S0816 Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma

Study Overview
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Brief Summary
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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. G-CSF may help lessen the side effects in patients receiving chemotherapy. Imaging procedures, such as fludeoxyglucose F 18-PET/CT imaging, may help doctors predict how patients will respond to treatment. PURPOSE: This phase II trial is studying fludeoxyglucose F 18-PET/CT imaging to see how well it works in assessing response to combination chemotherapy and allow doctors to plan better additional further treatment in treating patients with stage III or stage IV Hodgkin lymphoma.

Detailed Description
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OBJECTIVES: Primary To estimate the 2-year progression-free survival (PFS) of HIV-negative patients with stage III-IV Hodgkin lymphoma treated with response-adapted therapy based on fludeoxyglucose F 18 (FDG)-PET imaging after 2 courses of doxorubicin hydrochloride, bleomycin, vinblastine, and dacarbazine (ABVD). To estimate the 2-year PFS of patients who are PET-positive after treatment with 2 courses of ABVD and an escalated dose regimen comprising cyclophosphamide, doxorubicin hydrochloride, etoposide, vincristine sulfate, bleomycin, procarbazine hydrochloride, and prednisone (BEACOPP). Secondary To estimate the 2-year overall survival (OS) of patients treated with these regimens. To estimate the response rate (i.e., complete and partial responses) in patients treated with these regimens. To evaluate the toxicity of these response-adapted regimens. To document the feasibility of centralized, real-time review of FDG-PET imaging for U.S. cooperative group studies. To prospectively evaluate the overall response rate, complete response rate, PFS, and OS of HIV-positive patients treated with these response-adapted regimens. OUTLINE: This is a multicenter study. All patients undergo baseline whole-body fludeoxyglucose F 18 (FDG)-PET/CT imaging before beginning chemotherapy. Patients then receive doxorubicin hydrochloride IV, bleomycin IV, vinblastine IV, and dacarbazine IV (ABVD) on days 1 and 15. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Between days 22 and 25 of course 2, patients undergo a second FDG-PET/CT scan to assess response. Subsequent therapy is based on FDG-PET/CT scan results. Patients are stratified according to FDG-PET positivity (yes vs no). Patients who are FDG-PET-negative continue treatment with ABVD for up to 4 additional courses in the absence of disease progression or unacceptable toxicity. Patients who are FDG-PET-positive are then further stratified according to HIV positivity (yes or no) and receive 1 of the following treatment regimens: Escalated-dose BEACOPP chemotherapy: HIV-negative patients receive escalated-dose BEACOPP chemotherapy comprising doxorubicin hydrochloride IV and cyclophosphamide IV on day 1, etoposide IV on days 1-3, oral procarbazine hydrochloride on days 1-7, oral prednisone on days 1-14, and bleomycin IV and vincristine IV on day 8. Patients receive filgrastim (G-CSF) subcutaneously on days 8-14. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Standard-dose BEACOPP chemotherapy: HIV-positive patients receive standard dose BEACOPP chemotherapy comprising doxorubicin hydrochloride IV and cyclophosphamide IV on day 1, etoposide IV on days 1-3, oral procarbazine hydrochloride on days 1-7, oral prednisone on days 1-14, and bleomycin IV and vincristine IV on day 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Six to eight weeks after completion of chemotherapy, patients undergo a post-treatment FDG-PET/CT scan. Some patients may undergo bone marrow biopsy at 1 month after the last course of chemotherapy. After completion of study treatment, patients are followed up periodically for 7 years.

Official Title
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A Phase II Trial of Response-Adapted Therapy of Stage III-IV Hodgkin Lymphoma Using Early Interim FDG-PET Imaging

Conditions
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Lymphoma, Nonneoplastic Condition

Intervention / Treatment
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* Biological: bleomycin sulfate
* Biological: filgrastim
* Drug: ABVD regimen
* Drug: BEACOPP regimen
* Drug: cyclophosphamide
* Drug: dacarbazine
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Drug: prednisone
* Drug: procarbazine hydrochloride
* Drug: vinblastine sulfate
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed classical Hodgkin lymphoma (HL) (i.e., nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted) Previously untreated stage III or IV disease No nodular lymphocyte predominant disease Bidimensionally measurable disease Adequate biopsy samples from original diagnostic specimen must be available for pathologic review Tissue obtained from core biopsies allowed No tissue obtained from needle aspirations or cytologies Must have known HIV status No multi-drug resistant HIV infection, CD4 counts < 150/μL, or other concurrent AIDS-defining conditions in HIV-positive patients HIV-positive patients with CD4 counts ≥ 150/μL at the time of enrollment OR documented CD4 count > 250/μL at any time within 8 months prior to HL diagnosis allowed Must have undergone unilateral or bilateral bone marrow biopsy within the past 42 days Must have a diagnostic quality CT scan of the chest/abdomen and pelvis AND baseline FDG-PET scan within the past 28 days Combined PET/CT scans required No older stand-alone FDG-PET scans No low-resolution localization CT scans as part of a combined PET/CT scans PATIENT CHARACTERISTICS: Zubrod performance status 0-2 Serum erythrocyte sedimentation rate, lactate dehydrogenase (LDH), hemoglobin, albumin, white blood cell count (WBC), and lymphocytes measured within the past 28 days Serum estradiol (women only), testosterone (men only), follicle stimulating hormone (FSH) and luteinizing hormone (LH) (both men and women) levels must be drawn within 60 days prior to registration Not pregnant or nursing Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy No significant cardiac abnormalities as assessed by multiple gated acquisition scan (MUGA) or ECHO AND cardiac ejection fraction ≥ 45% in patients with a history of hypertension or cardiac symptoms Hepatitis B-negative (i.e., hepatitis B surface antigen-negative or anti-hepatitis B core antigen-negative) Patients immune to or immunized against hepatitis B (i.e., anti-hepatitis B surface antibody-positive) are eligible Hepatitis C-negative (i.e., anti-hepatitis C antibody-negative) No significant lung disease with abnormal lung function tests (i.e., diffusing capacity of lung for carbon monoxide (DLCO) > 25% below predicted after correction for hemoglobin) unless attributable to lymphoma No requirement for continuous supplemental oxygen therapy No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy, radiotherapy, or antibody therapy for lymphoma No prior solid organ transplantation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV Positive, PET Positive: BEACOPP standard<br>Etoposide 100 mg/m2 IV Days 1, 2, 3 Dox 25 mg/m2 IV Day 1 Cyclo 650mg/m2 IV Day 1 Procarb 100 mg/m2 PO Days 1-7 Pred 40 mg/m2 PO Days 1-14 Bleo 10u/m2 IV Day 8 Vincristine 1.4 mg/m2 IV Day 8 Q 21 Days x 6 cycles | Biological: bleomycin sulfate<br> <br> Drug: BEACOPP regimen<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: etoposide<br> <br> Drug: prednisone<br> <br> Drug: procarbazine hydrochloride<br> <br> Drug: vincristine sulfate<br> <br> |
| Experimental: HIV Negative, PET Positive: BEACOPP escalated<br>Etoposide 200 mg/m2 IV Days 1, 2, 3 Dox 35 mg/m2 IV Day 1 Cyclo 1,250 mg/m2 IV Day 1 Procarb 100 mg/m2 PO Days 1-7 Pred 40 mg/m2 PO Days 1-14 Bleo 10u/m2 IV Day 8 Vincristine 1.4 mg/m2 IV Day 8 G-CSF 5mcg/kg/day SQ Days 8-14 Q 21 Days x 6 cycles | Biological: bleomycin sulfate<br> <br> Biological: filgrastim<br> <br> Drug: BEACOPP regimen<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: etoposide<br> <br> Drug: prednisone<br> <br> Drug: procarbazine hydrochloride<br> <br> Drug: vincristine sulfate<br> <br> |
| Active Comparator: HIV Positive, PET Negative: ABVD<br>Doxorubicin 25 mg/m2 IV Bleomycin 10u/m2 IV Vinblastine 6mg/m2 IV Dacarbazine 375 mg/m2 IV Days 1, 15 Q 28 Days x 2 | Biological: bleomycin sulfate<br> <br> Drug: ABVD regimen<br> <br> Drug: dacarbazine<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: vinblastine sulfate<br> <br> |
| Active Comparator: HIV Negative, PET Negative: ABVD<br>Doxorubicin 25 mg/m2 IV Bleomycin 10u/m2 IV Vinblastine 6mg/m2 IV Dacarbazine 375 mg/m2 IV Days 1, 15 Q 28 Days x 2 | Biological: bleomycin sulfate<br> <br> Drug: ABVD regimen<br> <br> Drug: dacarbazine<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: vinblastine sulfate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of HIV-negative Patients With 2-year Progression-free Survival (PFS) Treated With 2 Initial Cycles of Adriamycin, Bleomycin, Vnblastine, and Dacarbazine (ABVD) Followed by Response-adapted Therapy Based on Interim FDG-PET Imaging. | Disease progression is defined using the 2007 revised Cheson et al. criteria that is at least 50% increase in sum of the product of the diameters (SPD) of target measurable nodal lesions over the smallest sum observed, or >= 50% increase in greatest transverse diameter (GTD) of any nodal > 1 cm in shortest axis, or >= 50% increase in the SPD of other target measurable lesions over the smallest sum observed, any new bone marrow involvement, any new lesion, lymph node with long axis is > 1.5 cm or if both long and short axes are > 1 cm, PET positive if patients with no pretreatment PET scan or when PET scan was positive before therapy. Progression-free survival is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. | 2 years | 
| Percentage of HIV-negative Patients Who Are PET-positive After 2 Cycles of ABVD With 2-year PFS | Disease progression is defined using the 2007 revised Cheson et al. criteria that is at least 50% increase in sum of the product of the diameters (SPD) of target measurable nodal lesions over the smallest sum observed, or >= 50% increase in greatest transverse diameter (GTD) of any nodal > 1 cm in shortest axis, or >= 50% increase in the SPD of other target measurable lesions over the smallest sum observed, any new bone marrow involvement, any new lesion, lymph node with long axis is > 1.5 cm or if both long and short axes are > 1 cm, PET positive if patients with no pretreatment PET scan or when PET scan was positive before therapy. Progression-free survival is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of HIV-negative Patients With 2-year Overall Survival (OS) Treated With 2 Initial Cycles of ABVD Followed by Response-Adapted Therapy Based on Interim FDG-PET Imaging | Measured from date of registration to date of death due to any cause. Patients last known to be alive and are censored at date of last contact. | 2 years | 
| Complete and Partial Response Rates for HIV-negative Patients Treated With Response- Adapted Therapy Based on FDG-PET Imaging After 2 Cycles of ABVD | Complete Response (CR) is a complete disappearance of all disease with the exception of the following. If no PET scan or when the PET scan was positive before therapy, a post-treatment residual mass of any size is permitted if it is PET negative. If the PET scan was negative before therapy, all nodal masses at baseline must have regressed. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow (BM) must be negative if positive at baseline. Normalization of markers. Partial Response (PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes. If PET scan or when the PET scan was positive before therapy, PET should be positive in at least one previously involved site. | 7 months after registration | 
| Number of HIV-negative Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. | Up to 1 year | 
| Percentage of HIV-positive Patients With 2-year Progression-free Survival (PFS) Treated With Initial 2 Cycles of Adriamycin, Bleomycin, Vnblastine, and Dacarbazine (ABVD) Followed by Response-adapted Therapy Based on Interim FDG-PET Imaging. | Disease progression is defined using the 2007 revised Cheson et al. criteria that is at least 50% increase in sum of the product of the diameters (SPD) of target measurable nodal lesions over the smallest sum observed, or >= 50% increase in greatest transverse diameter (GTD) of any nodal > 1 cm in shortest axis, or >= 50% increase in the SPD of other target measurable lesions over the smallest sum observed, any new bone marrow involvement, any new lesion, lymph node with long axis is >1.5 cm or if both long and short axes are > 1 cm, PET positive if patients with no pretreatment PET scan or when PET scan was positive before therapy. progression-free survival is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. | 2 years | 
| Percentage of HIV-positive Patients With 5-year Overall Survival (OS) Treated With 2 Initial Cycles of ABVD Followed by Response-Adapted Therapy Based on Interim FDG-PET Imaging. | Measured from date of registration to date of death due to any cause. Patients last known to be alive and are censored at date of last contact. | 5 years | 
| Complete and Partial Response Rates for HIV-positive Patients Treated With Response-Adapted Therapy Based on FDG-PET Imaging After 2 Cycles of ABVD | Complete Response (CR) is a complete disappearance of all disease with the exception of the following. If no PET scan or when the PET scan was positive before therapy, a post-treatment residual mass of any size is permitted if it is PET negative. If the PET scan was negative before therapy, all nodal masses at baseline must have regressed. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow (BM) must be negative if positive at baseline. Normalization of markers. Partial Response (PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes. If PET scan or when the PET scan was positive before therapy, PET should be positive in at least one previously involved site. | 7 months after registration | 
| Number of HIV-positive Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. | Up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, adult lymphocyte depletion Hodgkin lymphoma, adult lymphocyte predominant Hodgkin lymphoma, adult mixed cellularity Hodgkin lymphoma, adult nodular sclerosis Hodgkin lymphoma, HIV infection