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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Hodgkin Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage IV Adult Hodgkin Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Childhood Hodgkin Lymphoma; Childhood Nodular Lymphocyte Predominant Hodgkin Lymphoma; Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Childhood Lymphocyte Depletion Hodgkin Lymphoma; Childhood Lymphocyte Predominant Hodgkin Lymphoma; Childhood Mixed Cellularity Hodgkin Lymphoma; Childhood Nodular Sclerosis Hodgkin Lymphoma
• Intervention / Treatment: Drug: vinorelbine tartrate; Biological: filgrastim; Drug: bortezomib; Drug: ifosfamide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 29 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (enzyme inhibitor therapy, chemotherapy); 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: vinorelbine tartrate; Given IV; Other Names: Eunades; navelbine ditartrate; NVB; VNB; Biological: filgrastim; Given IV or SC; Other Names: G-CSF; Neupogen; Drug: bortezomib; Given IV; Other Names: MLN341; LDP 341; VELCADE; Drug: ifosfamide; Given IV; Other Names: Cyfos; Holoxan; IFX; IFF; IPP

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Terzah Horton, Children's Oncology Group

Publications and helpful links

General Publications

• Horton TM, Drachtman RA, Chen L, Cole PD, McCarten K, Voss S, Guillerman RP, Buxton A, Howard SC, Hogan SM, Sheehan AM, Lopez-Terrada D, Mrazek MD, Agrawal N, Wu MF, Liu H, De Alarcon PA, Trippet TM, Schwartz CL. A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study. Br J Haematol. 2015 Jul;170(1):118-22. doi: 10.1111/bjh.13388. Epub 2015 Apr 1.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (ACTUAL): June 1, 2008
• Study Completion (ACTUAL): December 31, 2016

Study Registration Dates

• First Submitted: September 26, 2006
• First Submitted That Met QC Criteria: September 26, 2006
• First Posted (ESTIMATE): September 28, 2006

Study Record Updates

• Last Update Posted (ACTUAL): March 24, 2021
• Last Update Submitted That Met QC Criteria: March 4, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Lymphoma; Sclerosis; Hodgkin Disease; Recurrence; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Ifosfamide; Bortezomib; Vinorelbine
• Other Study ID Numbers: NCI-2009-01063 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA098543 (U.S. NIH Grant/Contract); CDR0000500142; AHOD0521 (OTHER: CTEP)