Phase II Trial of Alemtuzumab (Campath) and Dose-Adjusted EPOCH-Rituximab (DA-EPOCH-R) in Relapsed or Refractory Diffuse Large B-Cell and Hodgkin Lymphomas

Background:

• Studies conducted at the National Cancer Institute suggest that certain chemotherapy drugs may be more effective if given by continuous infusion into the vein rather than by the standard method of rapid intravenous injection. One combination of six chemotherapy drugs, known as etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), has had a high degree of effectiveness in people with certain kinds of cancer.
• Recent evidence also indicates that the effects of chemotherapy may be improved by combining the treatment with monoclonal antibodies, which are purified proteins that are specially made to attach to foreign substances such as cancer cells. A monoclonal antibody called campath (alemtuzumab) has been manufactured to attach to a protein called Campath-1 antigen (CD52) that may target tumor cells or the surrounding inflammatory cells.
• Researchers are interested in developing new treatments for large B-cell lymphoma or Hodgkin lymphoma that can best be treated with chemotherapy. This protocol is specifically for people with diffuse large B-cell or Hodgkin lymphomas that have not responded to standard treatments.

Objectives:

- To test whether giving campath (alemtuzumab) in combination with continuous infusion EPOCH-R chemotherapy will improve the outcome of lymphoma treatment.

Eligibility:

- Individuals 18 years of age and older who have large B-cell lymphoma or Hodgkin lymphoma that has not responded well to standard treatments.

Design:

• During the study, patients will receive standard EPOCH-R chemotherapy, which includes the following drugs: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. The additional drug, campath, will be given by intravenous (IV) infusion on the first day of treatment over several hours.
• When the campath IV infusion and rituximab IV infusion are complete, the drugs doxorubicin, etoposide, and vincristine will each be given by continuous IV infusion over the next 4 days (that is, continuously for a total of 96 hours). Cyclophosphamide will be given by IV infusion over several hours on Day 5. Prednisone will be given by mouth twice each day for 5 days.
• Patients may be given other drugs to treat the side effects of chemotherapy, to prevent possible infections, and to improve white blood cell counts.
• The campath-EPOCH-R therapy will be repeated every 21 days, as a cycle of therapy, for a total of 6 cycles. Following the fourth and sixth treatment cycles (approximately weeks 12 and 18) of campath-EPOCH-R treatment, study researchers will perform blood tests and computed tomography (CT)/magnetic resonance imaging (MRI) scans on all patients to assess their response to the treatment.

Study Overview

• Status: Completed
• Conditions: Diffuse Large B-Cell Lymphoma; Hodgkin Lymphoma
• Intervention / Treatment: Biological: Campath; Biological: Rituximab; Drug: EPOCH

Detailed Description

Background:

Two signatures of the microenvironment were recently identified that are predictive of outcome in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and prednisone (R-CHOP). These signatures, called stromal 1 and stromal 2, are associated with genes expressed by infiltrating mononuclear cells. The stromal 2 signature, which includes genes associated with angiogenesis, is predictive of an inferior outcome. Based on these observations, we are interested in targeting the reactive cells in the microenvironment as a therapeutic strategy in patients with relapsed and refractory DLBCL. Along the same principles, we are also including patients with relapsed Hodgkin lymphoma (HL). The surrounding reactive cells around Hodgkin Reed Sternberg (HRS) cells are now not thought to be bystander cells and they appear to provide important survival signals to HRS cells.

• Campath-1 antigen (CD52) is one such promising target that is highly expressed in most of these infiltrating cells and on most DLBCL although not on HRS cells specifically. Anti-CD52 antibodies may have therapeutic value by depleting reactive B and T cells, and monocytes from the microenvironment.
• The dose of alemtuzumab in combination with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH) is 30 mg intravenous (IV), as determined by a prior study done in patients with untreated peripheral T-cell lymphoma. The main toxicities of this combination are myelosuppression and opportunistic infections.
• An important component of this study will be to obtain tumor tissue for gene expression profiling and to assess microenvironment signatures and look at other molecular signatures and targets before treatment and in patients who progress and ultimately correlate response and outcome with these various end-points.

Objectives:

- Assess response, progression free survival (PFS) and overall survival (OS) in relapsed/refractory DLBCL and Hodgkin Lymphoma.

Eligibility:

• Previously treated or refractory classical large B-cell lymphomas, Grey-zone lymphoma and Hodgkin lymphoma, including Lymphocyte predominant Hodgkin Lymphoma (LPHL).
• Age greater than or equal to 18 years with adequate organ functions.
• Human immunodeficiency virus (HIV) negative and no active central nervous system (CNS) lymphoma.

Study Design:

• Patients will receive 30mg of Alemtuzumab on day 1 of therapy, followed by Rituximab on day 1 and dose-adjusted EPOCH chemotherapy days 1-5, up to six cycles of therapy.
• Tumor biopsies will be done before treatment, after 1 cycle of therapy and at relapse.
• It is anticipated that up to 10-15 patients per year may be enrolled onto this trial. Thus, accrual of up to 52 patients is expected to require approximately 4-5 years.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

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

Description

• INCLUSION CRITERIA:

  1. Previously treated or refractory classical large B-cell lymphomas, Grey-zone lymphoma and Hodgkin lymphoma, including Lymphocyte predominant Hodgkin Lymphoma (LPHL).
  2. Confirmed pathological diagnosis by the Laboratory of Pathology, National Cancer Institute (NCI).
  3. Age greater than or equal to 18 years.
  4. Eastern Cooperative Oncology Group (ECOG) performance 0-2
  5. Laboratory tests: absolute neutrophil count (ANC) greater than or equal to 1000/mm(3), platelet greater than or equal to 75,000/mm(3). Creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 ml/min; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal (ULN). Total bilirubin < 2.0 mg/dl except < 5mg/dL in patients with Gilbert's (as defined as > 80% unconjugated hyperbilirubinemia without other known cause); unless impairment due to organ involvement by lymphoma.

EXCLUSION CRITERIA:

1. Active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year. If echocardiogram (ECHO) is obtained, the left ventricular ejection fraction (LVEF) should exceed 40%.
2. Human immunodeficiency virus (HIV) positive, because of the unknown effects of combined therapy with chemotherapy and an immunosuppressive agent on HIV progression.
3. Female subject of child-bearing potential not willing to use an acceptable method of birth control (i.e. a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and two years beyond treatment completion.
4. Female subject pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotrophin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for women without childbearing potential.
5. Male subject unwilling to use an acceptable method for contraception for the duration of the study and one year beyond treatment completion.
6. Invasive or active malignancy in past 2 years.
7. Serious concomitant medical illnesses that would jeopardize the patient s ability to receive the regimen with reasonable safety.
8. Active central nervous system (CNS) lymphoma. These patients have a poor prognosis and because they frequently develop progressive neurological dysfunction that would confound the evaluation of neurological and other adverse events.
9. Systemic cytotoxic therapy within 3 weeks of treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin + Rituximab + Campath; Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin (EPOCH) + Rituximab + campath every 3 weeks for six cycles

Biological: Campath; campath plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and rituximab every 3 weeks for up to 6 cycles; Other Names: Alemtuzumab; Biological: Rituximab; rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and campath every 3 weeks for up to 6 cycles; Other Names: Rituxan; Drug: EPOCH; Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) plus rituximab and campath every 3 weeks for up to 6 cycles; Other Names: Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS is the time interval from start of treatment to documented evidence of disease progression estimated using a Kaplan Meier curve. Progression was assessed by the International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphomas and is defined as ≥50% increase from nadir in the sum of the products of diameters of any previously identified abnormal node for partial response or non-responders. And an appearance of any new lesion during or at the end of therapy.	Time of progression or death, approximately 10 months
Overall Survival (OS)	OS is from enrollment to the day of death estimated using the Kaplan-Meier curve.	Median overall survival from enrollment to the day of death, approximately 17.9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response on Study and at Relapse After Dose Adjusted - Etoposide + Prednisone + Vincristine + Cyclophosphamide + Doxorubicin + Rituximab (DA-EPOCH-RC)	Clinical response was assessed by the International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphomas. Complete remission is complete disappearance of all detectable clinical and radiographic evidence of disease. Complete response unconfirmed is as per complete remission except that if a residual node is greater than 1.5cm, it must have decreased by greater than 75% in the sum of the products of the perpendicular diameters (SPD). Partial response is ≥50% decreased in the SPD of 6 largest dominant nodes or nodal masses. Relapsed disease is appearance of any new lesion or increase by ≥50% in the size of the previously involved sites. Stable disease is defined as less than a partial response but not progressive disease. Progression is ≥50% increase from nadir in the SPD of diameters of any previously identified abnormal node for partial response or non-responders; and an appearance of any new lesion during or at the end of therapy.	On study and at relapse after study treatment, approximately 10 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Date treatment consent signed to date off study, approximately 58 months and 18 days.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Wyndham H Wilson, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2009
• Primary Completion (Actual): August 6, 2021
• Study Completion (Actual): August 6, 2021

Study Registration Dates

• First Submitted: December 11, 2009
• First Submitted That Met QC Criteria: December 11, 2009
• First Posted (Estimate): December 14, 2009

Study Record Updates

• Last Update Posted (Actual): October 6, 2022
• Last Update Submitted That Met QC Criteria: September 11, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Immunosuppression; Microarray; Diffuse Large B-Cell Lymphoma; Hodgkin Lymphoma; B-Cell Lymphoma; Microenvironment
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Hodgkin Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Etoposide; Rituximab; Prednisone; Doxorubicin; Vincristine; Alemtuzumab
• Other Study ID Numbers: 100011; 10-C-0011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data will be available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No