Combination Chemotherapy With or Without Radiation Therapy in Treating Young Patients With Favorable-Risk Hodgkin Lymphoma

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00846742
• Collaborator: (none)
• Enrollment: 88
• Locations: 6
• Arm: 1
• Anticipated Duration (Months): 171.9
• Patients Per Site: 14.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial is studying how well combination chemotherapy with or without radiation therapy works in treating young patients with favorable-risk Hodgkin lymphoma. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine, mechlorethamine hydrochloride, vincristine sulfate, bleomycin, etoposide, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells for those patients that still had residual cancer at the end of chemotherapy. Giving combination chemotherapy with radiation therapy may kill more cancer cells and allow doctors to save the part of the body where the cancer started.

Condition or Disease	Intervention/Treatment	Phase
Hodgkin Lymphoma	Drug: Stanford V Chemotherapy; Radiation: Radiation Therapy	Phase 2

Detailed Description

Patients receive doxorubicin hydrochloride intravenously (IV) and vinblastine IV on day 1 of weeks 1, 3, 5, and 7; mechlorethamine hydrochloride IV on day 1 of weeks 1 and 5; vincristine sulfate IV and bleomycin IV on day 1 of weeks 2, 4, 6, and 8; etoposide IV on day 1 of weeks 3 and 7; and prednisone orally (PO) three times daily every other day for 8 weeks. Two to 3 weeks after all chemotherapy is given, patients not achieving a complete response undergo radiation therapy to individual nodal sites (tailored fields).

PRIMARY OBJECTIVES:

1. To increase the complete response rate of favorable risk patients (excluding all patients with stage IA nodular lymphocyte predominant Hodgkin lymphoma) after 8 weeks Stanford V by at least 20% compared to favorable risk patients on HOD 99 after 8 weeks vincristine, doxorubicin hydrochloride, methotrexate and prednisone (VAMP).

SECONDARY OBJECTIVES:

1. To estimate the disease failure rate within the radiation fields.

2. To examine patterns of treatment failure for children treated with low dose tailored field radiation therapy.

3. To describe acute hematologic and infectious toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia, and hospitalizations, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

4. To compare the survival distributions (event-free and overall) and cumulative incidence of local failure and toxicities of favorable risk patients treated with 8 weeks of Stanford V chemotherapy and low-dose tailored-field radiation to those on the favorable risk group of the HOD 99 study that received VAMP and low-dose involved-field radiation.

5. To compare the survival distributions between patients that will not be prescribed radiotherapy after 8 weeks Stanford V and those patients on HOD 99 that did not receive radiotherapy after VAMP.

6. To estimate the event-free survival distributions of favorable risk patients treated with Stanford V chemotherapy alone and patients treated with Stanford V chemotherapy plus low dose tailored field radiation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 88 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Reduced Duration Stanford V Chemotherapy With or Without Low-Dose Tailored-Field Radiation Therapy For Favorable Risk Pediatric Hodgkin Lymphoma
• Actual Study Start Date: Jun 5, 2009
• Actual Primary Completion Date: Jan 11, 2019
• Anticipated Study Completion Date: Oct 1, 2023

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment Participants receive Stanford V Chemotherapy with or without radiation therapy. Patients receive doxorubicin hydrochloride IV and vinblastine IV on day 1 of weeks 1, 3, 5, and 7; mechlorethamine hydrochloride IV on day 1 of weeks 1 and 5; vincristine sulfate IV and bleomycin IV on day 1 of weeks 2, 4, 6, and 8; etoposide IV on day 1 of weeks 3 and 7; and prednisone orally (PO) three times daily every other day of weeks 1-8. Beginning 2-3 weeks after completion of chemotherapy, patients not achieving complete response undergo radiation therapy to individual nodal sites (tailored fields)

Drug: Stanford V Chemotherapy; The Stanford V regimen is an abbreviated, multi-agent, dose-intensive regimen that utilizes many of the most active chemotherapy agents for Hodgkin lymphoma: Vinblastine, Doxorubicin, Vincristine, Bleomycin, Mechlorethamine, Etoposide, and Prednisone; Radiation: Radiation Therapy; Patients who achieve less than a complete response after 8 weeks of chemotherapy will receive 25.5 Gy to individual nodal sites (tailored fields) starting 2-3 weeks following completion of all chemotherapy and recovery of ANC to at least 1000.

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate Estimate [8 weeks]

   To increase the complete response rate of favorable risk patients (excluding all patients with stage IA nodular lymphocyte predominant Hodgkin lymphoma) after 8 weeks Stanford V by at least 20% compared to favorable risk patients on HOD 99 after 8 weeks VAMP (NCT number: NCT00145600) .Complete response definition: Disappearance of all measurable or evaluable disease, signs, symptoms and biochemical changes related to the tumor. Biopsy confirmation is not mandatory. Residual PET-negative CT scan abnormalities representing > 75% reduction (as measured by the product of 2 perpendicular diameters of lesions by CT or MR imaging) in the original tumor volume will be considered scar tissue without active tumor.

Secondary Outcome Measures

1. Disease Failure Rate Within Radiation Fields [median 2 year post therapy]

   Defined as disease that recurs in the initially involved nodal region within the field of irradiation. The disease failure rate within the radiation fields will be estimated with a 95% confidence interval using appropriate methods (e.g., estimate cumulative incidence in the presence of competing risks).

2. Treatment Failure Patterns for Children Treated With Tailored-field Radiation [median 2 years post therapy]

   Descriptive statistics related to local/distant failure will be produced. The cumulative incidence of local failure will be estimated and effects of prognostic factors will be examined. Effect of competing risks (distant failure, second malignancy and death) will be taken into account. Relapse rate within the radiation fields will be estimated and confidence interval will also be calculated.

3. Acute Hematologic Toxicities [6 months]

   Description of acute hematologic toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The acute hematologic toxicities were summarized descriptively.

4. Acute Infectious Toxicities [6 months]

   Description of acute infectious toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The acute infectious toxicities were summarized descriptively.

5. Comparison of Event-free and Overall Survival Distributions, Cumulative Incidence of Local Failure, and Toxicities of Patients Treated on This Study to Outcome and Toxicities in the Favorable Risk Group of HOD99 [median 2 years post therapy]

   Log-rank tests used to compare event-free survival and overall survival. Event-free survival is defined as time interval from the date of study enrollment to the date of first event (relapsed or progressive disease, second malignancy, or death from any cause) or to last follow-up for patients without events. Survival is defined as time interval from study enrollment to date of death from any cause or to date of last follow-up. Gray's test used to compare cumulative incidence of local failure between favorable risk patients treated on this protocol vs. treated on HOD99 and other regimens.

6. Comparison of Event-free Survival Distributions Between Patients That Will Not be Prescribed Radiotherapy After 8 Weeks Stanford V and Those Patients on HOD99 That Received VAMP Without Radiotherapy [median 2 years post therapy]

   Log-rank tests used to compare event-free survival and overall survival. Event-free survival is defined as time interval from the date of study enrollment to the date of first event (relapsed or progressive disease, second malignancy, or death from any cause) or to last follow-up for patients without events. Survival is defined as time interval from study enrollment to date of death from any cause or to date of last follow-up. Gray's test used to compare cumulative incidence of local failure between favorable risk patients treated on this protocol vs. treated on HOD99 and other regimens.

7. Event-free Survival Distributions of Favorable Risk Patients Treated With Stanford V Chemotherapy Alone and Patients Treated With Stanford V Chemotherapy Plus Low Dose Tailored-field Radiation [median 2 years post therapy]

   Event-free survival distributions of favorable risk patients treated with Stanford V chemotherapy alone and patients treated with Stanford V chemotherapy plus low dose tailored field radiation will be estimated by the Kaplan-Meier method.

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, previously untreated Hodgkin lymphoma.

• Age: Participants must be 21 years of age or younger

• Stage must be classified as one of the following:

Ann Arbor stage IA or IIA with:

• Non-bulky mediastinal disease (< 33% mediastinal to thoracic ratio on CXR)

• < 3 nodal regions involved on the same side of the diaphragm

• No "E" lesion

• Female patients who are post-menarchal must have a negative pregnancy test. Patients of reproductive potential must agree to use an effective contraceptive method.

• Signed informed consent

• If re-evaluation of a patient's disease shows intermediate risk features, the patient will be removed from the HOD08.

Exclusion Criteria:

• Intermediate or High risk disease, defined as Stage IB, any III or IV or IA/IIA with "E" lesion(s), 3 or more nodal sites involved, or bulky mediastinal adenopathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Packard Children's Hospital, Stanford University	Palo Alto	California	United States	94304
2	Rady Children's Hospital- San Diego	San Diego	California	United States	92123
3	Children's Hospital of Illinois at OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
4	Maine Children's Cancer Program (MCCP)	Scarborough	Maine	United States	04074
5	Dana-Farber Harvard Cancer Center	Boston	Massachusetts	United States	02115
6	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• St. Jude Children's Research Hospital

Investigators

• Principal Investigator: Jamie Flerlage, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 25, 2022

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT00846742
• Other Study ID Numbers: HOD08; NCI-2009-01138
• First Posted: Feb 19, 2009
• Last Update Posted: Aug 11, 2022
• Last Verified: Aug 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by St. Jude Children's Research Hospital: Hodgkin Lymphoma
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease

Study Results

Participant Flow

Recruitment Details	88 participants were enrolled from 5 institutions between June 2009 and October 2018.
Pre-assignment Detail	Two out of 88 enrolled patients are ineligible and were removed from the study. They were determined to be intermediate risk rather than low risk. One was taken off study after being re-consented on an expired consent and treated with cyclophosphamide instead of mechlorethamine; 1 patient withdrew from study but was evaluable for primary objective.

Arm/Group Title	Stanford V Chemotherapy
Arm/Group Description	Ann Arbor stage IA or IIA with: Non-bulky mediastinal disease (<33% mediastinal to thoracic ratio on chest x-ray) < 3 nodal regions involved on the same side of the diaphragm No extranodal extension of disease
Period Title: Overall Study
STARTED	85
With Radiation Therapy (RT)	17
Without Radiation Therapy (RT)	68
COMPLETED	84
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Stanford V Chemotherapy
Arm/Group Description	Ann Arbor stage IA or IIA with: Non-bulky mediastinal disease (<33% mediastinal to thoracic ratio on chest x-ray) < 3 nodal regions involved on the same side of the diaphragm No extranodal extension of disease
Overall Participants	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.6 (4.5)
Sex: Female, Male (Count of Participants)
Female	33 38.8%
Male	52 61.2%
Race/Ethnicity, Customized (Count of Participants)
White	66 77.6%
Black	8 9.4%
Asian	3 3.5%
Multiple Race (NOS)	3 3.5%
Other	3 3.5%
American Ind / Alaskan / White	1 1.2%
Asian and White	1 1.2%
Region of Enrollment (Count of Participants)
St. Jude Children's Research Hospital	46 54.1%
Stanford University Medical Center	15 17.6%
Dana Farber Cancer Institute	13 15.3%
Rady Children's Hospital San Diego	6 7.1%
Maine Medical Center	5 5.9%
Stage: IA, IIA (Count of Participants)
IA	29 34.1%
IIA	56 65.9%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate Estimate
Description	To increase the complete response rate of favorable risk patients (excluding all patients with stage IA nodular lymphocyte predominant Hodgkin lymphoma) after 8 weeks Stanford V by at least 20% compared to favorable risk patients on HOD 99 after 8 weeks VAMP (NCT number: NCT00145600) .Complete response definition: Disappearance of all measurable or evaluable disease, signs, symptoms and biochemical changes related to the tumor. Biopsy confirmation is not mandatory. Residual PET-negative CT scan abnormalities representing > 75% reduction (as measured by the product of 2 perpendicular diameters of lesions by CT or MR imaging) in the original tumor volume will be considered scar tissue without active tumor.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stanford V Chemotherapy
Arm/Group Description	Non-stage IA non-LP favorable risk participants receive 8 weeks of Stanford V chemotherapy.
Measure Participants	56
Number (95% Confidence Interval) [percentage of participants]	77 90.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stanford V Chemotherapy
	Comments	The proportion of patients' complete response rate was provided with a 95% confidence interval.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Comparison of proportion of patients' complete response rate between HOD99 (NCT number: NCT00145600) and HOD08
	Method	Exact Binominal Test
	Comments

2. Secondary Outcome

Title	Disease Failure Rate Within Radiation Fields
Description	Defined as disease that recurs in the initially involved nodal region within the field of irradiation. The disease failure rate within the radiation fields will be estimated with a 95% confidence interval using appropriate methods (e.g., estimate cumulative incidence in the presence of competing risks).
Time Frame	median 2 year post therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Treatment Failure Patterns for Children Treated With Tailored-field Radiation
Description	Descriptive statistics related to local/distant failure will be produced. The cumulative incidence of local failure will be estimated and effects of prognostic factors will be examined. Effect of competing risks (distant failure, second malignancy and death) will be taken into account. Relapse rate within the radiation fields will be estimated and confidence interval will also be calculated.
Time Frame	median 2 years post therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Acute Hematologic Toxicities
Description	Description of acute hematologic toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The acute hematologic toxicities were summarized descriptively.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stanford V Chemotherapy
Arm/Group Description	Ann Arbor stage IA or IIA with: Non-bulky mediastinal disease (<33% mediastinal to thoracic ratio on chest x-ray) < 3 nodal regions involved on the same side of the diaphragm No extranodal extension of disease
Measure Participants	85
Neutrophils/granulocytes (ANC/AGC)	64
Leukocytes (total WBC)	74
Lymphopenia	54
Hemoglobin	14
Platelets	1

5. Secondary Outcome

Title	Acute Infectious Toxicities
Description	Description of acute infectious toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The acute infectious toxicities were summarized descriptively.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stanford V Chemotherapy
Arm/Group Description	Ann Arbor stage IA or IIA with: Non-bulky mediastinal disease (<33% mediastinal to thoracic ratio on chest x-ray) < 3 nodal regions involved on the same side of the diaphragm No extranodal extension of disease
Measure Participants	85
Febrile neutropenia	8
Infection, Blood	2
Infection, Upper Airway NOS	1

6. Secondary Outcome

Title	Comparison of Event-free and Overall Survival Distributions, Cumulative Incidence of Local Failure, and Toxicities of Patients Treated on This Study to Outcome and Toxicities in the Favorable Risk Group of HOD99
Description	Log-rank tests used to compare event-free survival and overall survival. Event-free survival is defined as time interval from the date of study enrollment to the date of first event (relapsed or progressive disease, second malignancy, or death from any cause) or to last follow-up for patients without events. Survival is defined as time interval from study enrollment to date of death from any cause or to date of last follow-up. Gray's test used to compare cumulative incidence of local failure between favorable risk patients treated on this protocol vs. treated on HOD99 and other regimens.
Time Frame	median 2 years post therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Comparison of Event-free Survival Distributions Between Patients That Will Not be Prescribed Radiotherapy After 8 Weeks Stanford V and Those Patients on HOD99 That Received VAMP Without Radiotherapy
Description	Log-rank tests used to compare event-free survival and overall survival. Event-free survival is defined as time interval from the date of study enrollment to the date of first event (relapsed or progressive disease, second malignancy, or death from any cause) or to last follow-up for patients without events. Survival is defined as time interval from study enrollment to date of death from any cause or to date of last follow-up. Gray's test used to compare cumulative incidence of local failure between favorable risk patients treated on this protocol vs. treated on HOD99 and other regimens.
Time Frame	median 2 years post therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Event-free Survival Distributions of Favorable Risk Patients Treated With Stanford V Chemotherapy Alone and Patients Treated With Stanford V Chemotherapy Plus Low Dose Tailored-field Radiation
Description	Event-free survival distributions of favorable risk patients treated with Stanford V chemotherapy alone and patients treated with Stanford V chemotherapy plus low dose tailored field radiation will be estimated by the Kaplan-Meier method.
Time Frame	median 2 years post therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Acute adverse events were collected from study enrollment up to 4 weeks after completion of chemotherapy/radiation therapy, whichever came last. Long term toxicity was captured at every visit up to 5 years from study enrollment.
Arm/Group Title	Stanford V Chemotherapy
Arm/Group Description	Ann Arbor stage IA or IIA with: Non-bulky mediastinal disease (<33% mediastinal to thoracic ratio on chest x-ray) < 3 nodal regions involved on the same side of the diaphragm No extranodal extension of disease
All Cause Mortality
	Stanford V Chemotherapy
	Affected / at Risk (%)	# Events
Total	1/85 (1.2%)
Serious Adverse Events
	Stanford V Chemotherapy
	Affected / at Risk (%)	# Events
Total	1/85 (1.2%)
Blood and lymphatic system disorders
Leukocytes (total WBC)	1/85 (1.2%)	1
Neutrophils/granulocytes (ANC/AGC)	1/85 (1.2%)	1
Other (Not Including Serious) Adverse Events
	Stanford V Chemotherapy
	Affected / at Risk (%)	# Events
Total	58/85 (68.2%)
Blood and lymphatic system disorders
Neutrophils/granulocytes (ANC/AGC)	39/85 (45.9%)	63
Leukocytes (total WBC)	36/85 (42.4%)	73
Lymphopenia	22/85 (25.9%)	54
Hemoglobin	9/85 (10.6%)	14
Infections and infestations
Febrile neutropenia	6/85 (7.1%)	8

Limitations/Caveats

During a mechlorethamine shortage cyclophosphamide was administered instead leading to inferior outcome in intermediate and high risk patients. These patients were replaced in this protocol. The study was closed early after our new protocol opened.

More Information

Certain Agreements

All Principal Investigators ARE 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.