Maintenance Obinutuzumab in Treating Patients With Central Nervous System Lymphoma Who Have Achieved a Complete or Partial Response

• ClinicalTrials.gov Identifier: NCT02498951
• Recruitment Status: Recruiting
• First Posted: July 15, 2015
• Last Update Posted: June 13, 2022
• Sponsor: OHSU Knight Cancer Institute
• Collaborators: Genentech, Inc.; National Cancer Institute (NCI); Oregon Health and Science University
• Information provided by (Responsible Party): Edward Neuwelt, OHSU Knight Cancer Institute

Study Description

Brief Summary:

This randomized phase II trial studies how well obinutuzumab works as maintenance treatment in patients with central nervous system lymphoma who have achieved the disappearance of all signs of cancer in response to treatment (complete response) or a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment (partial response). Immunotherapy with obinutuzumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread.

Condition or disease	Intervention/treatment	Phase
Central Nervous System B-Cell Non-Hodgkin Lymphoma	Procedure: Cognitive Assessment; Biological: Obinutuzumab; Other: Quality-of-Life Assessment	Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine the effect of maintenance obinutuzumab on duration of response (partial response [PR] or complete response [CR]) in patients with CD20+ B-cell primary central nervous system lymphoma (PCNSL) who attain PR or CR to first-line treatment with high-dose methotrexate-based chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate overall survival after PR or CR (overall survival [OS]-PRCR). II. To evaluate neurocognitive function, quality of life, and neuroimaging as indicators of neurotoxicity.

III. Progression-free survival (PFS) and overall survival (OS) will be calculated.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (MAINTENANCE THERAPY): Patients receive obinutuzumab intravenously (IV) on days 1 and 2 for the first cycle, and on day 1 for the subsequent cycles. Cycles repeat every 60 days for 2 years in the absence of disease progression or unacceptable toxicity.

ARM II (OBSERVATION): Patients undergo observation for a total of 2 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Maintenance Obinutuzumab for Primary Central Nervous System Lymphoma Complete or Partial Responders
• Actual Study Start Date: July 12, 2016
• Estimated Primary Completion Date: January 1, 2024
• Estimated Study Completion Date: January 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (obinutuzumab); Patients receive obinutuzumab IV on days 1 and 2 for the first cycle, and on day 1 for the subsequent cycles, and on day 1 for the subsequent cycles. Cycles repeat every 60 days for 2 years in the absence of disease progression or unacceptable toxicity	Procedure: Cognitive Assessment; Ancillary studies; Biological: Obinutuzumab; Given IV; Other Names: Anti-CD20 Monoclonal Antibody R7159; GA-101; GA101; Gazyva; huMAB(CD20); R7159; RO 5072759; RO-5072759; RO5072759; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment
Active Comparator: Arm II (observation); Patients undergo observation for a total of 2 years.	Procedure: Cognitive Assessment; Ancillary studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment

Outcome Measures

Primary Outcome Measures :

1. Partial response (PR) or complete response (CR) duration [ Time Frame: From the date of brain magnetic resonance imaging (MRI) after completion of first-line treatment which confirms PR or CR, to disease progression or death, assessed up to 2 years ]
   PR or CR duration will be assessed using Kaplan-Meier product limit estimates and compared between patients with maintenance versus without obinutuzumab maintenance using the log-rank test. In addition, the Cox proportional hazard model will be used to estimate hazard ratios.

Secondary Outcome Measures :

1. Overall survival (OS) after CR [ Time Frame: From the date of brain MRI after completion of first-line treatment which confirms PR or CR, to death, assessed up to 2 years ]
   OS after PR or CR will be assessed using Kaplan-Meier product limit estimates and compared between patients with maintenance versus without obinutuzumab maintenance using the log-rank test. In addition, the Cox proportional hazard model will be used to estimate hazard ratios.
2. Neurocognitive function [ Time Frame: Up to 2 years ]
   Will be measured by the Wechsler Adult Intelligence Scale, Hopkins Verbal Learning Test-Revised, and Grooved Pegboard Test. Longitudinal data of neurocognitive function will be analyzed using a linear mixed model and toxicity indicators will be assessed using a chi-square or exact test.
3. Quality of life (QOL) [ Time Frame: Up to 2 years ]
   Will be measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30 and Brain Cancer Module-20. Longitudinal data of QOL will be analyzed using a linear mixed model and toxicity indicators will be assessed using a chi-square or exact test.
4. Progression free survival (PFS) [ Time Frame: From the start date of first-line primary central nervous system lymphoma (PCNSL) treatment to disease progression or death, assessed up to 2 years ]
   PFS will be assessed using Kaplan-Meier product limit estimates and compared between patients with obinutuzumab maintenance versus without maintenance using the log-rank test. Longitudinal data of neurocognitive function and QOL will be analyzed using a linear mixed model and toxicity indicators will be assessed using a chi-square or exact test.
5. Overall survival [ Time Frame: From the start date of first-line PCNSL treatment to death, assessed up to 2 years ]
   OS will be assessed using Kaplan-Meier product limit estimates and compared between patients with obinutuzumab maintenance versus without maintenance using the log-rank test. Longitudinal data of neurocognitive function and QOL will be analyzed using a linear mixed model and toxicity indicators will be assessed using a chi-square or exact test.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• CD20+ B-cell primary central nervous system lymphoma (PCNSL) confirmed at the time of diagnosis by histology, cytology, or immunocytochemistry from cerebrospinal fluid (CSF); diagnosis must be documented by pathology report
• Must have undergone first-line treatment with a high-dose methotrexate-based chemotherapy regimen with or without brain radiotherapy; high-dose methotrexate is defined as >= 3 grams/m^2; methotrexate dose reduction for creatinine clearance < 100 ml/min is permitted
• Must be within 75 days of completion of first-line treatment regimen; must have achieved objective response (PR or CR/unconfirmed complete response [CRu]) to first-line treatment
• Brain magnetic resonance imaging (MRI) documenting objective response must be obtained within 30 days of study enrollment
• If CSF was positive for lymphoma cells at diagnosis or during first-line treatment and/or a slit lamp examination was positive at diagnosis or during first-line treatment, then the CSF and vitreal studies must have been repeated and must have indicated CR; Note: CR requires complete disappearance of all enhancing abnormalities on gadolinium-enhanced MRI; if CSF was positive for lymphoma cells at diagnosis or during first-line treatment and/or slit lamp examination was positive at diagnosis or during first-line treatment, then the CSF and vitreal studies must have been repeated and must have indicated CR; for CRu, some patients will have a small but persistent enhancing abnormality on MRI related to biopsy or focal hemorrhage; it is often difficult to ascertain whether this represents a residual nidus of tumor or scar tissue; if the abnormality does not change or slowly involutes without therapy and corticosteroids, it is reasonable to categorize as a CRu; at the time CR/CRu is determined, the patient should not have used corticosteroids for at least two weeks
• Karnofsky performance status (KPS) >= 60; Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2
• Signed informed consent form (ICF)
• Ability and willingness to comply with the requirements of the study protocol
• Total bilirubin < 3 x the upper limit of normal (ULN), +/- 7 days from date of ICF signing
• Creatinine clearance > 30 mL/min (calculated according to institutional standards or using Cockcroft-Gault formula), +/- 7 days from date of ICF signing
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 5 x ULN, +/- 7 days from date of ICF signing
• Platelet >= 75,000 cells/mm^3, +/- 7 days from date of ICF signing
• Hemoglobin > 9 g/dL, +/- 7 days from date of ICF signing
• Absolute neutrophil count > 1.5 x 10^3 cells/mm^3, +/- 7 days from date of ICF signing
• Surgically sterile or agree to use effective contraception using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly while receiving obinutuzumab and >= 18 months after the last dose of obinutuzumab for women, and 180 days after the last dose of obinutuzumab for men

Exclusion Criteria:

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
• Clinical evidence of extra-central nervous system (CNS) (systemic) non-Hodgkin lymphoma
• Known hypersensitivity to any of the study drugs

• History of other malignancy that could affect compliance with the protocol or interpretation of results

  • Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible; patients with a malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for >= 2 years prior to enrollment
• Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 weeks prior to study enrollment
• Major surgery within 4 weeks prior to study enrollment
• Known infection with human immunodeficiency virus (HIV)

• Known positive hepatitis serologies:

  • Hepatitis B (HBV): patients with positive serology for hepatitis B defined as positivity for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc); patients who are positive for anti-HBc may be considered for inclusion in the study on a case-by-case basis if they are hepatitis B viral deoxyribonucleic acid (DNA) negative and are willing to undergo ongoing HBV DNA testing by real-time polymerase chain reaction (PCR); patients with positive serology may be referred to a hepatologist or gastroenterologist for appropriate monitoring and management
  • Hepatitis C (HCV): patients with positive hepatitis C serology unless HCV ribonucleic acid (RNA) is confirmed negative and may be considered for inclusion in the study on a case-by-case basis
• Women who are pregnant or lactating
• Vaccination with a live vaccine a minimum of 4 weeks prior to study enrollment

Contacts and Locations

Locations

United States, Colorado

University of Colorado; Recruiting

Denver, Colorado, United States, 80217-3364

Contact: Douglas E. Ney 720-848-0650

Principal Investigator: Douglas E. Ney

United States, Georgia

Piedmont Hospital; Recruiting

Atlanta, Georgia, United States, 30309

Contact: Erin M. Dunbar 470-572-3111 erin.dunbar@piedmont.org

Principal Investigator: Erin M. Dunbar

United States, Michigan

University of Michigan Comprehensive Cancer Center; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Yoshie Umemura 800-865-1125 yoshie@med.umich.edu

Principal Investigator: Yoshie Umemura

United States, North Carolina

Wake Forest University Health Sciences; Recruiting

Winston-Salem, North Carolina, United States, 27157

Contact: Roy E. Strowd 336-713-5440 rstrowd@wakehealth.edu

Principal Investigator: Roy E. Strowd

United States, Ohio

Cleveland Clinic Cancer Center/Fairview Hospital; Recruiting

Cleveland, Ohio, United States, 44111

Contact: David M. Peereboom 216-445-6068 peerebd@ccf.org

Principal Investigator: David M. Peereboom

United States, Oregon

Providence Portland Medical Center; Recruiting

Portland, Oregon, United States, 97213

Contact: Prakash Ambady 503-216-1150 Prakash.ambady@providence.org

Principal Investigator: Prakash Ambady

OHSU Knight Cancer Institute; Recruiting

Portland, Oregon, United States, 97239

Contact: Edward Neuwelt 503-494-5626 neuwelte@ohsu.edu

Principal Investigator: Edward Neuwelt

United States, Pennsylvania

Penn State Milton S Hershey Medical Center; Recruiting

Hershey, Pennsylvania, United States, 17033-0850

Contact: Michael J. Glantz mjg@massmed.org

Principal Investigator: Michael J. Glantz

United States, Rhode Island

Rhode Island Hospital; Recruiting

Providence, Rhode Island, United States, 02903

Contact: Peter Barth 401-444-8559 peter.barth@lifespan.org

Principal Investigator: Peter Barth

United States, Texas

UT Southwestern/Simmons Cancer Center-Dallas; Active, not recruiting

Dallas, Texas, United States, 75390

United States, Vermont

University of Vermont Medical Center; Recruiting

Burlington, Vermont, United States, 05401

Contact: Alissa A. Thomas 802-656-9427 Alissa.thomas@uvmhealth.org

Principal Investigator: Alissa A. Thomas

United States, Virginia

University of Virginia Cancer Center; Recruiting

Charlottesville, Virginia, United States, 22908

Contact: David Schiff 434-924-5610 DS4JD@hscmail.mcc.virginia.edu

Principal Investigator: David Schiff

Sponsors and Collaborators

OHSU Knight Cancer Institute

Genentech, Inc.

National Cancer Institute (NCI)

Oregon Health and Science University

Investigators

• Principal Investigator: Edward Neuwelt; OHSU Knight Cancer Institute

More Information

• Responsible Party: Edward Neuwelt, Principal Investigator, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT02498951
• Other Study ID Numbers: IRB00011601; NCI-2015-01014 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ML29496; IRB00011601 ( Other Identifier: OHSU Knight Cancer Institute ); R01CA137488 ( U.S. NIH Grant/Contract )
• First Posted: July 15, 2015
• Last Update Posted: June 13, 2022
• Last Verified: June 2022

• Studies a U.S. FDA-regulated Drug Product: Yes

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Obinutuzumab; Antineoplastic Agents, Immunological; Antineoplastic Agents