Clinical trial NCT01125293: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Waldenstrom's Macroglobulinemia
Keywords: everolimus
rituximab
bortezomib
RAD001
Rituxan
Velcade
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Novartis
name: Millennium Pharmaceuticals, Inc.
First posted: 2010-05-18
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Everolimus Maximum Tolerated Dose (MTD) Stage A [Phase I]
timeFrame: Assessed within the first cycle (28 days) of the study.
measure: Everolimus Maximum Tolerated Dose (MTD) Stage B [Phase I]
timeFrame: Assessed within the first cycle (28 days) of the study.
measure: Everolimus Dose Limiting Toxicity (DLT) [Phase I]
timeFrame: Assessed within the first cycle (28 days) of the study.
measure: Very-good-partial-response-or-better Rate [Phase II]
timeFrame: Up to 6 cycles (Day 168)
Secondary outcomes:
measure: Treatment-Emergent Sensory Neuropathy Rate [Phase I]
timeFrame: Adverse events were assessed each cycle (ever 28 days) for 6 cycles then every 3 months on maintenance. Duration of therapy for the Phase I study up to 41 months.
measure: Phase II Overall Response Rate
timeFrame: Up to 6 cycles (Day 168)
measure: 2-year Time-to-progression Probability (TTP) [Phase II]
timeFrame: Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.
measure: 2 Year Progression-free-survival [Phase II]
timeFrame: Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.
measure: Phase II Duration of Response (DoR)
timeFrame: Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.
measure: PTEN Mutation Rate [Phase II]
timeFrame: Samples were collected pre-therapy before the beginning therapy (baseline) and post-therapy after finishing the 6th treatment cycle (168 days).
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Irene Ghobrial, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ghobrial IM, Redd R, Armand P, Banwait R, Boswell E, Chuma S, Huynh D, Sacco A, Roccaro AM, Perilla-Glen A, Noonan K, MacNabb M, Leblebjian H, Warren D, Henrick P, Castillo JJ, Richardson PG, Matous J, Weller E, Treon SP. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia. 2015 Dec;29(12):2338-46. doi: 10.1038/leu.2015.164. Epub 2015 Jul 3.