicenter study.

INITIAL CHEMOTHERAPY: Patients receive doxorubicin hydrochloride intravenously (IV) over 10-30 minutes and cyclophosphamide IV over 1 hour on days 1-2, vincristine IV on days 1 and 8, prednisone orally (PO) on days 1-7, and filgrastim (G-CSF) subcutaneously (SC) on days 3-7 and 9-14. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving complete remission (CR) proceed to observation. Patients achieving partial remission proceed to radiotherapy. Patients who have a low-risk relapse after achieving CR on initial chemotherapy proceed to salvage chemotherapy followed by radiotherapy. Patients who have stable disease or disease progression go off study.

SALVAGE CHEMOTHERAPY: Patients receive ifosfamide IV continuously on days 1-4, vinorelbine ditartrate IV over 6-10 minutes on days 1-5, and G-CSF SC or IV beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients then receive dexamethasone IV over 15 minutes every 12 hours, etoposide phosphate IV over 3 hours every 12 hours, and cytarabine IV over 3 hours every 12 hours on days 1 and 2; cisplatin IV over 6 hours on day 1; and G-CSF SC or IV beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients then proceed to radiotherapy.

INVOLVED-FIELD RADIOTHERAPY (IFRT): Beginning 4 weeks after completion of chemotherapy, patients undergo IFRT once daily, 5 days a week, for 2.8 weeks. Patients who do not achieve CR go off study.

After completion of study treatment, patients are followed periodically for up to 10 years.

Study Design

Study Type:
Interventional
Actual Enrollment :
287 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase III Study for the Treatment of Children and Adolescents With Newly Diagnosed Low Risk Hodgkin Disease
Study Start Date :
Feb 1, 2006
Actual Primary Completion Date :
Mar 1, 2012
Actual Study Completion Date :
Jun 30, 2019

Arms and Interventions

ArmIntervention/Treatment
Experimental: Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim

Treatment consists of 3 cycles of Doxorubicin hydrochloride IV (25 mg/m2) days 1 & 2, Vincristine sulfate IV (1.4 mg/m2 [max 2.8 mg]) Days 1 & 8, Prednisone orally (40 mg/m2) Days 1-7, Cyclophosphamide IV (600 mg/m2) Days 1 & 2, Filgrastim by mouth or IV (5 micrograms/kg/dose) 24 hours after Cyclophosphamide complete. See detailed description for remainder of therapy.

Radiation: radiation therapy
Undergo radiation therapy
Other Names:
  • irradiation
  • radiotherapy
  • therapy, radiation
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
  • Drug: vincristine sulfate
    Given IV
    Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
  • Drug: prednisone
    Given orally
    Other Names:
  • DeCortin
  • Deltra
  • Drug: cyclophosphamide
    Given IV
    Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
  • Drug: ifosfamide
    Given IV
    Other Names:
  • Cyfos
  • Holoxan
  • IFF
  • IFX
  • IPP
  • Drug: vinorelbine tartrate
    Given IV
    Other Names:
  • Eunades
  • navelbine ditartrate
  • NVB
  • VNB
  • Drug: dexamethasone
    Given IV
    Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
  • Drug: etoposide phosphate
    Given IV
    Other Names:
  • ETOP
  • Etopophos
  • Drug: cisplatin
    Given IV
    Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
  • Drug: cytarabine
    Given IV
    Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
  • Biological: filgrastim
    Given IV or subcutaneously
    Other Names:
  • G-CSF
  • Neupogen
  • Outcome Measures

    Primary Outcome Measures

    1. Event Free Survival Without Receiving Radiation Therapy (EFSnoRT). [At 60 months]

      Survival is defined as the minimum time from study entry to requirement for additional chemotherapy and IFRT for retrieval, occurrence of a second malignant neoplasm, or death from any cause. Patients without report of such events where censored at last contact. Patients who achieve less than CR after 3 cycles of AV-PC will require IFRT and hence will satisfy this definition at the time of response evaluation. Patients who achieve a CR but who relapse will receive addition chemotherapy and IFRT or intense retrieval and hence will satisfy this definition at the time of the first relapse of Hodgkin disease. This endpoint will be used to compute event free survival without receiving radiation therapy (EFSnoRT).

    2. Intensive Therapy Free Survival (ITFS). [At 60 months]

      Survival is defined as the minimum time from study entry to a relapse of higher risk at any time, any relapse following treatment with protocol mandated IFRT, death from any cause, or the occurrence of a second malignant neoplasm. This will be used to compute intensive therapy free survival (ITFS). Patients without report of such events where censored at last contact. This differs from traditional EFS in that relapse after AVPC* x3 therapy alone that does not place the patient in a higher risk category is not considered a treatment failure. In this definition, higher-risk relapse refers to relapse involving sites and extent of disease that place the patient in the current COG definition of intermediate or high-risk disease. If a patient with CR who experiences a LR relapse is not retreated with protocol-mandated chemotherapy and IFRT, subsequent disease relapses will nevertheless be counted in the analysis of the treatment strategy.

    3. Event Free Survival (EFS) [At 60 months]

      Survival is defined as the minimum time from study entry to a relapse of any kind, death from any cause, or occurrence of a second malignant neoplasm. Patients without report of such events where censored at last contact. This will be used to compute event free survival (EFS).

    Secondary Outcome Measures

    1. Overall Survival [At 60 months]

      Survival is defined as time from study entry to death due to any cause. Patients alive at last contact where censored at last contact.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 21 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Histologically confirmed Hodgkin's lymphoma meeting the following criteria:

    • Newly diagnosed disease

    • Stage IA OR stage IIA without bulky disease

    • No lymphocyte-predominant histology

    • Staging on this study will be determined by the clinical stage; surgical staging is strongly discouraged, except for the rare situation of equivocal imaging studies below the diaphragm

    • Patients may not have received any previous chemotherapy or radiation therapy; patients may not have received systemic corticosteroids within 30 days of enrollment on this protocol; steroids used for treatment of contrast agent allergy required for computed tomography (CT) scans are acceptable

    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^3

    • Total bilirubin =< 1.5 x normal

    • Alanine (ALT) =< 2.5 x normal

    • Shortening fraction >= 27% by echocardiogram OR ejection fraction >= 50% by multi-gated acquisition (MUGA)

    • No pathologic prolongation of QTc interval on 12-lead electrocardiography (ECG)

    • Female patients of childbearing potential must have a negative pregnancy test

    • Lactating females must agree that they will not breastfeed a child while on this study

    • Fertile patients must use effective contraception

    • Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method

    • All patients and/or their parents or legal guardians must sign a written informed consent

    • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Children's Oncology GroupArcadiaCaliforniaUnited States91006-3776

    Sponsors and Collaborators

    • Children's Oncology Group
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Frank Keller, MD, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT00302003
    Other Study ID Numbers:
    • AHOD0431
    • NCI-2009-00377
    • CDR0000459962
    • U10CA098543
    • COG-AHOD0431
    First Posted:
    Mar 13, 2006
    Last Update Posted:
    Mar 30, 2021
    Last Verified:
    Aug 1, 2016

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Arm/Group DescriptionTreatment consists of 3 cycles of Doxorubicin hydrochloride IV (25 mg/m2) days 1 & 2, Vincristine sulfate IV (1.4 mg/m2 [max 2.8 mg]) Days 1 & 8, Prednisone orally (40 mg/m2) Days 1-7, Cyclophosphamide IV (600 mg/m2) Days 1 & 2, Filgrastim by mouth or IV (5 micrograms/kg/dose) 24 hours after Cyclophosphamide complete. See detailed description for remainder of therapy. radiation therapy: Undergo radiation therapy doxorubicin hydrochloride: Given IV vincristine sulfate: Given IV prednisone: Given orally cyclophosphamide: Given IV ifosfamide: Given IV vinorelbine tartrate: Given IV dexamethasone: Given IV etoposide phosphate: Given IV cisplatin: Given IV cytarabine: Given IV filgrastim: Given IV or subcutaneously
    Period Title: Overall Study
    STARTED287
    COMPLETED207
    NOT COMPLETED80

    Baseline Characteristics

    Arm/Group TitleDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Arm/Group DescriptionTreatment consists of 3 cycles of Doxorubicin hydrochloride IV (25 mg/m2) days 1 & 2, Vincristine sulfate IV (1.4 mg/m2 [max 2.8 mg]) Days 1 & 8, Prednisone orally (40 mg/m2) Days 1-7, Cyclophosphamide IV (600 mg/m2) Days 1 & 2, Filgrastim by mouth or IV (5 micrograms/kg/dose) 24 hours after Cyclophosphamide complete. See detailed description for remainder of therapy. radiation therapy: Undergo radiation therapy doxorubicin hydrochloride: Given IV vincristine sulfate: Given IV prednisone: Given orally cyclophosphamide: Given IV ifosfamide: Given IV vinorelbine tartrate: Given IV dexamethasone: Given IV etoposide phosphate: Given IV cisplatin: Given IV cytarabine: Given IV filgrastim: Given IV or subcutaneously
    Overall Participants287
    Age (Count of Participants)
    <=18 years
    272
    94.8%
    Between 18 and 65 years
    15
    5.2%
    >=65 years
    0
    0%
    Age (Years) [Median (Full Range) ]
    Median (Full Range) [Years]
    15
    Sex: Female, Male (Count of Participants)
    Female
    160
    55.7%
    Male
    127
    44.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    43
    15%
    Not Hispanic or Latino
    227
    79.1%
    Unknown or Not Reported
    17
    5.9%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    3
    1%
    Asian
    8
    2.8%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    29
    10.1%
    White
    220
    76.7%
    More than one race
    0
    0%
    Unknown or Not Reported
    27
    9.4%
    Region of Enrollment (participants) [Number]
    United States
    250
    87.1%
    Australia
    3
    1%
    Canada
    25
    8.7%
    Israel
    1
    0.3%
    Mexico
    1
    0.3%
    New Zealand
    2
    0.7%
    Puerto Rico
    4
    1.4%
    Switzerland
    1
    0.3%

    Outcome Measures

    1. Primary Outcome
    TitleEvent Free Survival Without Receiving Radiation Therapy (EFSnoRT).
    DescriptionSurvival is defined as the minimum time from study entry to requirement for additional chemotherapy and IFRT for retrieval, occurrence of a second malignant neoplasm, or death from any cause. Patients without report of such events where censored at last contact. Patients who achieve less than CR after 3 cycles of AV-PC will require IFRT and hence will satisfy this definition at the time of response evaluation. Patients who achieve a CR but who relapse will receive addition chemotherapy and IFRT or intense retrieval and hence will satisfy this definition at the time of the first relapse of Hodgkin disease. This endpoint will be used to compute event free survival without receiving radiation therapy (EFSnoRT).
    Time FrameAt 60 months

    Outcome Measure Data

    Analysis Population Description
    Eligible (n=278) and evaluable response and review of response, n=275. Follow-up for censored patients (n=138) is 76 months (range: 1.8 to 108 months).
    Arm/Group TitleGroup 1
    Arm/Group DescriptionDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Measure Participants275
    Number (95% Confidence Interval) [Probability of survival]
    0.49
    2. Primary Outcome
    TitleIntensive Therapy Free Survival (ITFS).
    DescriptionSurvival is defined as the minimum time from study entry to a relapse of higher risk at any time, any relapse following treatment with protocol mandated IFRT, death from any cause, or the occurrence of a second malignant neoplasm. This will be used to compute intensive therapy free survival (ITFS). Patients without report of such events where censored at last contact. This differs from traditional EFS in that relapse after AVPC* x3 therapy alone that does not place the patient in a higher risk category is not considered a treatment failure. In this definition, higher-risk relapse refers to relapse involving sites and extent of disease that place the patient in the current COG definition of intermediate or high-risk disease. If a patient with CR who experiences a LR relapse is not retreated with protocol-mandated chemotherapy and IFRT, subsequent disease relapses will nevertheless be counted in the analysis of the treatment strategy.
    Time FrameAt 60 months

    Outcome Measure Data

    Analysis Population Description
    Eligible (n=278) and evaluable response and review of response, n=275. Follow-up for censored patients (n=245) is 76 months (range: 4.7 to 109 months).
    Arm/Group TitleGroup 1
    Arm/Group DescriptionDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Measure Participants275
    Number (95% Confidence Interval) [Probability of survival]
    0.89
    3. Primary Outcome
    TitleEvent Free Survival (EFS)
    DescriptionSurvival is defined as the minimum time from study entry to a relapse of any kind, death from any cause, or occurrence of a second malignant neoplasm. Patients without report of such events where censored at last contact. This will be used to compute event free survival (EFS).
    Time FrameAt 60 months

    Outcome Measure Data

    Analysis Population Description
    Eligible (n=278). Follow-up for censored patients (n=223) is 75 months (range: 4.7 to 108 months).
    Arm/Group TitleGroup 1
    Arm/Group DescriptionDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Measure Participants278
    Number (95% Confidence Interval) [Probability of survival]
    0.79
    4. Secondary Outcome
    TitleOverall Survival
    DescriptionSurvival is defined as time from study entry to death due to any cause. Patients alive at last contact where censored at last contact.
    Time FrameAt 60 months

    Outcome Measure Data

    Analysis Population Description
    Eligible (n=278). Follow-up for censored patients (n=277) is 76 months (range: 4.7 to 109 months).
    Arm/Group TitleGroup 1
    Arm/Group DescriptionDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Measure Participants278
    Number (95% Confidence Interval) [Probability of survival]
    0.99

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group TitleDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Arm/Group DescriptionTreatment consists of 3 cycles of Doxorubicin hydrochloride IV (25 mg/m2) days 1 & 2, Vincristine sulfate IV (1.4 mg/m2 [max 2.8 mg]) Days 1 & 8, Prednisone orally (40 mg/m2) Days 1-7, Cyclophosphamide IV (600 mg/m2) Days 1 & 2, Filgrastim by mouth or IV (5 micrograms/kg/dose) 24 hours after Cyclophosphamide complete. See detailed description for remainder of therapy. radiation therapy: Undergo radiation therapy doxorubicin hydrochloride: Given IV vincristine sulfate: Given IV prednisone: Given orally cyclophosphamide: Given IV ifosfamide: Given IV vinorelbine tartrate: Given IV dexamethasone: Given IV etoposide phosphate: Given IV cisplatin: Given IV cytarabine: Given IV filgrastim: Given IV or subcutaneously
    All Cause Mortality
    Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Affected / at Risk (%)# Events
    Total/ (NaN)
    Serious Adverse Events
    Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Affected / at Risk (%)# Events
    Total2/278 (0.7%)
    Infections and infestations
    Infections and infestations - Other, specify1/278 (0.4%) 1
    Investigations
    CPK increased1/278 (0.4%) 1
    Metabolism and nutrition disorders
    Acidosis1/278 (0.4%) 1
    Vascular disorders
    Thromboembolic event1/278 (0.4%) 1
    Other (Not Including Serious) Adverse Events
    Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
    Affected / at Risk (%)# Events
    Total80/278 (28.8%)
    Blood and lymphatic system disorders
    Febrile neutropenia18/278 (6.5%) 18
    Ear and labyrinth disorders
    Hearing impaired2/278 (0.7%) 2
    Tinnitus2/278 (0.7%) 2
    Endocrine disorders
    Delayed puberty1/278 (0.4%) 1
    Hypothyroidism1/278 (0.4%) 1
    Eye disorders
    Eye pain1/278 (0.4%) 1
    Optic nerve disorder1/278 (0.4%) 1
    Gastrointestinal disorders
    Abdominal pain3/278 (1.1%) 3
    Constipation3/278 (1.1%) 3
    Enterocolitis1/278 (0.4%) 1
    Esophageal pain1/278 (0.4%) 1
    Esophagitis1/278 (0.4%) 1
    Ileus2/278 (0.7%) 2
    Mucositis oral4/278 (1.4%) 4
    Nausea10/278 (3.6%) 10
    Oral pain2/278 (0.7%) 2
    Vomiting10/278 (3.6%) 10
    General disorders
    Fatigue4/278 (1.4%) 4
    Pain2/278 (0.7%) 2
    Immune system disorders
    Anaphylaxis1/278 (0.4%) 1
    Infections and infestations
    Bladder infection1/278 (0.4%) 1
    Catheter related infection2/278 (0.7%) 2
    Infections and infestations - Other, specify12/278 (4.3%) 12
    Lung infection1/278 (0.4%) 1
    Skin infection1/278 (0.4%) 1
    Soft tissue infection1/278 (0.4%) 1
    Tracheitis1/278 (0.4%) 1
    Upper respiratory infection2/278 (0.7%) 2
    Injury, poisoning and procedural complications
    Vascular access complication4/278 (1.4%) 4
    Investigations
    Alanine aminotransferase increased2/278 (0.7%) 2
    Aspartate aminotransferase increased2/278 (0.7%) 2
    Lymphocyte count decreased1/278 (0.4%) 1
    Neutrophil count decreased7/278 (2.5%) 7
    Platelet count decreased1/278 (0.4%) 1
    White blood cell decreased6/278 (2.2%) 6
    Metabolism and nutrition disorders
    Hyperglycemia3/278 (1.1%) 3
    Hyperkalemia1/278 (0.4%) 1
    Hypermagnesemia1/278 (0.4%) 1
    Hypokalemia7/278 (2.5%) 7
    Hyponatremia1/278 (0.4%) 1
    Hypophosphatemia3/278 (1.1%) 3
    Musculoskeletal and connective tissue disorders
    Arthralgia1/278 (0.4%) 1
    Bone pain2/278 (0.7%) 2
    Generalized muscle weakness1/278 (0.4%) 1
    Myalgia3/278 (1.1%) 3
    Nervous system disorders
    Headache3/278 (1.1%) 3
    Neuralgia4/278 (1.4%) 4
    Peripheral motor neuropathy2/278 (0.7%) 2
    Peripheral sensory neuropathy1/278 (0.4%) 1
    Syncope2/278 (0.7%) 2
    Vasovagal reaction1/278 (0.4%) 1
    Psychiatric disorders
    Agitation1/278 (0.4%) 1
    Anxiety1/278 (0.4%) 1
    Depression1/278 (0.4%) 1
    Insomnia2/278 (0.7%) 2
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm1/278 (0.4%) 1
    Pharyngeal mucositis1/278 (0.4%) 1
    Pharyngolaryngeal pain1/278 (0.4%) 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular1/278 (0.4%) 1
    Vascular disorders
    Hypotension2/278 (0.7%) 2
    Thromboembolic event2/278 (0.7%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Must obtain prior Sponsor approval.

    Results Point of Contact

    Name/TitleResults Reporting Coordinator
    OrganizationChildren's Oncology Group
    Phone626-447-0064
    Emailresultsreportingcoordinator@childrensoncologygroup.org
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT00302003
    Other Study ID Numbers:
    • AHOD0431
    • NCI-2009-00377
    • CDR0000459962
    • U10CA098543
    • COG-AHOD0431
    First Posted:
    Mar 13, 2006
    Last Update Posted:
    Mar 30, 2021
    Last Verified:
    Aug 1, 2016