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)
• Enrollment: 287
• Location: 1
• Arm: 1
• Duration (Months): 160.9
• Patients Per Site Per Month: 1.8

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.

Condition or Disease	Intervention/Treatment	Phase
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	Radiation: radiation therapy; Drug: doxorubicin hydrochloride; Drug: vincristine sulfate; Drug: prednisone; Drug: cyclophosphamide; Drug: ifosfamide; Drug: vinorelbine tartrate; Drug: dexamethasone; Drug: etoposide phosphate; Drug: cisplatin; Drug: cytarabine; Biological: filgrastim	Phase 3

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

Arm

Intervention/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

	Site	City	State	Country	Postal Code
1	Children's Oncology Group	Arcadia	California	United States	91006-3776

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:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

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

• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Ifosfamide; Doxorubicin; Liposomal doxorubicin; Etoposide; Vincristine; Vinorelbine; Etoposide phosphate

Study Results

Participant Flow

Arm/Group Title	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Arm/Group Description	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
Period Title: Overall Study
STARTED	287
COMPLETED	207
NOT COMPLETED	80

Baseline Characteristics

Arm/Group Title	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Arm/Group Description	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
Overall Participants	287
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

Title	Event Free Survival Without Receiving Radiation Therapy (EFSnoRT).
Description	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

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 Title	Group 1
Arm/Group Description	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Measure Participants	275
Number (95% Confidence Interval) [Probability of survival]	0.49

2. Primary Outcome

Title	Intensive Therapy Free Survival (ITFS).
Description	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

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 Title	Group 1
Arm/Group Description	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Measure Participants	275
Number (95% Confidence Interval) [Probability of survival]	0.89

3. Primary Outcome

Title	Event Free Survival (EFS)
Description	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

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 Title	Group 1
Arm/Group Description	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Measure Participants	278
Number (95% Confidence Interval) [Probability of survival]	0.79

4. Secondary Outcome

Title	Overall Survival
Description	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

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 Title	Group 1
Arm/Group Description	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Measure Participants	278
Number (95% Confidence Interval) [Probability of survival]	0.99

Adverse Events

Arm/Group Title	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
Arm/Group Description	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
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
Total	2/278 (0.7%)
Infections and infestations
Infections and infestations - Other, specify	1/278 (0.4%)	1
Investigations
CPK increased	1/278 (0.4%)	1
Metabolism and nutrition disorders
Acidosis	1/278 (0.4%)	1
Vascular disorders
Thromboembolic event	1/278 (0.4%)	1
Other (Not Including Serious) Adverse Events
	Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim
	Affected / at Risk (%)	# Events
Total	80/278 (28.8%)
Blood and lymphatic system disorders
Febrile neutropenia	18/278 (6.5%)	18
Ear and labyrinth disorders
Hearing impaired	2/278 (0.7%)	2
Tinnitus	2/278 (0.7%)	2
Endocrine disorders
Delayed puberty	1/278 (0.4%)	1
Hypothyroidism	1/278 (0.4%)	1
Eye disorders
Eye pain	1/278 (0.4%)	1
Optic nerve disorder	1/278 (0.4%)	1
Gastrointestinal disorders
Abdominal pain	3/278 (1.1%)	3
Constipation	3/278 (1.1%)	3
Enterocolitis	1/278 (0.4%)	1
Esophageal pain	1/278 (0.4%)	1
Esophagitis	1/278 (0.4%)	1
Ileus	2/278 (0.7%)	2
Mucositis oral	4/278 (1.4%)	4
Nausea	10/278 (3.6%)	10
Oral pain	2/278 (0.7%)	2
Vomiting	10/278 (3.6%)	10
General disorders
Fatigue	4/278 (1.4%)	4
Pain	2/278 (0.7%)	2
Immune system disorders
Anaphylaxis	1/278 (0.4%)	1
Infections and infestations
Bladder infection	1/278 (0.4%)	1
Catheter related infection	2/278 (0.7%)	2
Infections and infestations - Other, specify	12/278 (4.3%)	12
Lung infection	1/278 (0.4%)	1
Skin infection	1/278 (0.4%)	1
Soft tissue infection	1/278 (0.4%)	1
Tracheitis	1/278 (0.4%)	1
Upper respiratory infection	2/278 (0.7%)	2
Injury, poisoning and procedural complications
Vascular access complication	4/278 (1.4%)	4
Investigations
Alanine aminotransferase increased	2/278 (0.7%)	2
Aspartate aminotransferase increased	2/278 (0.7%)	2
Lymphocyte count decreased	1/278 (0.4%)	1
Neutrophil count decreased	7/278 (2.5%)	7
Platelet count decreased	1/278 (0.4%)	1
White blood cell decreased	6/278 (2.2%)	6
Metabolism and nutrition disorders
Hyperglycemia	3/278 (1.1%)	3
Hyperkalemia	1/278 (0.4%)	1
Hypermagnesemia	1/278 (0.4%)	1
Hypokalemia	7/278 (2.5%)	7
Hyponatremia	1/278 (0.4%)	1
Hypophosphatemia	3/278 (1.1%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	1/278 (0.4%)	1
Bone pain	2/278 (0.7%)	2
Generalized muscle weakness	1/278 (0.4%)	1
Myalgia	3/278 (1.1%)	3
Nervous system disorders
Headache	3/278 (1.1%)	3
Neuralgia	4/278 (1.4%)	4
Peripheral motor neuropathy	2/278 (0.7%)	2
Peripheral sensory neuropathy	1/278 (0.4%)	1
Syncope	2/278 (0.7%)	2
Vasovagal reaction	1/278 (0.4%)	1
Psychiatric disorders
Agitation	1/278 (0.4%)	1
Anxiety	1/278 (0.4%)	1
Depression	1/278 (0.4%)	1
Insomnia	2/278 (0.7%)	2
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/278 (0.4%)	1
Pharyngeal mucositis	1/278 (0.4%)	1
Pharyngolaryngeal pain	1/278 (0.4%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/278 (0.4%)	1
Vascular disorders
Hypotension	2/278 (0.7%)	2
Thromboembolic event	2/278 (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.