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

A Phase III Study for the Treatment of Children and Adolescents With Newly Diagnosed Low Risk Hodgkin Disease

Status
Completed
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00302003
Enrollment
287
Registered
2006-03-13
Start date
2006-02-28
Completion date
2019-06-30
Last updated
2021-03-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Childhood Favorable Prognosis Hodgkin Lymphoma, Childhood Lymphocyte Depletion Hodgkin Lymphoma, Childhood Mixed Cellularity Hodgkin Lymphoma, Childhood Nodular Sclerosis Hodgkin Lymphoma, Stage I Childhood Hodgkin Lymphoma, Stage II Childhood Hodgkin Lymphoma

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: I. 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. II. 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. III. 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. IV. Maintain the overall survival for patients with low-risk Hodgkin's lymphoma at or above 97%. V. 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. VI. 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. VII. 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.

Interventions

BIOLOGICALfilgrastim

Given IV or subcutaneously

RADIATIONradiation therapy

Undergo radiation therapy

DRUGdoxorubicin hydrochloride

Given IV

DRUGvincristine sulfate

Given IV

DRUGprednisone

Given orally

DRUGcyclophosphamide

Given IV

DRUGifosfamide

Given IV

DRUGvinorelbine tartrate

Given IV

DRUGdexamethasone

Given IV

DRUGetoposide phosphate

Given IV

DRUGcisplatin

Given IV

DRUGcytarabine

Given IV

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Children's Oncology Group
Lead SponsorNETWORK

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
No minimum to 21 Years
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

Design outcomes

Primary

MeasureTime frameDescription
Event Free Survival Without Receiving Radiation Therapy (EFSnoRT).At 60 monthsSurvival 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).
Intensive Therapy Free Survival (ITFS).At 60 monthsSurvival 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.
Event Free Survival (EFS)At 60 monthsSurvival 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

MeasureTime frameDescription
Overall SurvivalAt 60 monthsSurvival is defined as time from study entry to death due to any cause. Patients alive at last contact where censored at last contact.

Countries

United States

Participant flow

Participants by arm

ArmCount
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 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
287
Total287

Withdrawals & dropouts

PeriodReasonFG000
Overall StudyIneligible9
Overall StudyLack of Efficacy62
Overall StudyLost to Follow-up1
Overall StudyPhysician Decision2
Overall StudyProtocol Violation1
Overall StudyWithdrawal by Subject5

Baseline characteristics

CharacteristicDoxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Age, Categorical
<=18 years
272 Participants
Age, Categorical
>=65 years
0 Participants
Age, Categorical
Between 18 and 65 years
15 Participants
Age, Continuous15 Years
Ethnicity (NIH/OMB)
Hispanic or Latino
43 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
227 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
17 Participants
Race (NIH/OMB)
American Indian or Alaska Native
3 Participants
Race (NIH/OMB)
Asian
8 Participants
Race (NIH/OMB)
Black or African American
29 Participants
Race (NIH/OMB)
More than one race
0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
Race (NIH/OMB)
Unknown or Not Reported
27 Participants
Race (NIH/OMB)
White
220 Participants
Region of Enrollment
Australia
3 participants
Region of Enrollment
Canada
25 participants
Region of Enrollment
Israel
1 participants
Region of Enrollment
Mexico
1 participants
Region of Enrollment
New Zealand
2 participants
Region of Enrollment
Puerto Rico
4 participants
Region of Enrollment
Switzerland
1 participants
Region of Enrollment
United States
250 participants
Sex: Female, Male
Female
160 Participants
Sex: Female, Male
Male
127 Participants

Adverse events

Event typeEG000
affected / at risk
deaths
Total, all-cause mortality
— / —
other
Total, other adverse events
80 / 278
serious
Total, serious adverse events
2 / 278

Outcome results

Primary

Event Free Survival (EFS)

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).

Time frame: At 60 months

Population: Eligible (n=278). Follow-up for censored patients (n=223) is 75 months (range: 4.7 to 108 months).

ArmMeasureValue (NUMBER)
Group 1Event Free Survival (EFS)0.79 Probability of survival
Primary

Event Free Survival Without Receiving Radiation Therapy (EFSnoRT).

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).

Time frame: At 60 months

Population: 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).

ArmMeasureValue (NUMBER)
Group 1Event Free Survival Without Receiving Radiation Therapy (EFSnoRT).0.49 Probability of survival
Primary

Intensive Therapy Free Survival (ITFS).

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.

Time frame: At 60 months

Population: 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).

ArmMeasureValue (NUMBER)
Group 1Intensive Therapy Free Survival (ITFS).0.89 Probability of survival
Secondary

Overall Survival

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

Time frame: At 60 months

Population: Eligible (n=278). Follow-up for censored patients (n=277) is 76 months (range: 4.7 to 109 months).

ArmMeasureValue (NUMBER)
Group 1Overall Survival0.99 Probability of survival

Source: ClinicalTrials.gov · Data processed: Feb 19, 2026