714leukemiaPhase 1NCT00671112
Everolimus and Bortezomib in Treating Patients With Relapsed or Refractory Lymphoma
A Phase 1 study testing Bortezomib and Everolimus in people with 714leukemia and Lymphoma, run by Brian Hill, MD, PhD at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- 714leukemia, Lymphoma
- What is being tested?
- Bortezomib and Everolimus
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2008to Oct 2015
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Able to provide voluntary written informed consent, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.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.)
- "Relapsed or refractory" refers to patients who have received at least 1 prior treatment regimen for lymphoma (which may include prior autologous stem cell transplantation) and have demonstrated evidence of progressive disease by clinical and/or radiographic characteristics.
- "Indolent lymphoma" is included, and refers to small lymphocytic lymphoma/B-cell chronic lymphocytic leukemia (SLL/CLL); lymphoplasmacytic lymphoma (with or without Waldenstrom's macroglobulinemia); hairy cell leukemia; follicular lymphoma (FL) of any grade; marginal zone B-cell lymphoma; or mantle cell lymphoma.
- Transformed lymphoma is included if patients are ineligible for (or refuse) hematopoetic stem cell transplant.
- In addition, cutaneous B and T cell lymphoma are permitted. Cutaneous T cell lymphoma must be refractory to 1 prior systemic therapy (topical therapy, photopheresis, radiation are not considered systemic therapy). Transformed B and T cell cutaneous lymphoma are also permitted.
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- Relapsed/refractory diffuse large B cell lymphoma (DLBCL) is allowed if the patient is not eligible for, or refuses, hematopoetic stem cell transplant.
- Relapsed/refractory nodal, leukemic, and extranodal T cell lymphomas are eligible. Subtypes eligible include anaplastic large cell lymphoma, angioimmunoblastic T cell lymphoma, PTCL-NOS, 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.
- Plasma cell myeloma and Hodgkin lymphoma are excluded.
- 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:
- Absolute neutrophil count (ANC) ≥1,000/uL
- Platelet count (Plt) ≥ 75,000/uL
- Hemoglobin (Hgb) ≥ 9.0 g/dL
- 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:
- Are postmenopausal for at least 1 year before the Screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse
- Male patients, even if surgically sterilized (ie, status post-vasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study treatment, OR
- Agree to completely abstain from heterosexual intercourse
- Able to adhere to the study visit schedule and other protocol requirements.
Who cannot join
- 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.
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- 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:
- unstable angina pectoris, any history of congestive heart failure, any history of known myocardial infarction, uncontrolled cardiac arrhythmia
- severely impaired lung function
- uncontrolled diabetes as defined by fasting serum glucose >1.5x ULN, off medications
- any active (acute or chronic) or uncontrolled infection/ disorders.
- nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy
- liver disease including a known history of viral hepatitis B or C, evidence of cirrhosis, chronic active hepatitis or chronic persistent hepatitis
- a known history of HIV seropositivity
- Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, 44195
About this study
Official title: 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.
Read the detailed description
OBJECTIVES:
Primary
- 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
Secondary
- 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.
- Conditions
- 714leukemia, Lymphoma
- Being tested
- Bortezomib, Everolimus
- Keywords
- 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
- Medical subject headings
- Lymphoma, Lymphoma, Follicular, Lymphoma, Mantle-Cell, Lymphoma, B-Cell, Marginal Zone, Leukemia, Lymphocytic, Chronic, B-Cell, Waldenstrom Macroglobulinemia, Leukemia, Hairy Cell, Lymphoma, T-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BortezomibDrug
Also called Velcade
Patients will be assigned to one of the following dose levels of Bortezomib: 0.7mg/m2, 1.0 mg/m2, or 1.3mg/m2 on days 1,4,8,11 of a 21 day cycle.
The appropriate amount of bortezomib will be drawn from the injection vial and administered as an intravenous (IV) push or sub-cutaneously over 3 to 5 seconds followed by a standard saline flush or through a running IV line.
EverolimusDrug
Also called RAD001
Everolimus 5 mg PO every other day, 5 mg by mouth (PO) daily, or 10 mg PO daily
| Study group | Role | What they receive |
|---|---|---|
| Everolimus and Bortezomib | Experimental | Patients will receive a combination of Everolimus by mouth and Bortezomib intravenously for a 21 day cycle. Receives: Drug: Bortezomib; Drug: Everolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated dose of everolimus in combination with bortezomib
Defined as the highest dose level at which 0 out of 3, or 1 out of 6, subjects experiences dose-limiting toxicity (DLT).
Measured: after 1 course (21 days)
Secondary outcomes (5)
Frequency counts and percentage of patients experiencing toxicities
Adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0.
Measured: After 1 course (21 days)
Pharmacokinetics
Measured: after 1 course (21 days)
Response rate
Response assessment will use response definitions of the International Working Group (2007 guidelines). Estimated with exact 95% confidence intervals.
Measured: Every 3 courses (9 weeks) for the first 12 courses, after 5th restaging scan every 6 courses (18 weeks) until off study
6-month progression-free survival
Measured: 6 months
Correlation of tumor characteristics with response to treatment
Exploratory analyses will be done using logistic regression to assess associations between tumor characteristics or biomarkers and response.
Measured: after one course (21 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 May 2008 (estimated)
- Study startJun 2008
- Primary completionOct 2015
Why it stopped: Treatment ineffective
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for 714leukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brian Hill, MD, PhD
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI), The Leukemia and Lymphoma Society
- Responsible party
- Sponsor-investigator, Brian Hill, MD, PhD, Case Comprehensive Cancer Center
- Investigators
- Brian Hill, MD, PhD, Principal investigator, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00671112
- Sponsor's protocol ID
- CASE2407
- Other IDs
- P30CA043703, CASE-2407, NCI-2010-01386
- Status last verified
- Oct 2015
- First submitted
- 2 May 2008
- Last updated
- 28 Oct 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Trial of the Combination of Everolimus (RAD001) and Bortezomib (VELCADE) for Relapsed or Refractory Lymphoma
- ClinicalTrials.gov ID
- NCT00671112
- Acronym / sponsor ID
- CASE2407
- Conditions
- 714leukemia, Lymphoma
- Keywords
- 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
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Treatment ineffective
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Brian Hill, MD, PhDUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI), The Leukemia and Lymphoma Society
- Study start
- Jun 2008
- Primary completion
- Oct 2015 (actual)
- First posted
- 5 May 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
OBJECTIVES:
Primary
- 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
Secondary
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Everolimus and Bortezomib | Experimental | Drug: Bortezomib, Drug: EverolimusPatients will receive a combination of Everolimus by mouth and Bortezomib intravenously for a 21 day cycle. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- 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.
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BortezomibAlso: VelcadePatients will be assigned to one of the following dose levels of Bortezomib: 0.7mg/m2, 1.0 mg/m2, or 1.3mg/m2 on days 1,4,8,11 of a 21 day cycle. The appropriate amount of bortezomib will be drawn from the injection vial and administered as an intravenous (IV) push or sub-cutaneously over 3 to 5 seconds followed by a standard saline flush or through a running IV line. | Drug | Everolimus and Bortezomib |
| EverolimusAlso: RAD001Everolimus 5 mg PO every other day, 5 mg by mouth (PO) daily, or 10 mg PO daily | Drug | Everolimus and Bortezomib |
Primary outcome
Maximum tolerated dose of everolimus in combination with bortezomib
Time frame: after 1 course (21 days)
Defined as the highest dose level at which 0 out of 3, or 1 out of 6, subjects experiences dose-limiting toxicity (DLT).
5 secondary outcomes
Frequency counts and percentage of patients experiencing toxicities
Time frame: After 1 course (21 days)
Pharmacokinetics
Time frame: after 1 course (21 days)
Response rate
Time frame: Every 3 courses (9 weeks) for the first 12 courses, after 5th restaging scan every 6 courses (18 weeks) until off study
6-month progression-free survival
Time frame: 6 months
Correlation of tumor characteristics with response to treatment
Time frame: after one course (21 days)
Results and safety
The study was stopped early (reason given: Treatment ineffective). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2015.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brian Hill, MD, PhD principal investigator
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Bortezomib and Everolimus in people with 714leukemia and Lymphoma, run by Brian Hill, MD, PhD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 27 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Treatment ineffective). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum tolerated dose of everolimus in combination with bortezomib (time frame: after 1 course (21 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2015.