Combination Chemotherapy in Treating Young Patients With Hodgkin's Lymphoma

NCT ID: NCT00433459

Last Updated: 2020-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 2134 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2013-01-31

Brief Summary

RATIONALE: 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. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying different combination chemotherapy regimens to compare how well they work in treating young patients with Hodgkin's lymphoma.

Detailed Description

OBJECTIVES:

Primary

• Determine whether the 5-year event-free survival (EFS) rate in pediatric patients with Hodgkin's lymphoma with an adequate response after 2 courses of vincristine, etoposide, prednisone, and doxorubicin hydrochloride (OEPA) (without radiotherapy) are consistent with an estimated target EFS rate of 90%.
• Compare the EFS (without a deterioration) of patients treated with procarbazine hydrochloride vs dacarbazine (treatment groups 2 and 3).
• Determine the treatment outcome of a standardized risk-adapted relapse strategy in these patients.

Secondary

• Determine whether the 5-year EFS rate in patients with Hodgkin's lymphoma with an inadequate response after 2 OEPA courses and standard involved-field radiotherapy are consistent with an estimated target EFS rate of 90%.
• Determine whether a positive positron emission tomography scan before planned high-dose chemotherapy with autologous stem cell transplantation has a negative prognostic significance.
• Compare the effect of dacarbazine vs procarbazine on the rate of infertility in males and premature menopause in females (treatment groups 2 and 3).

Tertiary

• Determine the impact of real-time central staging and response assessment on treatment outcome in these patients.

OUTLINE: This is a randomized, controlled, parallel-group, open-label, multicenter study. Patients are stratified according to staging and response assessment (central vs local) and disease stage (IA/B or IIA [first-line treatment group 1] vs I_EA/B, II_EA, IIB, or IIIA [first-line treatment group 2] vs II_EB, III_E A/B, IIIB, or IVA/B [first-line treatment group 3]).

• First-line treatment group 1: Patients receive oral prednisone (or prednisolone) 3 times daily on days 1-15, vincristine IV on days 1, 8, and 15, doxorubicin hydrochloride IV over 1-6 hours on days 1 and 15, and etoposide (or etoposide phosphate) IV over 1-2 hours on days 1-5 (OEPA).

Treatment repeats every 28 days for 2 courses in the absence of unacceptable toxicity. Patients are assessed by fludeoxyglucose F 18 positron emission tomography (^18FDG-PET) scan. Patients with inadequate response undergo radiotherapy within 35 days after completion of OEPA.

• First-line treatment group 2: Patients receive OEPA as in group 1. After completion of OEPA, patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral prednisone (or prednisolone) 3 times daily and oral procarbazine hydrochloride 2-3 times a day on days 1-15 and vincristine IV and cyclophosphamide IV over 1 hour on days 1 and 8 (COPP).
• Arm II: Patients receive oral prednisone (or prednisolone) 3 times daily on days 1-15, dacarbazine IV over 15-30 minutes on days 1-3, and vincristine IV and cyclophosphamide IV over 1 hour on days 1 and 8 (COPDAC).

In both arms, treatment repeats every 28 days for 2 courses in the absence of unacceptable toxicity. Patients are assessed by ^18FDG-PET scan. Patients with an inadequate response undergo radiotherapy within 35 days after completion of COPP or COPDAC.

• First-line treatment group 3: Patients receive OEPA as in group 1. After completion of OEPA, patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive COPP as in arm I of group 2.
• Arm II: Patients receive COPDAC as in arm II of group 2. In both arms, treatment repeats every 28 days for 4 courses in the absence of unacceptable toxicity. Patients are assessed by ^18FDG-PET scan. Patients with an inadequate response undergo radiotherapy within 35 days after completion of COPP or COPDAC.

Patients with biopsy-confirmed disease progression OR relapse after first-line treatment on this study or on protocols DAL-HD 90, GPOH-HD 95, GPOHHD 2002 Pilot, or similar treatment proceed to second-line therapy. Patients are stratified according to relapse/progression status (late relapse from first-line treatment group 1 [second-line treatment group 1] vs early relapse from first-line treatment groups 1, 2, or 3 or late relapse from first-line treatment groups 2 or 3 [second-line treatment group 2] vs disease progression [second-line treatment group 3]). Patients undergo a ^18FDG-PET scan prior to beginning second-line therapy.

• Second-line treatment group 1: Patients receive ifosfamide IV over 22 hours and etoposide IV over 1-2 hours and oral prednisone three times daily on days 1-5 (IEP). Patients then receive doxorubicin hydrochloride IV over 1-6 hours, bleomycin IV, vinblastine IV, and dacarbazine IV over 15-30 minutes on days 22 and 36 (ABVD). Treatment repeats every 50 days for 2 courses in the absence of disease progression or unacceptable toxicity.

After chemotherapy treatment, patients undergo radiotherapy.

• Second-line treatment group 2: Patients receive IEP and ABVD as in group 1. Autologous stem cells are collected after course 1 or 2 of IEP/ABVD.

After chemotherapy, patients with an adequate response undergo radiotherapy. Patients with an inadequate response undergo high-dose chemotherapy comprising carmustine IV over 1-2 hours on day -7, etoposide IV and cytarabine IV over 30 minutes twice daily on days -6 to -3, and melphalan IV over 1½ hours on day -2. Patients then undergo autologous hematopoietic stem cell transplantation (HSCT).

Patients undergo a ^18FDG-PET scan on day 50-54. Patients with ^18FDG-PET scan positive disease undergo radiotherapy.

• Second-line treatment group 3: Patients receive IEP and ABVD as in group 1. All patients then undergo high-dose chemotherapy and HSCT as in group 2.

Patients undergo a ^18FDG-PET scan on day 50-54. Patients with ^18FDG-PET scan positive disease undergo radiotherapy.

After completion of study therapy, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 2,150 patients will be accrued for this study.

Conditions

Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

COPP

procarbazine-containing consolidation chemotherapy arm

Group Type: ACTIVE_COMPARATOR

cyclophosphamide

Intervention Type: DRUG

drug is used in first line treatment in combination (COPP or COPDAC)

prednisolone

Intervention Type: DRUG

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

prednisone

Intervention Type: DRUG

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

procarbazine hydrochloride

Intervention Type: DRUG

drug is used in first line treatment in combination (COPP)

vincristine sulfate

Intervention Type: DRUG

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

fludeoxyglucose F 18

Intervention Type: RADIATION

used as a diagnostic marker for metabolically active tumour at staging and response assessment

radiation therapy

Intervention Type: RADIATION

part of combination treatment (combined modality between chemo- and radiotherapy)

COPDAC

procarbazine-free consolidation chemotherapy arm

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

drug is used in first line treatment in combination (COPP or COPDAC)

dacarbazine

Intervention Type: DRUG

drug is used in first line treatment in combination (COPDAC)

prednisolone

Intervention Type: DRUG

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

prednisone

Intervention Type: DRUG

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

vincristine sulfate

Intervention Type: DRUG

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

fludeoxyglucose F 18

Intervention Type: RADIATION

used as a diagnostic marker for metabolically active tumour at staging and response assessment

radiation therapy

Intervention Type: RADIATION

part of combination treatment (combined modality between chemo- and radiotherapy)

Interventions

cyclophosphamide

drug is used in first line treatment in combination (COPP or COPDAC)

Intervention Type: DRUG

dacarbazine

drug is used in first line treatment in combination (COPDAC)

Intervention Type: DRUG

prednisolone

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

Intervention Type: DRUG

prednisone

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

Intervention Type: DRUG

procarbazine hydrochloride

drug is used in first line treatment in combination (COPP)

Intervention Type: DRUG

vincristine sulfate

drug is used in first line treatment in combination (OEPA, COPP or COPDAC)

Intervention Type: DRUG

fludeoxyglucose F 18

used as a diagnostic marker for metabolically active tumour at staging and response assessment

Intervention Type: RADIATION

radiation therapy

part of combination treatment (combined modality between chemo- and radiotherapy)

Intervention Type: RADIATION

Other Intervention Names

CYC; DTIC; VCR; IFRT

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed classical Hodgkin's lymphoma

• No lymphocyte-predominant Hodgkin's lymphoma
• Fine-needle biopsy not sufficient
• No prior treatment for Hodgkin's lymphoma except for recommended pre-phase therapy for a large mediastinal tumor

PATIENT CHARACTERISTICS:

• No known hypersensitivity or contraindication to study drugs
• No other current malignancy
• No severe concurrent disease (e.g., immune deficiency syndrome)
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for up to 1 year after completion of study treatment
• No known HIV positivity

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy or radiotherapy
• At least 30 days since prior and no other concurrent investigational drugs or participation in another investigational trial

• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Deutsche Krebshilfe e.V., Bonn (Germany)

OTHER

Sponsor Role: collaborator

Euronet Worldwide

OTHER

Sponsor Role: collaborator

Christine Mauz-Körholz

OTHER

Sponsor Role: lead

Responsible Party

Christine Mauz-Körholz

Prof. Dr. med. Christine Mauz-Körholz

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Dieter Koerholz, MD

Role: STUDY_CHAIR

Martin-Luther-Universität Halle-Wittenberg

W. Hamish Wallace, MD

Role: PRINCIPAL_INVESTIGATOR

Royal Hospital for Sick Children

Judith Landman-Parker, MD

Role: PRINCIPAL_INVESTIGATOR

Hopital d'Enfants Trousseau

Locations

Universitaetsklinikum Giessen-Marburg

Giessen, , Germany

Royal Hospital for Sick Children

Edinburgh, Scotland, United Kingdom

Countries

Germany; United Kingdom

References

Daw S, Claviez A, Kurch L, Stoevesandt D, Attarbaschi A, Balwierz W, Beishuizen A, Cepelova M, Ceppi F, Fernandez-Teijeiro A, Fossa A, Georgi TW, Hjalgrim LL, Hraskova A, Leblanc T, Mascarin M, Pears J, Landman-Parker J, Prelog T, Klapper W, Ramsay A, Kluge R, Dieckmann K, Pelz T, Vordermark D, Korholz D, Hasenclever D, Mauz-Korholz C. Transplant and Nontransplant Salvage Therapy in Pediatric Relapsed or Refractory Hodgkin Lymphoma: The EuroNet-PHL-R1 Phase 3 Nonrandomized Clinical Trial. JAMA Oncol. 2025 Mar 1;11(3):258-267. doi: 10.1001/jamaoncol.2024.5636.

Reference Type: DERIVED

PMID: 39745682 (View on PubMed)

Pabari R, McCarten K, Flerlage J, Lai H, Mauz-Korholz C, Dieckmann K, Palese M, Kaste S, Castellino SM, Kelly KM, Stoevesandt D, Kurch L. Hodgkin lymphoma involving the extra-axial CNS: an AHOD1331, PHL-C1, and PHL-C2 report from the COG and EuroNet-PHL. Blood Adv. 2024 Sep 24;8(18):4856-4865. doi: 10.1182/bloodadvances.2023012346.

Reference Type: DERIVED

PMID: 39058968 (View on PubMed)

Castellino SM, Giulino-Roth L, Harker-Murray P, Kahn JM, Forlenza C, Cho S, Hoppe B, Parsons SK, Kelly KM; COG Hodgkin Lymphoma Committee. Children's Oncology Group's 2023 blueprint for research: Hodgkin lymphoma. Pediatr Blood Cancer. 2023 Sep;70 Suppl 6(Suppl 6):e30580. doi: 10.1002/pbc.30580. Epub 2023 Jul 28.

Reference Type: DERIVED

PMID: 37505794 (View on PubMed)

Mauz-Korholz C, Landman-Parker J, Fernandez-Teijeiro A, Attarbaschi A, Balwierz W, Bartelt JM, Beishuizen A, Boudjemaa S, Cepelova M, Ceppi F, Claviez A, Daw S, Dieckmann K, Fossa A, Gattenlohner S, Georgi T, Hjalgrim LL, Hraskova A, Karlen J, Kurch L, Leblanc T, Mann G, Montravers F, Pears J, Pelz T, Rajic V, Ramsay AD, Stoevesandt D, Uyttebroeck A, Vordermark D, Korholz D, Hasenclever D, Wallace WH, Kluge R. Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study. Lancet Oncol. 2023 Mar;24(3):252-261. doi: 10.1016/S1470-2045(23)00019-0.

Reference Type: DERIVED

PMID: 36858722 (View on PubMed)

Mauz-Korholz C, Landman-Parker J, Balwierz W, Ammann RA, Anderson RA, Attarbaschi A, Bartelt JM, Beishuizen A, Boudjemaa S, Cepelova M, Claviez A, Daw S, Dieckmann K, Fernandez-Teijeiro A, Fossa A, Gattenlohner S, Georgi T, Hjalgrim LL, Hraskova A, Karlen J, Kluge R, Kurch L, Leblanc T, Mann G, Montravers F, Pears J, Pelz T, Rajic V, Ramsay AD, Stoevesandt D, Uyttebroeck A, Vordermark D, Korholz D, Hasenclever D, Wallace WH. Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. Lancet Oncol. 2022 Jan;23(1):125-137. doi: 10.1016/S1470-2045(21)00470-8. Epub 2021 Dec 9.

Reference Type: DERIVED

PMID: 34895479 (View on PubMed)

Related Links

https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?a=8&id=NCI-2014-02026&loc=0&rl=2&st=C7258&t=C9357

Clinical trial summary from the National Cancer Institute's PDQ® database

Other Identifiers

EURONET-PHL-C1

Identifier Type: -

Identifier Source: secondary_id

EU-20703

Identifier Type: -

Identifier Source: secondary_id

EUDRACT-2006-000995-33

Identifier Type: -

Identifier Source: secondary_id

CCLG-HD-2007-10

Identifier Type: -

Identifier Source: secondary_id

CDR0000531687

Identifier Type: -

Identifier Source: org_study_id