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A Phase 1 Trial of the Combination of Everolimus (RAD001) and Bortezomib (VELCADE) for Relapsed or Refractory Lymphoma

Phase 1
18 Years
Open (Enrolling)
714leukemia, Lymphoma

Thank you

Trial Information

A Phase 1 Trial of the Combination of Everolimus (RAD001) and Bortezomib (VELCADE) for Relapsed or Refractory Lymphoma



- Determine the maximum tolerated dose of everolimus (up to 10 mg PO daily) in
combination with bortezomib in patients with relapsed/refractory indolent or mantle
cell non-Hodgkin's lymphoma (NHL) including cutaneous forms, or relapsed/refractory
aggressive NHL ineligible for hematopoetic stem cell transplantation


- Evaluate the toxicity of this combination.

- Assess the pharmacokinetics interactions between these agents.

- Assess the response rate and 6-month progression-free survival in treated patients.

- Obtain preliminary data to assess associations between tumor characteristics and
response to treatment. in those subjects who underwent biopsy prior to study treatment.

OUTLINE: This is a dose-escalation study.

Patients receive bortezomib IV on days 1, 4, 8, and 11. Patients also receive oral
everolimus once daily or once every other day on days 1-21 in all courses. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.

Patients will undergo blood sample collection on Cycle 1, Day 11 for pharmacokinetic
studies. Baseline tumor expression of mTOR and NFkB -related proteins (i.e., pS6K, pAKT, and
cREL) and FOXP3 is assessed by immunohistochemistry.

Inclusion Criteria


- Histologically confirmed relapsed or refractory Non-Hodgkin lymphoma (NHL), according
to the World Health Organization (WHO)/Revised European-American Lymphoma
Classification, including any of the following subtypes:

- Mantle cell lymphoma

- Hairy cell leukemia

- Grade I, II, or III follicular lymphoma

- Marginal zone B-cell lymphoma

- Small lymphocytic lymphoma/B-cell chronic lymphocytic leukemia (SLL/CLL)

- Lymphoplasmacytic lymphoma (with or without Waldenstrom macroglobulinemia)

- History of transformed lymphoma and relapsed or refractory diffuse large B cell
lymphoma are included if patients are ineligible for or refuse hematopoietic stem
cell transplant

- Cutaneous B and T cell lymphoma are permitted. Cutaneous T cell lymphoma must be
refractory to 1 prior systemic therapy (topical therapy, photopheresis, and radiation
are not considered systemic therapy. Transformed B and T cell cutaneous lymphoma are

- Relapsed or refractory nodal, leukemic, and extranodal T cell lymphomas are eligible.
Subtypes that are eligible include:

- Anaplastic large cell lymphoma

- Angioimmunoblastic T cell lymphoma


- Nasal or disseminated extranodal T/NK lymphoma

- Enteropathy-associated T cell lymphoma

- Hepatosplenic gamma/delta T cell lymphoma

- Subcutaneous panniculitis-like T cell lymphoma

- T-prolymphocytic leukemia

- Adult T-cell leukemia/lymphoma

- Large granular lymphocytic leukemia

- Aggressive NK leukemia

- Refractory to or relapsed after receiving ≥ 1 prior treatment regimen for lymphoma
(which may have included prior autologous stem cell transplantation) AND demonstrated
evidence of progressive disease by clinical and/or radiographic characteristics

- Measurable disease by radiographic criteria (≥ 2 cm by CT scan)

- Patients with leukemic forms of SLL/CLL must have an absolute lymphocytosis > 5
times 10^9/L with a B-cell phenotype and > 30% bone marrow lymphocytes

- No plasma cell myeloma or Hodgkin lymphoma

- No uncontrolled brain or leptomeningeal metastases, including ongoing requirement for
glucocorticoids for brain or leptomeningeal metastases


- ECOG performance status 0-2

- Bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless attributed to active
hemolysis or ineffective erythropoiesis)

- AST or ALT ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement by

- ANC ≥ 1,500/μL

- WBC ≥ 3,000/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9.0 g/dL

- Creatinine ≤ 1.5 times ULN

- Fasting cholesterol > 300 mg/dL (or > 7.75 mmol/L)

- Fasting triglycerides > 2.5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Histologic confirmation of diagnosis, either are initial diagnosis or at any
subsequent relapse. Biopsy is not required at relapse, but is suggested

- No other malignancies within the past 3 years, except for adequately treated
carcinoma of the cervix, basal cell or squamous cell carcinoma of the skin, or
curatively treated low-risk prostate cancer

- No severe and/or uncontrolled medical condition that would preclude study
participation, including the following:

- Unstable angina pectoris

- New York Heart Association class III or IV symptomatic congestive heart failure

- Myocardial infarction within the past 6 months

- Serious uncontrolled cardiac arrhythmia

- Severely impaired lung function

- Any active (acute or chronic) or uncontrolled infection and/or disorder

- Liver disease (e.g., viral hepatitis B or C, cirrhosis, chronic active
hepatitis, or chronic persistent hepatitis)

- Known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, or diarrhea, or malabsorption syndrome)

- Non-malignant medical illness that is uncontrolled or whose control may be
jeopardized by study therapy

- None of the following diabetic conditions:

- Diabetes mellitus currently requiring insulin therapy

- Preexisting poorly controlled diabetes mellitus (e.g., hemoglobin A1c value > 9%
within the past 4 weeks)

- Uncontrolled diabetes, defined by fasting serum glucose > 1.5 times ULN (off

- No preexisting peripheral neuropathy ≥ grade 2

- No active bleeding diathesis

- No known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus,
temsirolimus) or to its excipients, or to bortezomib, boron, or mannitol

- No history of noncompliance to medical regimens

- No personal, medical, or psychiatric reason that would preclude compliance with study


- More than 4 weeks since prior chemotherapy or investigational drug

- More than 3 months since prior monoclonal antibody

- More than 1 week since prior and no concurrent strong P450/CY3PA4 inhibitors

- No prior allogeneic stem cell transplantation

- No prior small bowel resection that may significantly alter the absorption of

- No concurrent immunization with attenuated live vaccine

- No concurrent chronic treatment with systemic steroids or other immunosuppressive

- No other concurrent investigational or anticancer agents

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of everolimus in combination with bortezomib

Outcome Description:

Defined as the highest dose level at which 0 out of 3, or 1 out of 6, subjects experiences dose-limiting toxicity (DLT).

Outcome Time Frame:

after 1 course (21 days)

Safety Issue:


Principal Investigator

Brian Hill, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2008

Completion Date:

Related Keywords:

  • 714leukemia
  • 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
  • Waldenstrom's macroglobulinemia
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • splenic marginal zone lymphoma
  • refractory hairy cell leukemia
  • B-cell chronic lymphocytic leukemia
  • refractory chronic lymphocytic leukemia
  • hairy cell leukemia
  • cutaneous B and T cell lymphoma
  • transformed lymphoma
  • transformed B and T cell cutaneous lymphoma
  • relapsed or refractory diffuse large B cell lymphoma
  • extranodal T cell lymphomas
  • anaplastic large cell lymphoma
  • angioimmunoblastic T cell lymphoma
  • nasal or disseminated extranodal T/NK lymphoma
  • enteropathy-associated T cell lymphoma
  • hepatosplenic gamma/delta T cell lymphoma
  • subcutaneous panniculitis-like T cell lymphoma
  • T-prolymphocytic leukemia
  • adult T-cell leukemia/lymphoma
  • large granular lymphocytic leukemia
  • aggressive NK leukemia
  • Leukemia
  • Lymphoma



Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Cleveland, Ohio  44195