Lymphoma
Conditions
Keywords
stage I adult Hodgkin lymphoma, stage II adult Hodgkin lymphoma
Brief summary
RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride, bleomycin sulfate, vinblastine, dacarbazine, cyclophosphamide, etoposide, procarbazine hydrochloride, vincristine sulfate, and prednisone, 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 combination chemotherapy together with radiation therapy may kill more cancer cells. Comparing results of imaging procedures, such as PET scans and CT scans, done before, during, and after chemotherapy may help doctors predict a patient's response to treatment and help plan the best treatment. PURPOSE: This phase II clinical trial studies how well chemotherapy based on PET/CT scan works in treating patients with stage I or stage II Hodgkin lymphoma.
Detailed description
OBJECTIVES: Primary * To evaluate the progression-free survival (PFS) at 36 months following registration for patients who are positron emission tomography (PET) negative after 2 courses of ABVD, and receive 4 additional courses of doxorubicin hydrochloride, bleomycin sulfate, vinblastine, and dacarbazine (ABVD) followed by involved-nodal radiotherapy \[INRT\] of 30-30.6 Gy. Secondary * To evaluate the PET-negative rate after 2 courses of ABVD chemotherapy in patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease. * To evaluate the PFS at 36 months for patients who are PET positive after 2 courses of chemotherapy and receive 4 courses of escalated bleomycin sulfate, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, and prednisone (BEACOPP) followed by INRT of 30-30.6 Gy. * To evaluate the complete response (CR) rate and overall survival (OS) for PET-positive and PET-negative patients after 2 courses of ABVD. * To identify sites of relapse following combined-modality therapy (CMT) for patients with large mediastinal adenopathy and correlate with RT fields. * To assess toxicity on both arms of study. * To assess reproductive function at baseline and at 3 years after ABVD or escalated BEACOPP with specific serum markers. * To bank serum and plasma at baseline and selected time points to assess the prognostic value of various markers such as, but not limited to, SCD30, IL10, CCL17, CCL22, and MDC. * To create tissue microarrays (TMAs) from patient tumor blocks for future biomarker assessment including, but not limited to, bcl-2, FOXP3, and macrophage content. * To measure serum TARC levels pre-treatment and post two courses of ABVD and correlate with PET-CT findings (performed at same time points) and 3 year PFS. Tertiary * To assess the predictive value of fludeoxyglucose F 18 (18FDG) uptake, as measured by semi-quantitative measurements including standard uptake variables (SUVs), with respect to response at the end of chemotherapy and PFS. * To compare the predictive value for response and PFS of FDG uptake alone to that of FDG uptake in combination with CT size change information. * To compare the predictive value for response and PFS of FDG uptake alone to that of FDG uptake in combination with available serum and tissue molecular biomarkers. * To compare the results of the secondary imaging objectives with the corresponding CALGB 50801 results (contingent on reaching agreement with CALGB on the combined analysis of the two studies). OUTLINE: This is a multicenter study. Induction ABVD chemotherapy: Patients receive doxorubicin hydrochloride IV, bleomycin sulfate IV, vinblastine IV over 3-5 minutes, and dacarbazine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients are then assigned to an intervention arm according to fludeoxyglucose F 18 (18 FDG) positron emission tomography (PET)/computed tomography (CT) results (negative vs positive). * ABVD (18FDG-PET/CT negative): Patients receive doxorubicin hydrochloride, bleomycin sulfate, vinblastine, and dacarbazine as in induction chemotherapy. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Within 3-6 weeks after completion of chemotherapy, patients undergo involved-node radiotherapy (INRT) 5 days a week for approximately 3½ weeks. * Escalated or standard BEACOPP\* (18FDG-PET/CT positive): Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 60 minutes on day 1, etoposide IV over 60 minutes on days 1-3, procarbazine hydrochloride orally (PO) on days 1-7, prednisone PO on days 1-14, and bleomycin sulfate IV and vincristine sulfate IV on day 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Within 3-6 weeks after completion of chemotherapy, patients who achieve complete response with a negative 18FDG-PET/CT scan undergo INRT 5 days a week for approximately 3½ weeks. NOTE: \*HIV-positive patients whose 18FDG-PET/CT scans are positive after two courses of induction ABVD receive 4 courses of standard BEACOPP followed by INRT. Patients undergo 18FDG-PET scans at baseline, and within 8-10 days after 2 courses of ABVD induction chemotherapy. Patients also undergo 18FDG-PET/CT\*\* scan within 3-8 weeks after completion of 4 courses of BEACOPP and 6 courses of ABVD, and 3 months after completion of INRT. NOTE: \*\*If PET/CT remains positive, then a biopsy may be performed if medically appropriate or clinically feasible at the discretion of the treating physician. If biopsy is positive, patients will be followed for survival and secondary malignancies or new primaries. Patients may undergo blood sample collection for correlative studies. After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually for up to 10 years.
Interventions
DRUGDoxorubicin
IV
DRUGBleomycin
IV
DRUGVinblastine
IV
DIAGNOSTIC_TESTPET
fludeoxyglucose F 18 Imaging exam
RADIATIONINRT
selective external radiation therapy
DRUGDacarbazine
IV
DRUGEtoposide
IV
DRUGCyclophosphamide
May be given orally, IV push, or by IV infusion
DRUGVincristine
IV
DRUGProcarbazine
PO
DRUGPrednisone
PO
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven classical Hodgkin lymphoma subclassified according to the World Health Organization (WHO) Classification of Tumors, 4th edition (2008) * Patients must have clinical stage IA, IB, IIA, or IIB disease * Patients with E extensions will be eligible if all other criteria have been met * Patients must have a mediastinal mass \> 0.33-cm maximum intrathoracic diameter on standing postero-anterior chest x-ray or measuring \> 10 cm in its largest diameter on axial CT images * Bone marrow biopsy is required * ECOG performance status 0-2 * ANC ≥ 1,000/μL * Platelet count ≥ 100,000/μL * Hemoglobin ≥ 10 g/dL * Serum creatinine ≤ 2 mg/dL * Direct bilirubin ≤ 2 mg/dL * AST/ALT ≤ 2 times upper limit of normal * Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception * LVEF by ECHO or MUGA normal unless thought to be disease related * DLCO ≥ 60% with no symptomatic pulmonary disease unless thought to be disease related * Patients with a history of intravenous drug abuse, or any behavior associated with an increased risk of HIV infection, should be tested for exposure to the HIV virus, and an HIV test is required for entry on this protocol * HIV-positive patients are eligible if they have CD4 counts ≥ 400/mm³ and are on concurrent antiretrovirals * Patient HIV status must be known prior to registration * HIV-positive patients must not have multi-drug resistant HIV infections; CD4 counts \< 400/mm³; or other concurrent AIDS-defining conditions * Concurrent antiretroviral therapy for HIV-positive patients (CD4 counts ≥ 400/mm³) allowed
Exclusion criteria
* Nodular lymphocyte-predominant Hodgkin lymphoma * Pregnant or nursing * Currently active second malignancy other than non-melanoma skin cancers * Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse * Prior treatment (chemotherapy or radiation therapy) for Hodgkin lymphoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Rate | Assessed at 36 months | Progression-free survival is defined as the time from study entry to lymphoma progression or death from any cause. Proportion of patients who are progression-free and alive at 36 months will be reported. Progression is defined as appearance of any new lesions more than 1.5 cm in any axis, at least a 50% increase from nadir in sum of the product of the diameters (SPD) of any previously involved nodes or extranodal masses or the size of other lesions, or at least 50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival at 36 Months Among Patients Who Are PET Positive After Induction Treatment | Assessed at 36 months | Progression-free survival is defined as the time from study entry to lymphoma progression or death from any cause. Proportion of patients who are progression-free and alive at 36 months will be reported. Progression is defined as appearance of any new lesions more than 1.5 cm in any axis, at least a 50% increase from nadir in sum of the product of the diameters (SPD) of any previously involved nodes or extranodal masses or the size of other lesions, or at least 50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. |
| Complete Response (CR) Rate After Induction Treatment | Assessed at end of Cycle 2 | Complete response (CR) is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. |
| Overall Survival | Assessed at 36 months | Overall survival is defined as the time from study entry to death or date last known alive. |
| Proportion of Patients Who Are PET Negative After Induction Treatment | Assessed at end of Cycle 2 | — |
| Serum and Plasma Banking | Baseline and post cycle 2 | To bank serum and plasma at baseline and follow-up time point to assess the prognostic value of various markers, such as but not limited to, SCD30, IL10, CCL17, CCL22, and MDC. |
| Biomarker Assessment Using Tissue Microarrays (TMAs) | Baseline and relapse/progression | To create TMAs from patient tumor blocks for future biomarker assessment including but not limited to bcl-2, FOXP3, and macrophage content. |
| The Association Between Thymus and Activation-related Chemokine (TARC) Levels and PET-CT Findings as Well as 3-year PFS | Baseline and cycle 2 for TARC assessments; 3 years for PFS | To measure serum TARC levels pre-treatment and after two cycles of ABVD and evaluate the associations between TARC levels and PET-CT findings as well as 3-year PFS. |
| Sites of Relapse Following Combined Modality Treatment | Assessed at 3, 12, 18, 24 and 36 months after INRT | — |
Countries
United States
Participant flow
Recruitment details
This study was activated on April 2, 2012, accrued its first patient on May 24, 2013, and closed on January 24, 2014 with a final accrual of 6 patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (ABVD + INRT) Induction ABVD chemotherapy: Patients receive doxorubicin hydrochloride IV, bleomycin sulfate IV, vinblastine IV over 3-5 minutes, and dacarbazine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for 2 courses.
PET-CT scan: Then patients undergo fludeoxyglucose F 18 (18 FDG) positron emission tomography (PET)/computed tomography (CT). If results are negative, patients receive the following treatment.
ABVD + INRT: Patients receive doxorubicin hydrochloride, bleomycin sulfate, vinblastine, and dacarbazine as in induction chemotherapy. Treatment repeats every 28 days for 4 courses. Within 3-6 weeks after completion of chemotherapy, patients undergo involved-node radiotherapy (INRT) 5 days a week for approximately 3½ weeks. | 4 |
| Arm B (ABVD + BEACOPP + INRT) Induction ABVD chemotherapy: Patients receive doxorubicin hydrochloride IV, bleomycin sulfate IV, vinblastine IV over 3-5 minutes, and dacarbazine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for 2 courses.
PET-CT scan: Then patients undergo fludeoxyglucose F 18 (18 FDG) positron emission tomography (PET)/computed tomography (CT). If results are positive, patients receive the following treatment.
BEACOPP + INRT: Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 60 minutes on day 1, etoposide IV over 60 minutes on days 1-3, procarbazine hydrochloride orally (PO) on days 1-7, prednisone PO on days 1-14, and bleomycin sulfate IV and vincristine sulfate IV on day 8. Treatment repeats every 21 days for 4 courses. Within 3-6 weeks after completion of chemotherapy, patients who achieve complete response with a negative 18FDG-PET/CT scan undergo INRT 5 days a week for approximately 3½ weeks. | 1 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Step 1: Induction Tx (ABVD Then PET/CT) | Ineligible | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm A (ABVD + INRT) | Arm B (ABVD + BEACOPP + INRT) | Total |
|---|---|---|---|
| Age, Continuous | 40 years | 35 years | 40 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 1 Participants | 5 Participants |
| Region of Enrollment United States | 4 participants | 1 participants | 5 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 0 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 | 0 / 1 |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 1 / 1 |
| serious Total, serious adverse events | 5 / 6 | 3 / 4 | 1 / 1 |
Outcome results
Primary
Progression-free Survival Rate
Progression-free survival is defined as the time from study entry to lymphoma progression or death from any cause. Proportion of patients who are progression-free and alive at 36 months will be reported. Progression is defined as appearance of any new lesions more than 1.5 cm in any axis, at least a 50% increase from nadir in sum of the product of the diameters (SPD) of any previously involved nodes or extranodal masses or the size of other lesions, or at least 50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
Time frame: Assessed at 36 months
Population: Only eligible and treated patients are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABVD + INRT | Progression-free Survival Rate | NA proportion of participants |
| ABVD + BEACOPP + INRT | Progression-free Survival Rate | NA proportion of participants |
Secondary
Biomarker Assessment Using Tissue Microarrays (TMAs)
To create TMAs from patient tumor blocks for future biomarker assessment including but not limited to bcl-2, FOXP3, and macrophage content.
Time frame: Baseline and relapse/progression
Population: The study was terminated early due to slow accrual. Biomarker data were not collected.
Secondary
Complete Response (CR) Rate After Induction Treatment
Complete response (CR) is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy.
Time frame: Assessed at end of Cycle 2
Population: Only eligible and treated patients are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABVD + INRT | Complete Response (CR) Rate After Induction Treatment | 1.0 proportion of participants |
Secondary
Overall Survival
Overall survival is defined as the time from study entry to death or date last known alive.
Time frame: Assessed at 36 months
Population: Only eligible and treated patients are included in this analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABVD + INRT | Overall Survival | NA months |
| ABVD + BEACOPP + INRT | Overall Survival | NA months |
Secondary
Progression-free Survival at 36 Months Among Patients Who Are PET Positive After Induction Treatment
Progression-free survival is defined as the time from study entry to lymphoma progression or death from any cause. Proportion of patients who are progression-free and alive at 36 months will be reported. Progression is defined as appearance of any new lesions more than 1.5 cm in any axis, at least a 50% increase from nadir in sum of the product of the diameters (SPD) of any previously involved nodes or extranodal masses or the size of other lesions, or at least 50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
Time frame: Assessed at 36 months
Population: Only patients who are PET positive are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABVD + INRT | Progression-free Survival at 36 Months Among Patients Who Are PET Positive After Induction Treatment | NA proportion of participants |
Secondary
Proportion of Patients Who Are PET Negative After Induction Treatment
Time frame: Assessed at end of Cycle 2
Population: Only eligible and treated patients are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABVD + INRT | Proportion of Patients Who Are PET Negative After Induction Treatment | 0.8 proportion of participants |
Secondary
Serum and Plasma Banking
To bank serum and plasma at baseline and follow-up time point to assess the prognostic value of various markers, such as but not limited to, SCD30, IL10, CCL17, CCL22, and MDC.
Time frame: Baseline and post cycle 2
Population: The study was terminated early due to slow accrual. Biomarker data were not collected.
Secondary
Sites of Relapse Following Combined Modality Treatment
Time frame: Assessed at 3, 12, 18, 24 and 36 months after INRT
Population: The study was terminated early due to slow accrual. Relapse data were not collected.
Secondary
The Association Between Thymus and Activation-related Chemokine (TARC) Levels and PET-CT Findings as Well as 3-year PFS
To measure serum TARC levels pre-treatment and after two cycles of ABVD and evaluate the associations between TARC levels and PET-CT findings as well as 3-year PFS.
Time frame: Baseline and cycle 2 for TARC assessments; 3 years for PFS
Population: The study was terminated early due to slow accrual. TARC data were not collected.