A Phase 1 Trial of the Combination of Everolimus (RAD001) and Bortezomib (VELCADE) for Relapsed or Refractory Lymphoma
A Phase 1 Trial of the Combination of Everolimus (RAD001) and Bortezomib (VELCADE) for Relapsed or Refractory Lymphoma
RATIONALE: Everolimus and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with bortezomib in treating patients with relapsed or refractory lymphoma.
OBJECTIVES:
Primary
Secondary
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:
Able to provide voluntary written informed consent, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
Diagnosed with relapsed or refractory NHL, limited to subtypes listed below. The subject must have histologic information of diagnosis according to review at the Cleveland Clinic Foundation, either at initial diagnosis or at any subsequent relapse. (Biopsy is not required at relapse, but is suggested. Biopsy at outside institution, reviewed at the Cleveland Clinic, is acceptable.)
Prior therapy with bortezomib is allowed. Patients who have received prior bortezomib therapy must have received bortezomib >6 months ago, and must have shown some response. Patients that did not respond to prior bortezomib therapy are not eligible.
Measurable disease by one of the following: radiographic criteria (≥2 cm by computed tomography); lymphoma involving peripheral blood with more than 5000 leukemia cells/mm3, or any degree of bone marrow infiltration on bone marrow biopsy. Skin involvement with or without nodal or bone marrow involvement permitted for cutaneous lymphomas is also permitted. (see section 6.0, Measurement of Effect).
Eastern Cooperative Group (ECOG) Performance Status of 0-2.
Serum bilirubin levels ≤1.5 times the upper limit of the normal (ULN) range for the laboratory. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis. Serum AST or serum ALT levels must be ≤2.5 x ULN, or ≤5 x ULN for patients with liver involvement by lymphoma.
Must have adequate bone marrow function:
Must have adequate renal function: Creatinine ≤ 1.5 X ULN.
Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test within 7 days of starting study drug. In addition, sexually active WCBP must agree to use adequate contraceptive methods (tubal ligation; intrauterine device; or barrier contraceptive with spermicide) while on study. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. WCBP must agree to have pregnancy tests every 4 weeks while on study drug. Male subject agrees to use an acceptable method of contraception for the duration of the study.
Female patients who:
Male patients, even if surgically sterilized (ie, status post-vasectomy), who:
Able to adhere to the study visit schedule and other protocol requirements.
Exclusion Criteria:
Prior treatment with any investigational drug, chemotherapy, or monoclonal antibody within the preceding 1 month
Chronic treatment with systemic steroids or another immunosuppressive agent.
Patients should not receive immunization with attenuated live vaccines during study period.
History of allogeneic stem cell transplantation.
Any patient with known diabetes mellitus currently requiring insulin therapy, or any patient with preexisting diabetes mellitus in poor control, defined as a hemoglobin A1C (HbA1C) value of over 9% within 4 weeks of starting therapy
Fasting serum cholesterol >300 mg/dL OR >7.75 mmol/L or fasting triglycerides > 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases.
Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or low-risk prostate cancer after curative therapy.
Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
Patients with an active, bleeding diathesis
Breast feeding or pregnant females
Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients, or to bortezomib, boron, or mannitol
History of noncompliance to medical regimens
Patients unwilling or unable for any reason (personal, medical, or psychiatric) to comply with the protocol
Patients with preexisting peripheral neuropathy grade ≥ 2 will not be eligible
Patients taking concomitant medications (chronically or within 1 week of study drug administration) which are strong inhibitors of hepatic metabolism via P450/CY3PA4 isoenzyme will be excluded.
Patients who have received hematopoietic growth factors (filgrastim, pegfilgrastim, or sargramostim) within 28 days of first dose of screening.
Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.