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A Phase I Study of Ipilimumab in Combination With Rituximab in Patients With Relapsed/Refractory CD20+ B-Cell Lymphoma


Phase 1
18 Years
N/A
Open (Enrolling)
Both
B-cell Chronic Lymphocytic Leukemia, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Hairy Cell Leukemia, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Testicular Lymphoma, Waldenström Macroglobulinemia

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Trial Information

A Phase I Study of Ipilimumab in Combination With Rituximab in Patients With Relapsed/Refractory CD20+ B-Cell Lymphoma


PRIMARY OBJECTIVES:

I. To determine a recommended phase II dose for ipilimumab in combination with rituximab.

SECONDARY OBJECTIVES:

I. To obtain preliminary information on the effect of adding ipilimumab to rituximab in
regard to: immune response; clinical anti-tumor response/overall remission rate (ORR)
(complete remission + partial remission); progression free survival (PFS).

OUTLINE: This is a dose-escalation study of ipilimumab followed by a randomized study.

PART I:

INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes once every 3 weeks
for 12 weeks and rituximab IV over 2-6 hours once weekly for 4 weeks.

MAINTENANCE: Patients receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours
once every 12 weeks for up to 1 year.

PART II: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive rituximab
IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab IV over 90 minutes once weekly in
weeks 1, 4, 7, and 10. Patients then receive ipilimumab IV over 90 minutes and rituximab IV
over 2-6 hours once every 12 weeks for up to 1 year in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab
IV over 90 minutes once weekly in weeks 3, 6, 9, and 12. Patients then receive ipilimumab IV
over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 months.


Inclusion Criteria:



- Previously treated, histologically confirmed CD20+ B cell lymphoma; bone marrow
biopsies as the sole means of diagnosis are not acceptable, but they may be submitted
in conjunction with nodal biopsies or extra nodal biopsies; fine needle aspirates are
not acceptable

- All patients must be informed of the investigative nature of the clinical trial and
give written informed consent in accordance with institutional and federal guidelines

- Able to adhere to the study visit schedule and other protocol requirements

- Karnofsky >= 70%

- Life expectancy expected to be greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 50,000/mcL

- Total bilirubin =< 2.0 times institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Serum creatinine =< 2.0 x upper limit of normal or calculated creatinine clearance >=
30 ml/min/1.73 M^2 by the modified Cockcroft and Gault Formula or creatinine
clearance >= 30 mL/min obtained from a 24-hour urine collection

- At least one measurable lesion according to International workshop lymphoma response
criteria (Cheson 2007); there must be measurable lymphadenopathy to follow with
serial exam and/or imaging

- All previous cancer therapy, including radiation, hormonal therapy and surgery, must
have been discontinued at least 4 weeks prior to treatment in this study

- Patients must have evidence of progression of disease during or after last treatment

- Submission of original biopsy for review and verification by Participating Center
hematopathologist

- Disease free of prior malignancies for >= 3 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix
or breast

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients with a history of prior treatment with ipilimumab

- Patients with a history of prior treatment with an anti-PD 1 antibody, CD137 agonist
or other immune activating therapy such as anti-CD 40 antibody are excluded unless 5
half-lives of the agent (minimum of 8 weeks) have intervened since the therapy;
patients who have received prior vaccine therapy are eligible

- Patients who are receiving any other investigational agents

- Autoimmune disease: patients with a history of inflammatory bowel disease, including
ulcerative colitis and Crohn's disease, are excluded from this study, as are patients
with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic
progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
vasculitis [e.g., Wegener's Granulomatosis]); central nervous system (CNS) or motor
neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and
Myasthenia Gravis, multiple sclerosis)

- Patients with known immune impairment who may be unable to respond to anti-cytotoxic
T-lymphocyte antigen 4 (CTLA 4) antibody

- Patients with known brain metastases are excluded

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to rituximab

- Patients on systemic corticosteroids (except for patients on stable doses of hormone
replacement therapy such as hydrocortisone), or other immunosuppressants (e.g.,
infliximab, mycophenolate mofetil) are excluded

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Patients with chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C
infections are excluded

- Pregnant women are excluded from this study

- HIV-positive patients on combination antiretroviral therapy are ineligible

- Rituximab within three months

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4 ( v4)

Outcome Description:

Tables will be created to summarize the toxicities and side effects by dose, course, organ and severity.

Outcome Time Frame:

Up to 12 months

Safety Issue:

Yes

Principal Investigator

Joseph Tuscano

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02213

NCT ID:

NCT01729806

Start Date:

November 2012

Completion Date:

Related Keywords:

  • B-cell Chronic Lymphocytic Leukemia
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Intraocular Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Hairy Cell Leukemia
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell

Name

Location

City of HopeDuarte, California  91010
UC Davis Comprehensive Cancer CenterSacramento, California  95817
University of Southern CaliforniaLos Angeles, California  90033
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033