SGN-30 and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

Study Overview
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Brief Summary
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This randomized phase II trial studies the side effects and how well giving monoclonal antibody SGN-30 together with combination chemotherapy works in treating patients with Hodgkin lymphoma that has returned after a period of improvement or did not respond to previous treatment. Monoclonal antibodies, such as SGN-30, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as gemcitabine hydrochloride, vinorelbine tartrate, and pegylated liposomal doxorubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving monoclonal antibody SGN-30 together with combination chemotherapy may kill more cancer cells and shrink tumors.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the complete and partial response rates following treatment with the anti-cluster of differentiation (CD) 30 antibody, SGN-30 (monoclonal antibody SGN-30), and gemcitabine (gemcitabine hydrochloride), vinorelbine (vinorelbine tartrate), and pegylated liposomal doxorubicin (pegylated liposomal doxorubicin hydrochloride) (GVD) in patients with relapsed or refractory Hodgkin lymphoma (HL). II. To assess time to progression and overall survival in patients treated with SGN-30 and GVD in patients with relapsed or refractory Hodgkin lymphoma (HL). III. To evaluate the toxicity of SGN-30 in combination with GVD in patients with relapsed and refractory HL. SECONDARY OBJECTIVES: I. To determine the pharmacokinetic profile of SGN-30 when combined with GVD chemotherapy. II. To correlate soluble (s) CD30 levels with response to treatment. III. To determine the incidence of human anti-chimeric antibodies (HACA) formation following repetitive SGN-30 dosing. IV. To correlate Fc gamma receptor polymorphisms with response to treatment. OUTLINE: Part 1 (closed to accrual as of 5/18/2007): Patients receive monoclonal antibody SGN-30 intravenously (IV) over 2 hours, vinorelbine tartrate IV over 6-10 minutes, gemcitabine hydrochloride IV over 30 minutes, and pegylated doxorubicin hydrochloride liposome IV over 90 minutes on days 1 and 8. Treatment repeats every 21 days until 10 out of 16 patients complete 1 course in the absence of unacceptable toxicity. Subsequent patients receive treatment on part 2. Part 2: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive monoclonal antibody SGN-30 IV over 2 hours, vinorelbine tartrate IV over 6-10 minutes, gemcitabine hydrochloride IV over 30 minutes, and pegylated doxorubicin hydrochloride liposome IV over 90 minutes on days 1 and 8. Arm II (closed to accrual as of 12/4/07): Patients receive placebo IV over 2 hours, vinorelbine tartrate IV over 6-10 minutes, gemcitabine hydrochloride IV over 30 minutes, and pegylated doxorubicin hydrochloride liposome IV over 90 minutes on days 1 and 8. Treatment in both arms repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. NOTE: Treatment with SGN-30/placebo was stopped on 4/12/2007 due to pulmonary toxicity. After completion of study treatment, patients are followed up periodically for up to 10 years.

Official Title
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A Randomized Double-Blinded Placebo Controlled Phase II Study of the Anti-CD30 Antibody, SGN-30 (NSC #731636), in Combination With Gemcitabine, Vinorelbine, and Pegylated Liposomal Doxorubicin (GVD) for Patients With Relapsed/Refractory Hodgkin Lymphoma

Conditions
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Adult Lymphocyte Depletion Hodgkin Lymphoma, Adult Lymphocyte Predominant Hodgkin Lymphoma, Adult Mixed Cellularity Hodgkin Lymphoma, Adult Nodular Sclerosis Hodgkin Lymphoma, Recurrent Adult Hodgkin Lymphoma

Intervention / Treatment
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* Biological: monoclonal antibody SGN-30
* Other: placebo
* Drug: vinorelbine tartrate
* Drug: pegylated liposomal doxorubicin hydrochloride
* Drug: gemcitabine hydrochloride
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented CD30-positive classical Hodgkin lymphoma according to the World Health Organization (WHO) classification of lymphoid malignancies that is recurrent or refractory after at least one prior therapy Note: Patients with nodular lymphocyte predominant HL are not eligible; all other subtypes including nodular sclerosis, lymphocyte-depleted, lymphocyte rich, and mixed cellularity HL may be enrolled Core needle biopsies are acceptable if they contain adequate tissue for primary diagnosis and immunophenotyping; bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies; fine needle aspirates are not acceptable; if the original diagnostic specimen is not available, specimens obtained at relapse may be submitted; if multiple specimens are available, please submit the most recent; failure to submit pathology specimens within 60 days of patient registration will be considered a major protocol violation Patients must have relapsed or refractory disease after at least one prior therapy, with at least a 3 week interval from the completion of the most recent chemotherapy or radiotherapy regimen; recovery to =< grade 1 from all toxicities related to the prior treatments is required; patients who have previously received a stem cell transplant are permitted to enroll on this study Prior treatment with an anti-CD30 antibody, gemcitabine, vinorelbine, or pegylated liposomal doxorubicin is not permitted No uncontrolled angina, no myocardial infarction (MI) within 6 months of study entry, and no New York Heart Association (NYHA) class II or greater congestive heart failure (CHF) Baseline left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) must be >= 45% Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Measurable disease must be present on either physical examination or imaging studies; evaluable or non-measurable disease alone is not acceptable Measurable disease is defined as any lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm Non-measurable disease includes all other lesions, including small lesions (< 10 mm) and truly non-measurable lesions Lesions that are considered non-measurable include the following: Bone lesions (lesions, if present, should be noted) Bone marrow involvement (if present, this should be noted) Ascites Pleural/pericardial effusion Lymphangitis cutis/pulmonis Pregnant or nursing women may not be enrolled; women of childbearing potential must have a negative serum or urine pregnancy test prior to registration; women and men of reproductive potential should agree to use an effective means of birth control Corrected diffusion capacity of carbon monoxide (DLCO) >= 50% Absolute neutrophil count (ANC) >= 1,200/uL Platelet count >= 100,000/uL Creatinine =< 2.0 mg/dL Bilirubin =< 2.0 mg/dL Absent a history of Gilbert's disease Aspartate aminotransferase (AST) =< 2.0 x upper limits of normal

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (SGN-30, chemotherapy)<br>Participants receive one of the following regimens every cycle depending on history of prior stem cell transplant. Cycle is 21 days. No prior stem cell transplant: SGN-30: 12 mg/kg IV days 1 & 8, vinorelbine: 20 mg/m^2 IV days 1 & 8, gemcitabine: 1000 mg/m^2 IV days 1 & 8, pegylated doxorubicin HCl liposome: 15 mg IV days 1 & 8. Prior stem cell transplant SGN-30: 12 mg/kg IV days 1 & 8, vinorelbine: 15 mg/m^2 IV days 1 & 8, gemcitabine: 800 mg/m^2 IV days 1 & 8, pegylated doxorubicin HCl liposome: 10 mg IV days 1 & 8. | Biological: monoclonal antibody SGN-30<br>* Given IV<br>* Other names: SGN-30;Drug: vinorelbine tartrate<br>* Given IV<br>* Other names: VNB;Drug: pegylated liposomal doxorubicin hydrochloride<br>* Given IV<br>* Other names: LipoDox;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Active Comparator: Arm II (placebo, chemotherapy)<br>Participants receive one of the following regimens every cycle depending on history of prior stem cell transplant. Cycle is 21 days. No prior stem cell transplant: SGN-30: 12 mg/kg IV days 1 & 8, vinorelbine: 20 mg/m^2 IV days 1 & 8, gemcitabine: 1000 mg/m^2 IV days 1 & 8, pegylated doxorubicin HCl liposome: 15 mg IV days 1 & 8. Prior stem cell transplant SGN-30: 12 mg/kg IV days 1 & 8, vinorelbine: 15 mg/m^2 IV days 1 & 8, gemcitabine: 800 mg/m^2 IV days 1 & 8, pegylated doxorubicin HCl liposome: 10 mg IV days 1 & 8. | Other: placebo<br>* Given IV<br>* Other names: PLCB;Drug: vinorelbine tartrate<br>* Given IV<br>* Other names: VNB;Drug: pegylated liposomal doxorubicin hydrochloride<br>* Given IV<br>* Other names: LipoDox;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response (OR) | The number of participants who respond (complete or partial) to treatment. Response was defined using the revised criteria for malignant lymphoma. Complete response (CR): complete disappearance of all detectable disease; partial response (PR): >= 50% reduction in sum of the product of diameters of indicator lesions. | Up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival (EFS) | Event free survival is the time from trial entry until progression, death, or termination of treatment due to nonresponse. Patients who went on to receive a stem cell transplant (SCT) were not censored from the EFS survival at the time of transplant and were only considered failures at the time of relapse or death from any cause. The median EFS with 95% confidence interval (CI) was estimated using the Kaplan Meier method. | Up to 10 years | 
| Overall Survival (OS) At 1 Year | Percentage of patients who were alive at 1 year. The 1-year survival rate was estimated using the Kaplan Meier method. | 1 year |