Bortezomib, Ifosfamide, and Vinorelbine Tartrate in Treating Young Patients With Hodgkin's Lymphoma That is Recurrent or Did Not Respond to Previous Therapy

Study Overview
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Brief Summary
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This phase II trial studies the side effects and efficacy of bortezomib with ifosfamide and vinorelbine in children and young adults with Hodgkin's lymphoma that was recurrent or did not respond to previous therapy. Bortezomib is an inhibitor of protein degradation. Bortezomib degrades short-lived regulatory proteins in the cell, and has been reported to increase the tumor cells. Bortezomib may increase the effectiveness of ifosfamide and vinorelbine (two standard drugs given to children with Hodgkin Lymphoma that has come back after initial treatment) by making cancer cells more sensitive to effectiveness of standard chemotherapy by preventing anti-death responses in these drugs. Giving bortezomib together with ifosfamide and vinorelbine tartrate should kill more cancer cells than are killed with ifosfamide and vinorelbine alone.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the efficacy and safety of bortezomib (as a chemosensitizing agent) in pediatric patients and young adults with primary refractory Hodgkin's lymphoma (HL) or HL in first relapse. II. Determine the response rate in patients treated with bortezomib, ifosfamide, and vinorelbine ditartrate (vinorelbine tartrate) (IVB) and compare the response rate to the historical response rate in patients treated with ifosfamide and vinorelbine ditartrate alone. SECONDARY OBJECTIVES: I. Determine the overall response rate (complete and partial response) and induction success rate after 2 or 4 courses of therapy and the reinduction rate (complete response) after 4 courses of therapy. II. Determine the proportion of patients able to mobilize sufficient hematopoietic stem cells (CD34+) after 2 courses of IVB. OUTLINE: This is a multicenter, open-label, pilot study. Patients receive ifosfamide intravenously (IV) continuously over days 1-4, vinorelbine tartrate IV over 6-10 minutes on days 1 and 5, and bortezomib intravenously on days 1, 4, and 8, and filgrastim (G-CSF) by vein or subcutaneously beginning on day 6 and continuing until blood counts recover or peripheral blood stem cells (PBSC) are harvested. Treatment cycles repeat every 21 days for up to 2 or 4 courses in the absence of disease progression or unacceptable toxicity. Patients undergo autologous PBSC harvesting according to institutional guidelines after the second course of therapy. After completion of study treatment, patients are followed every 6 months for 2 years and then annually thereafter.

Official Title
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A Phase II Study of Bortezomib (Velcade, PS-341) in Combination With Ifosfamide/Vinorelbine in Pediatric Patients and Young Adults With Refractory/Recurrent Hodgkin Disease

Conditions
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Adult Lymphocyte Depletion Hodgkin Lymphoma, Adult Lymphocyte Predominant Hodgkin Lymphoma, Adult Mixed Cellularity Hodgkin Lymphoma, Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma, Adult Nodular Sclerosis Hodgkin Lymphoma, Childhood Lymphocyte Depletion Hodgkin Lymphoma, Childhood Lymphocyte Predominant Hodgkin Lymphoma, Childhood Mixed Cellularity Hodgkin Lymphoma, Childhood Nodular Lymphocyte Predominant Hodgkin Lymphoma, Childhood Nodular Sclerosis Hodgkin Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Stage I Adult Hodgkin Lymphoma, Stage I Childhood Hodgkin Lymphoma, Stage II Adult Hodgkin Lymphoma, Stage II Childhood Hodgkin Lymphoma, Stage III Adult Hodgkin Lymphoma, Stage III Childhood Hodgkin Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Childhood Hodgkin Lymphoma

Intervention / Treatment
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* Drug: ifosfamide
* Drug: bortezomib
* Drug: vinorelbine tartrate
* Biological: filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed Hodgkin's lymphoma at time of relapse or disease progression, meeting all of the following criteria: Stage I-IV disease No morphologically unclassifiable disease Meets 1 of the following criteria: Mixed cellularity Lymphocytic depletion (LD) LD, diffuse fibrosis LD, reticular Lymphocyte predominance (LP) LP, diffuse LP, nodular Nodular sclerosis (NS) NS, cellular phase NS, lymphocytic predominance NS, mixed cellularity NS, LD Not otherwise specified Primary refractory disease OR disease in first relapse, except for the following: Patients who achieved a complete response after treatment on protocol COG-AHOD0431 who experience a biopsy-proven recurrence after doxorubicin hydrochloride, vincristine, prednisone, and cyclophosphamide without involved-field radiotherapy Patients on the observation-only arm of protocol COG-AHOD0431 Any measurable, focal mass lesion of a visceral organ (e.g., liver, spleen, or kidney) Patients with metastatic disease to bone marrow and granulocytopenia, anemia, and/or thrombocytopenia are allowed provided both of the following criteria are met: Platelet count ≥ 20,000/mm³ (platelet transfusion allowed) Hemoglobin ≥ 8 g/dL (packed red blood cell transfusion allowed) Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lanksy PS 60-100% (for patients =< 16 years of age) Life expectancy >= 2 months Absolute neutrophil count >= 1,000/mm^3 Platelet count >= 75,000/mm^3 (transfusion independent) (for patients with no bone marrow involvement) Creatinine =< 1.5 times upper limit of normal (ULN) Creatinine clearance or radioisotope glomerular filtration rate >= 70 mL/min/1.73 m^2 AST and ALT =< 2.5 times ULN Bilirubin =< 1.5 times ULN Shortening fraction >= 27% by echocardiogram OR LVEF >= 50% by gated radionuclide study Patients with a seizure disorder are eligible if on a nonenzyme-inducing anticonvulsant and seizures are well controlled No CNS toxicity > grade 2 No serious intercurrent illnesses No known hypersensitivity to E. coli-derived proteins, filgrastim (G-CSF), or any component of the study drugs No peripheral neuropathy > grade 1 No known hypersensitivity to bortezomib, boron, or mannitol No other concurrent chemotherapy or immunomodulating agents (including steroids) Concurrent corticosteroids allowed for treatment or prophylaxis of anaphylactic reactions No dexamethasone or aprepitant as an antiemetic Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Recovered from prior therapy No prior bortezomib or other proteasome inhibitors At least 3 weeks since prior chemotherapy (4 weeks for nitrosoureas) More than 14 days since prior investigational drugs No concurrent enzyme inducing anticonvulsants that alter p450 metabolism, including phenytoin, carbamazepine, phenobarbital, or other anticonvulsants Benzodiazepine or gabapentin allowed

Ages Eligible for Study
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Maximum Age: 29 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy, chemotherapy)<br>Patients receive ifosfamide IV continuously over days 1-4, vinorelbine ditartrate IV over 6-10 minutes on days 1 and 5, bortezomib IV on days 1, 4, and 8, and filgrastim (G-CSF) IV or subcutaneously beginning on day 6 and continuing until blood counts recover or PBSC are harvested. Treatment repeats every 21 days for up to 2 or 4 courses in the absence of disease progression or unacceptable toxicity. Patients undergo autologous PBSC harvesting according to institutional guidelines after the second course of therapy. | Drug: ifosfamide<br>* Given IV<br>* Other names: IPP;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: vinorelbine tartrate<br>* Given IV<br>* Other names: VNB;Biological: filgrastim<br>* Given IV or SC<br>* Other names: Neupogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) | CR is defined as at least 80% reduction in the sum of the products of the perpendicular diameters of each of the nodal masses or return to normal size, along with negative nuclear medicine imaging. | After 2 cycles of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 or 4 Toxicity | Grade 3 and 4 non-hematologic toxicity during protocol therapy. The number of patients that experience CTC Version 4 grade 3 or higher non-hematologic at any time during protocol therapy | 4 weeks following completion of therapy | 
| Overall Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | After 2 cycles and 4 cycles | 
| Induction Success Rate | Induction success is defined as achieving CR or PR without a targeted primary toxicity. Primary toxicity includes toxic death (which is any death predominantly attributable to treatment-related toxicities or complications, occurring during or within one month of the completion of therapy), Non-hematologic grades 3 or 4 toxicities attributable to drug (with the specific exclusion of 1) Grade 3 or 4 nausea or vomiting, 2) grade 3 transaminases (AST/ALT) elevations which return to < grade 1 prior to the time of the next treatment course, 3) grade 3 or 4 fever or infection, and 4) Grade 3 mucositis.) and Hematologic toxicity (Delay of >2 weeks in the start of re-induction cycle 2 or in hematologic recovery after cycle 2 secondary to severe myelosuppression, infection, or sepsis.) | After 2 cycles and 4 cycles | 
| Rate of Successful PBSC Harvest | Success is defined as the ability to harvest 2x10^6 CD34+ cells/kg within 5 collection days. | After 2 cycles | 
| Biological Markers | Assessing baseline NF-kB protein levels in tumor tissue | Before, during, and after treatment |