Everolimus, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Untreated Diffuse Large B-Cell Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Alliance for Clinical Trials in Oncology
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology ( North Central Cancer Treatment Group )
ClinicalTrials.gov Identifier:
NCT01334502
First received: April 12, 2011
Last updated: July 22, 2013
Last verified: July 2013
  Purpose

RATIONALE: Everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer cells in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Giving everolimus together with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and the best dose of everolimus when given together with rituximab and combination chemotherapy in treating patients with newly diagnosed untreated diffuse large B-cell lymphoma.


Condition Intervention Phase
Lymphoma
Biological: rituximab
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: everolimus
Drug: prednisone
Drug: vincristine sulfate
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I and Feasibility Study of Everolimus (RAD001) Plus R-CHOP for New Untreated Diffuse Large B-Cell Lymphoma (DLBCL)

Resource links provided by NLM:


Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • MTD of everolimus in combination with R-CHOP [ Time Frame: Up to 15 months post registration to Phase I portion of the study ] [ Designated as safety issue: No ]
  • Adverse events profile [ Time Frame: Up to 15 months post registration to Phase I portion of the study ] [ Designated as safety issue: Yes ]
  • Toxicity profile [ Time Frame: Up to 15 months post registration to Phase I portion of the study ] [ Designated as safety issue: Yes ]
  • Proportion of patients who have a significant toxicity [ Time Frame: Up to 2.5 years post registration to Feasibility portion of the study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Rate of EFS [ Time Frame: Up to 5 years post treatment of the feasibility portion of the study ] [ Designated as safety issue: No ]
  • Overall response rate, CR rate, overall survival, PFS, and duration of response [ Time Frame: Up to 5 years post treatment of the feasibility portion of the study ] [ Designated as safety issue: No ]

Estimated Enrollment: 37
Study Start Date: March 2012
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: everolimus and RCHOP
Patients registered to the study will receive an assigned dose of everolimus by mouth and RCHOP for a maximum of six cycles. Each cycle is a total of 21 days. RCHOP consists of 375 mg/m2 IV rituximab, 750 mg/m2 IV cyclophosphamide, 50 mg/m2 IV doxorubicin, 1.4 mg/m2 IV vincristine and 100 mg/m2 by mouth QD prednisone. The study includes a Phase I component to determine the maximum tolerated dose of everolimus and the second component determines the feasibility of therapy administered to lymphoma patients.
Biological: rituximab
PO
Drug: cyclophosphamide
IV
Drug: doxorubicin hydrochloride
IV
Drug: everolimus
PO
Drug: prednisone
PO
Drug: vincristine sulfate
IV

Detailed Description:

OBJECTIVES:

Primary

  • To establish the maximum-tolerated dose (MTD) of everolimus in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone) chemotherapy.
  • To assess the feasibility of everolimus in combination with standard R-CHOP chemotherapy in patients with newly diagnosed diffuse large B-cell lymphoma.

Secondary

  • To describe the toxicities associated with everolimus in combination with R-CHOP chemotherapy.
  • To further describe the toxicities associated with everolimus in combination with R-CHOP chemotherapy.
  • To assess the rate of event-free survival (EFS) at 12 months for diffuse large B-cell lymphoma patients treated with everolimus in combination with R-CHOP chemotherapy.
  • To evaluate overall response rate, complete response rate, duration of response, EFS, overall survival, and progression-free survival for patients treated with everolimus in combination with R-CHOP chemotherapy.

Tertiary

  • To profile gene expression using immunohistochemistry and categorize patients as germinal-center B-cell-like (GBC) vs activated B-cell-like (ABC) vs unclassified lymphoma subtype. (exploratory)
  • To determine whether previously identified predictive markers in large cell lymphoma remain valid with the addition of everolimus to R-CHOP chemotherapy. (exploratory)

OUTLINE: This is a multicenter, dose-escalation study of everolimus followed by a feasability expanded-cohort study.

Patients receive everolimus orally (PO) once daily (QD) on days 1-10 or 1-14; rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV over 15-60 minutes, and vincristine sulfate IV on day 1; and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Tumor biopsies are collected for laboratory studies and patients may undergo blood and needle biopsy sample collection for correlative studies.

After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Untreated, histological diagnosis of CD20-positive diffuse large B-cell lymphoma
  • Stage II-IV (Ann Arbor Staging)
  • Measurable or assessable disease defined as at least one of the following:

    • A lymph node or tumor mass that is ≥ 2.0 cm in at least one dimension by CT portion of PET/CT scan, CT scan, or MRI
    • Diffuse infiltration of an organ such as the stomach, bone marrow, peripheral blood, liver, lungs, or bowel by lymphoma without a discrete mass would constitute assessable, but not measurable, disease
  • Diagnostic tissue slides and paraffin-embedded block must be available
  • No CNS lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Absolute neutrophil count (ANC) ≥ 1,500/mm³
  • Peripheral platelet count ≥ 100,000/mm³
  • Hemoglobin (HgB) > 9.0 g/dL
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

    • For total bilirubin > 1.5 times ULN, the direct bilirubin must be normal
  • Alkaline phosphatase ≤ 3 times ULN (≤ 5 times ULN if evidence of direct liver involvement by lymphoma)
  • AST ≤ 3 times ULN (≤ 5 times ULN if evidence of direct liver involvement by lymphoma)
  • Creatinine ≤ ULN
  • Negative serum or urine pregnancy test
  • Not pregnant or nursing
  • Men or women of childbearing potential must be willing to employ adequate contraception throughout the study and for12 months after the last dose of study drug
  • Willing to return to the National Central Cancer Treatment Group (NCCTG) enrolling institution for follow-up
  • Willing to provide archival tissue from the primary diagnosis (original lymphoma lymph node tissue biopsy)
  • Willing to abstain from eating grapefruit or drinking grapefruit juice for the duration of the study
  • Diabetic patients who are taking insulin or oral anti-diabetic therapy must have HbA1c ≤ 8%, or a fasting serum glucose ≤ 110% ULN
  • HIV-positive patients must have CD4 count ≥ 400/mm³
  • No co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • No immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be HIV positive with a CD4 count of < 400/mm³
  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Severely impaired lung function
    • Uncontrolled diabetes as defined by fasting serum glucose > 1.5 times ULN

      • Optimal glycemic control should be achieved before starting trial therapy
    • Psychiatric illness/social situations that would limit compliance with study requirements
    • Liver disease such as cirrhosis or severe hepatic impairment
    • Chronic active hepatitis
    • Chronic persistent hepatitis or history of hepatitis B or C
  • No other active malignancy except non-melanotic skin cancer or carcinoma in situ of the cervix

    • If there is a history of prior malignancy, patients must not be receiving other specific treatment (other than hormonal therapy) for their cancer
  • No positive hepatitis B antigen (HBsAg) or hepatitis C serology (HCV) tests meeting the following criteria:

    • Hepatitis B surface antigen (HbsAg) and antibody to hepatitis B core (anti-HBc) or hepatitis C antibody
    • All patients must be screened prior to registration
    • Patients who have evidence of chronic or acute infection with either hepatitis B or C may not be treated on this protocol

PRIOR CONCURRENT THERAPY:

  • Not receiving any other investigational agent that would be considered as a treatment for the primary neoplasm
  • No planned immunization with attenuated live vaccines ≤ 7 days prior to registration or during study period

    • Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus
    • Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines
  • Not currently on enzyme-inducing anti-convulsants or other strong inducers of CYP3A4 (efavirenz, nevirapine, barbiturates, carbamazepine, modafinil, phenobarbital, phenytoin, rifabutin, rifampin, pioglitazone, or St. John wort) or strong inhibitors of CYP3A4 (indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, saquinavir, or telithromycin)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01334502

Locations
United States, Minnesota
Mayo Clinic Cancer Center Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Office - All Mayo Clinic Locations    507-538-7623      
Sponsors and Collaborators
North Central Cancer Treatment Group
Investigators
Principal Investigator: Patrick Johnston, MD, PhD Mayo Clinic
  More Information

Additional Information:
No publications provided

Responsible Party: Alliance for Clinical Trials in Oncology ( North Central Cancer Treatment Group )
ClinicalTrials.gov Identifier: NCT01334502     History of Changes
Other Study ID Numbers: N1085, NCCTG-N1085, CDR0000698584, NCI-2011-02643
Study First Received: April 12, 2011
Last Updated: July 22, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Alliance for Clinical Trials in Oncology:
contiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Everolimus
Sirolimus
Rituximab
Liposomal doxorubicin
Doxorubicin
Prednisone
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on August 18, 2014