Brief Title
Everolimus, Bortezomib and/or Rituximab in Patients With Relapsed/Refractory Waldenstrom's Macroglobulinemia
Official Title
Phase I/II Study of Combination Everolimus (RAD001), and Rituximab (Rituxan), OR Everolimus, Bortezomib (Velcade, PS-341), and Rituximab in Patients With Relapsed and/or Relapsed/Refractory Waldenstrom's Macroglobulinemia
Brief Summary
The purpose of this research study is to test the safety of the combination of everolimus,
rituximab and bortezomib. Everolimus is a drug that works by preventing cells in your body
from growing and dividing. Information from basic and other clinical research suggests that
everolimus may also inhibit tumor growth in people with relapsed or refractory lymphoma. The
FDA has approved everolimus for the treatment of multiple myeloma, a cancer that is closely
related to Waldenstrom's Macroglobulinemia. Rituximab is approved by the FDA for the
treatment of non-Hodgkin's lymphoma, which included Waldenstrom's Macroglobulinemia.
Funding Source - FDA OOPD
Detailed Description
Study Design
This is a phase I/II study. The phase I portion of the study will determine the maximum
tolerated dose of everolimus, rituximab, and bortezomib combination, while the phase II
portion will evaluate the depth of responses to the everolimus, rituximab, and bortezomib
combination. If patients show response, they will continue on therapy for a total of 6
cycles, and then go on maintenance therapy with everolimus alone until progression. Patients
on maintenance will be monitored every 3 months for response. Because of the potential of an
IgM flare after rituximab, patients who show an increase in IgM after rituximab in the first
3 months will not be deemed as having progressive disease unless they show evidence of
clinical progression and not just an increase of IgM levels. If biochemical progression is
confirmed by m-spike, but the participant is clinically benefitting from therapy, the
participant may continue on treatment for a few additional points of assessment and
re-discuss benefit of therapy. Additionally, if the participant progressed because the
treatment was held, participant may remain on study at the discretion of the overall
Principal Investigator. Relapse from CR is defined by the reappearance of monoclonal IgM
protein and/or recurrence of bone marrow involvement, lymphadenopathy/splenomegaly or
symptoms attributable to active disease (Owen et al., 2012). Progression from PR is defined
by ≥ 25% increase in IgM level from lowest recorded value and confirmed by a repeat
assessment. The development of new signs and symptoms of disease, including Bing Neel
syndrome and histological transformation, is also considered as evidence of disease
progression. An absolute increase of at least 5 g/l is required to define progression when
the IgM level is the only applicable criterion (Owen et al., 2012).
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Everolimus Maximum Tolerated Dose (MTD) Stage A [Phase I]
Secondary Outcome
Treatment-Emergent Sensory Neuropathy Rate [Phase I]
Condition
Waldenstrom's Macroglobulinemia
Intervention
Everolimus
Study Arms / Comparison Groups
Phase I Stage A Level 1
Description: Combination of everolimus & rituximab for 6 cycles: Everolimus 5 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
46
Start Date
April 2010
Completion Date
August 2014
Primary Completion Date
December 2013
Eligibility Criteria
Inclusion Criteria:
- 18 years of age or older
- Patients must have received prior therapies for their WM and have relapsed or
refractory WM requiring therapy. Any number of prior therapies is acceptable. Patients
must not have been refractory to rituximab. The last rituximab must be at least 3
months prior to the start of treatment. Prior treatment with bortezomib and/or
everolimus is permitted.
- Measurable monoclonal IgM protein in the serum OR measurable quantitative
immunoglobulin M (serum IgM).
- Lymphoplasmacytic cells in the bone marrow during any previous bone marrow biopsy.
- CD20 positive disease based on any previous bone marrow immuno-histochemistry or flow
cytometric analysis performed prior to enrollment.
- ECOG Performance Status 0, 1 or 2
- Laboratory values as outlined in the protocol
- Capable of swallowing intact study medication tablets
- Life expectancy of 12 weeks or greater
Exclusion Criteria:
- Uncontrolled infection
- Other active malignancies
- Cytotoxic chemotherapy 3 weeks or less, or biologic or targeted novel therapy 2 weeks
or less, or corticosteroids 2 weeks or less, or radiation therapy 2 weeks or less, or
any ancillary treatment considered investigation 2 weeks or less, prior to
registration. Patients may be receiving chronic corticosteroids if they are being
given for disorders other than WM.
- Pregnant women, nursing women, men or women of childbearing potential who are
unwilling to employ adequate contraception throughout the trial and for 8 weeks after
the last dose of study treatment.
- Known to be HIV positive, or Hepatitis B positive. If the status of HIV is not known
and patients are not at risk, then patients will not be specifically tested for HIV.
Patients will be tested for Hepatitis B at time of screening. If patients are not
considered high risk and have been vaccinated at an earlier date, results of the test
are not required at the time of registration. For patients that are high risk, results
must be obtained prior to registration.
- Patient has Grade 2 or higher peripheral neuropathy within 14 days of enrollment
- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection fo basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
- Severely impaired lung function
- Uncontrolled diabetes
- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis
- Impairment of gastrointestinal function or gastrointestinal disease
- Patients with active, bleeding diathesis
- Myocardial infarction within 6 months prior to enrollment or had NYHA Class III or IV
heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
electrocardiographic evidence of acute ischemia or active conduction system
abnormalities.
- Hypersensitivity to everolimus or other rapamycins or to is excipients
- Patients who may need or are receiving live vaccines for immunization
- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Irene Ghobrial, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01125293
Organization ID
09-280
Secondary IDs
R01FD003743; X05310
Responsible Party
Principal Investigator
Study Sponsor
Dana-Farber Cancer Institute
Collaborators
Novartis
Study Sponsor
Irene Ghobrial, MD, Principal Investigator, Dana-Farber Cancer Institute
Verification Date
April 2021