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Lenalidomide Plus Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma

Primary Purpose

Recurrent/Refractory CNS, Intraocular Lymphoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lenalidomide
Rituximab
Sponsored by
James Rubenstein
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent/Refractory CNS focused on measuring Recurrent, Refractory, CNS, Intraocular, Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Ability to give written informed consent and willingness to comply with the requirements of the protocol
  • Age eighteen years or older
  • Tumors must be CD20+ on prior pathologic analysis
  • All prospective participants must have an Ommaya reservoir (or equivalent ventricular access device) inserted as part of their standard clinical care prior to initiation of study treatment.
  • No concurrent methotrexate, thiotepa, cytarabine, or investigational agents
  • Absolute neutrophil count (ANC) > 1,500 (growth factors permitted)
  • Platelets >50,000 (platelet transfusion allowed)
  • Total bilirubin </= 1.5 x upper limit of normal (ULN)
  • aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)) </= 3 x ULN.
  • Stable dose of glucocorticoids pre-therapy. If patients are receiving dexamethasone, the dose of dexamethasone should not increase during the 96 hours prior to initiation of therapy.
  • Renal function assessed by calculated creatinine clearance. Patients must have calculated creatinine clearance (CrCl) >/= 60ml/min by Cockcroft-Gault formula or 24 hour urine demonstrating CrCl >/= 60ml/min .
  • Females of childbearing potential (FCBPs)† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 Milli-International Units per millilitre (mIU/mL) within 10 - 14 days and again within 24 hours prior to receiving lenalidomide for Cycle 1 and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBPs must also agree to ongoing pregnancy testing and for 28 days after receiving their last dose of lenalidomide.
  • Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.
  • Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to aspirin may use warfarin or low molecular weight heparin).
  • All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.

Exclusion Criteria:

  • Intraventricular chemotherapy or radiation therapy within 4 days of starting treatment
  • Intravenous rituximab within 30 days of starting treatment
  • Persistent neurotoxicity from intraventricular methotrexate, cytarabine, thiotepa
  • Anticipated survival of less than 1 month
  • Pregnant women and women of child-bearing potential who are not using an effective method of birth control.
  • Known hypersensitivity to thalidomide or lenalidomide
  • The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
  • Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
  • Contraindication to aspirin. If unable to take aspirin, contraindication to warfarin or low molecular weight heparin.

Sites / Locations

  • University of California, San Francisco

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Study intervention

Arm Description

Lenalidomide Plus Rituximab

Outcomes

Primary Outcome Measures

To establish the maximal tolerated dose (MTD) of Lenalidomide in patients with recurrent CNS NHL and intraocular NHL

Secondary Outcome Measures

To define the extent of cerebrospinal fluid (CSF) penetration of lenalidomide.
To assess the clinical efficacy Lenalidomide monotherapy as measured by cytologic, neurologic, radiographic, and ocular (for patients with intraocular lymphoma) response criteria.
To define the immunological effects of lenalidomide using flow-cytometry CSF as well as genomic markers of recurrent/refractory CNS lymphoma.
To assess the clinical efficacy of combined intraventricular plus systemic rituximab administration in combination with lenalidomide as measured by cytologic, neurologic, and radiographic response criteria.
Objective only applies to patients with recurrent CNS lymphoma not responding to lenalidomide as monotherapy
To determine a potential impact of intravenous rituximab administration on the rate of rituximab clearance from the CSF after intraventricular rituximab administration.

Full Information

First Posted
February 27, 2012
Last Updated
August 7, 2020
Sponsor
James Rubenstein
Collaborators
Celgene, Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01542918
Brief Title
Lenalidomide Plus Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma
Official Title
Lenalidomide Plus Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
December 17, 2012 (Actual)
Primary Completion Date
April 7, 2016 (Actual)
Study Completion Date
August 30, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
James Rubenstein
Collaborators
Celgene, Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase I study, which means that the goal is to see if the study treatment is safe. The purpose of this study is to test the safety of Lenalidomide at different dose levels, and to test the safety of Lenalidomide alone or in combination with Rituximab (also known as Rituxan®).
Detailed Description
Rationale for the Proposed Study There is evidence that immunomodulatory drugs such as lenalidomide stimulate immune effectors such as natural killer (NK) cells, and thus promote rituximab efficacy via ADCC. Because of the evidence for synergy between rituximab and lenalidomide in NHL, patients who do not respond to lenalidomide monotherapy will receive combined intravenous plus intraventricular rituximab in addition to lenalidomide. To maximize delivery to the central nervous system (CNS), the investigators propose to administer rituximab via both intravenous and intraventricular routes. The rationale for intraventricular administration of rituximab is the demonstration that approximately 0.1% of systemically administered rituximab penetrates the cerebral spinal fluid (CSF) but that intraventricular administration of rituximab is both feasible and achieves high concentrations that are associated with anti-lymphoma activity. This study will thus build upon the two Phase 1 trials of intraventricular rituximab that have been conducted at University of California, San Francisco (UCSF) to define the safety of the intraventricular route of administration; this study will, however, be the first to evaluate the combination of intraventricular plus intravenous treatment. The rationale for intravenous administration of rituximab in recurrent CNS lymphoma is that the blood-brain-barrier is likely partially disrupted, particularly when there is lymphoma-associated contrast enhancement detectable on the MRI, and the fact that there is evidence for activity when rituximab is administered intravenously, both as monotherapy (Batchelor et al., 2011) and potentially in combination with chemotherapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent/Refractory CNS, Intraocular Lymphoma
Keywords
Recurrent, Refractory, CNS, Intraocular, Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Study intervention
Arm Type
Experimental
Arm Description
Lenalidomide Plus Rituximab
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Other Intervention Name(s)
Revlimid
Intervention Description
Formulation of Dosage forms: 5 mg, 10 mg, 15 mg and 25 mg capsules. Dosage: 10 mg - 30 mg (Treatment 1 and Treatment 2) Route of administration: Oral
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan, MabThera
Intervention Description
Formulation of Dosage forms: 100 mg/IO mL and 500 mg/50 mL solution in a single-use vial Dosage: 375 mg/m2, intravenous (Treatment 2, Cycle 1 only); 25 mg intraventricular injection (Treatment 2, all cycles) Route of administration: Intravenous (Treatment 2, Cycle 1 only); Intraventricular injection (Treatment 2, all cycles)
Primary Outcome Measure Information:
Title
To establish the maximal tolerated dose (MTD) of Lenalidomide in patients with recurrent CNS NHL and intraocular NHL
Time Frame
Participants will be followed for the duration of treatment, an expected average of 4 months.
Secondary Outcome Measure Information:
Title
To define the extent of cerebrospinal fluid (CSF) penetration of lenalidomide.
Time Frame
Participants will have CSF withdrawn every 4 weeks while on treatment. Average study participation is approximately 4 months.
Title
To assess the clinical efficacy Lenalidomide monotherapy as measured by cytologic, neurologic, radiographic, and ocular (for patients with intraocular lymphoma) response criteria.
Time Frame
Participants will have weekly evaluations at clinic visits for the duration of treatment. Average study participation is approximately 4 months.
Title
To define the immunological effects of lenalidomide using flow-cytometry CSF as well as genomic markers of recurrent/refractory CNS lymphoma.
Time Frame
Participants will have CSF withdrawn every 4 weeks while on treatment. Average study participation is approximately 4 months.
Title
To assess the clinical efficacy of combined intraventricular plus systemic rituximab administration in combination with lenalidomide as measured by cytologic, neurologic, and radiographic response criteria.
Description
Objective only applies to patients with recurrent CNS lymphoma not responding to lenalidomide as monotherapy
Time Frame
Participants will have weekly evaluations at clinic visits for the duration of treatment. Average study participation is approximately 4 months.
Title
To determine a potential impact of intravenous rituximab administration on the rate of rituximab clearance from the CSF after intraventricular rituximab administration.
Time Frame
Participants will have CSF withdrawn every 4 weeks while on treatment. Average study participation is approximately 4 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ability to give written informed consent and willingness to comply with the requirements of the protocol Age eighteen years or older Tumors must be CD20+ on prior pathologic analysis All prospective participants must have an Ommaya reservoir (or equivalent ventricular access device) inserted as part of their standard clinical care prior to initiation of study treatment. No concurrent methotrexate, thiotepa, cytarabine, or investigational agents Absolute neutrophil count (ANC) > 1,500 (growth factors permitted) Platelets >50,000 (platelet transfusion allowed) Total bilirubin </= 1.5 x upper limit of normal (ULN) aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)) </= 3 x ULN. Stable dose of glucocorticoids pre-therapy. If patients are receiving dexamethasone, the dose of dexamethasone should not increase during the 96 hours prior to initiation of therapy. Renal function assessed by calculated creatinine clearance. Patients must have calculated creatinine clearance (CrCl) >/= 60ml/min by Cockcroft-Gault formula or 24 hour urine demonstrating CrCl >/= 60ml/min . Females of childbearing potential (FCBPs)† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 Milli-International Units per millilitre (mIU/mL) within 10 - 14 days and again within 24 hours prior to receiving lenalidomide for Cycle 1 and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBPs must also agree to ongoing pregnancy testing and for 28 days after receiving their last dose of lenalidomide. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to aspirin may use warfarin or low molecular weight heparin). All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®. Exclusion Criteria: Intraventricular chemotherapy or radiation therapy within 4 days of starting treatment Intravenous rituximab within 30 days of starting treatment Persistent neurotoxicity from intraventricular methotrexate, cytarabine, thiotepa Anticipated survival of less than 1 month Pregnant women and women of child-bearing potential who are not using an effective method of birth control. Known hypersensitivity to thalidomide or lenalidomide The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible. Contraindication to aspirin. If unable to take aspirin, contraindication to warfarin or low molecular weight heparin.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James Rubenstein, MD, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
29986852
Citation
Rubenstein JL, Geng H, Fraser EJ, Formaker P, Chen L, Sharma J, Killea P, Choi K, Ventura J, Kurhanewicz J, Lowell C, Hwang J, Treseler P, Sneed PK, Li J, Wang X, Chen N, Gangoiti J, Munster PN, Damato B. Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv. 2018 Jul 10;2(13):1595-1607. doi: 10.1182/bloodadvances.2017014845.
Results Reference
derived

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Lenalidomide Plus Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma

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