Brief Title
Bortezomib, Rituximab, and Dexamethasone With or Without Temsirolimus in Treating Patients With Untreated or Relapsed Waldenstrom Macroglobulinemia or Relapsed or Refractory Mantle Cell or Follicular Lymphoma
Official Title
A Randomized Phase I/II Study of Bortezomib, Rituximab, Dexamethasone and Temsirolimus in Patients With Relapsed Waldenstrom Macroglobulinemia and Relapsed/Refractory Mantle Cell, Follicular, Marginal Zone or Small Lymphocytic Lymphomas (Phase I), and Untreated/Relapsed Waldenstrom Macroglobulinemia (Phase II)
Brief Summary
This randomized phase I/II trial studies the side effects and the best dose of temsirolimus
when given together with bortezomib, rituximab, and dexamethasone and to see how well they
work compared to bortezomib, rituximab, and dexamethasone alone in treating patients with
untreated or relapsed Waldenstrom macroglobulinemia or relapsed or refractory mantle cell or
follicular lymphoma. Bortezomib and temsirolimus may stop the growth of cancer cells by
blocking some of the enzymes needed for cell growth. Bortezomib may also stop the growth of
cancer cells by blocking blood flow to the tumor. Monoclonal antibodies, such as rituximab,
can block cancer growth in difference ways. Some block the ability of cancer cells to grow
and spread. Others find cancer cells and help kill them or carry cancer-killing substances to
them. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the
growth of cancer cells, either by killing the cells or by stopping them from dividing. It is
not yet known whether bortezomib, rituximab, and dexamethasone are more effective with
temsirolimus in treating non-Hodgkin lymphoma.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of temsirolimus in combination with
bortezomib, rituximab, dexamethasone in patients with relapsed Waldenstrom's
macroglobulinemia and relapsed/refractory mantle cell, follicular, marginal zone or small
lymphocytic lymphoma. (Phase I) II. To evaluate whether the addition of temsirolimus to the
regimen of bortezomib, rituximab, dexamethasone improves progression-free survival in
patients with previously untreated or relapsed Waldenstrom's macroglobulinemia. (Phase II)
SECONDARY OBJECTIVES:
I. To define and describe the toxicities of temsirolimus in combination with bortezomib,
rituximab, and dexamethasone. (Phase I) II. To evaluate time to progression of bortezomib,
rituximab, dexamethasone +/- temsirolimus in patients. (Phase II) III. To evaluate major and
minor response by 6 cycles of therapy of bortezomib, rituximab, dexamethasone +/-
temsirolimus. (Phase II) IV. To evaluate time to response and duration of response of
bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) V. To evaluate toxicity of
bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VI. To evaluate time to
next therapy of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VII. To
evaluate overall survival of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase
II) VIII. To describe treatment-related fatigue, physical and functional well-being during
and after treatment. (Phase II) IX. To compare the change in treatment related fatigue,
physical and functional well-being over 6 cycles of bortezomib, rituximab, dexamethasone +/-
temsirolimus. (Quality of Life) X. To prospectively assess health-related quality of life
longitudinally (pre-treatment to 3 year follow-up assessment) among trial participants.
(Quality of Life) XI. To describe treatment-related peripheral neuropathy associated with
bortezomib neurotoxicity. (Quality of Life)
OUTLINE: This is a phase I, dose-escalation study of temsirolimus followed by a randomized
phase II study.
PHASE I: Patients receive temsirolimus intravenously (IV) over 30-60 minutes on days 1, 8,
15, and 22; rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4
only); and bortezomib IV or subcutaneously (SC) and dexamethasone orally (PO) on days 1, 8,
and 15. Courses repeat every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses
1 and 4 only) and bortezomib IV or SC and dexamethasone PO on days 1, 8, and 15. Treatment
repeats every 28 days for 6 courses in the absence of disease progression or unacceptable
toxicity.
ARM II: Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and
rituximab, bortezomib, and dexamethasone as in arm I. Treatment repeats every 28 days for 6
courses in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed up every 3 months for 2 years, every
6 months for 3 years, and then yearly for 5 years.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Phase I: The Maximum Tolerated Dose (MTD) of Temsirolimus in Combination With Bortezomib, Rituximab and Dexamethasone
Secondary Outcome
Phase II: Time to Progression
Condition
Recurrent Follicular Lymphoma
Intervention
Bortezomib
Study Arms / Comparison Groups
Arm I (rituximab, bortezomib, dexamethasone)
Description: Patients receive rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4 only) and bortezomib IV or SC and dexamethasone PO on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
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
9
Start Date
July 20, 2011
Completion Date
September 1, 2021
Primary Completion Date
December 8, 2014
Eligibility Criteria
Inclusion Criteria:
- Histologically proven diagnosis
- For phase I portion (Arm A, B, C and D), patients must have of one of the following:
- Relapsed Waldenstrom's macroglobulinemia
- Relapsed/refractory mantle cell lymphoma; previous treatment with at least one
standard regimen and no longer responsive to that regimen
- Relapsed/refractory follicular lymphoma; previous treatment with at least one
standard regimen and no longer responsive to that regimen
- Relapsed/refractory marginal zone lymphoma; previous treatment with at least one
standard regimen and no longer responsive to that regimen
- Relapsed/refractory small lymphocytic lymphoma; previous treatment with at least
one standard regimen and no longer responsive to that regimen
- For phase II portion (Arm E and F), patients must have a diagnosis of symptomatic
Waldenstrom's macroglobulinemia, either untreated or relapsed, confirmed by the
presence of all of the following:
- Bone marrow lymphoplasmacytosis with
- >= 10% lymphoplasmatic cells (measured within 28 days prior to registration)
OR
- Aggregates or sheets of one of the following: lymphocytes, plasma cells or
lymphoplasmacytic cells on the bone marrow biopsy (measured within 28 days
prior to registration)
- Measurable disease defined as a quantitative immunoglobulin M (IgM) monoclonal
protein of >= 1000 mg/dL obtained within 28 days prior to registration
- Cluster of differentiation 20 (CD20) positive bone marrow or lymph node by
immunohistochemistry or flow cytometry obtained within 28 days prior to
registration
- Lymph node biopsy must be done =< 28 days prior to registration if used as an
eligibility criterion for study entry
- Serum protein electrophoresis (SPEP) is required to be performed within 28 days
prior to registration
- Additional requirements for Waldenstrom's macroglobulinemia (WM) patients (phase I and
II):
- In addition to measurable disease, patients must have symptomatic disease defined by
one or more of the following:
- Laboratory studies defining eligibility (hemoglobin [Hgb], platelet count,
viscosity) must have been obtained within 28 days prior to registration; if more
than one test was obtained, the most recent one will be utilized
- Hemoglobin =< 11 g/dL
- Hyperviscosity syndrome or measured viscosity level of >= 4 centipoise
- NOTE: for these patients it is strongly recommended that they undergo
therapeutic plasmapheresis prior to initiation of therapy
- Platelet count < 100,000/mm^3
- Symptomatic lymphadenopathy, splenomegaly, or hepatomegaly
- Constitutional symptoms including fever, night sweats, or unexplained weight loss
(at least 10% of body weight in < 6 months)
- Symptomatic cryoglobulinemia
- Additional requirements for WM patients (phase I):
- Patients must have received previous treatment with at least one standard regimen
and are no longer responsive to that regimen
- There must have been at least 21 days since the last regimen and patient must
have recovered from any previous treatment-related toxicity to =< grade 1
- Additional requirements for WM patients (phase II):
- For previously treated patients, no more than 4 prior regimens are allowed
- If last regimen is with rituximab there must have been at least 6 months since
last rituximab dose, and if without rituximab there must have been at least 3
months since last regimen
- For all phase I patients, there must have been at least 21 days since last regimen and
any previous non-hematologic treatment related toxicity must have resolved to =< grade
1
- Patients must not be receiving concurrent steroids > 10 mg prednisone (or equivalent)
per day
- Prior irradiation is allowed if >= 28 days prior to registration have elapsed since
the date of last treatment
- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x institutional upper limit of normal (ULN), within 28 days prior to registration
- NOTE: in case one or both of these thresholds are exceeded, the patient can only
be included after initiation of appropriate lipid lowering medication; patients
cannot be enrolled if they do not meet these criteria on or off lipid lowering
medication; patients must start lipid lowering medication and cholesterol and
triglycerides must be below said levels before study entry
- Patients must not have had prior exposure to mammalian target of rapamycin (m-TOR)
inhibitors (sirolimus, temsirolimus, everolimus)
- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study within 2 weeks prior to registration to rule out
pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)
- Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception throughout the study and for 8 weeks following
discontinuation of everolimus
- Patients must have no history of prior malignancy except for adequately treated basal
cell or squamous cell skin cancer or in-situ cervical cancer; the patient may also
have had other cancer for which the patient was curatively treated with surgery alone
and from which the patient has been disease free for >= 5 years
- Platelets >= 75,000 mm^3
- Neutrophils >= 1,000 mm^3
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
institutional ULN
- Direct bilirubin =< 1.5 mg/dL
- Serum creatinine =< 2.5 mg/dL
- Patients must be tested for hepatitis B surface antigen (HBsAg) and hepatitis B core
antibody (anti-HBc) within 28 days of registration and will not be eligible if found
to be positive
- Patients must not have any severe and/or uncontrolled medical condition or other
conditions that could affect their participation in the study, including, but not
restricted to:
- Symptomatic congestive heart failure of New York Heart Association class III or
IV
- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 3 months of start of study treatment, serious uncontrolled
cardiac arrhythmia or any other clinically significant heart disease
- Severely impaired lung function as defined as spirometry and diffusing capacity
of the lung for carbon monoxide (DLCO) (corrected for Hgb) that is < 50% of the
normal predicted value and/or oxygen (O2) saturation < 88% at rest on room air
- Active (acute or chronic) or uncontrolled severe infections
- Patients must have Eastern Cooperative Oncology Group (ECOG)-American College of
Radiology Imaging Network (ACRIN) performance status of =< 2
- Patients must not have grade 2 or higher neuropathy
- Patients must not have concurrent use of angiotensin-converting enzyme (ACE)
inhibitors (angioedema), and no concurrent use of strong cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) inducers and inhibitors
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Leonard T Heffner, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01381692
Organization ID
NCI-2011-02650
Secondary IDs
NCI-2011-02650
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Leonard T Heffner, Principal Investigator, ECOG-ACRIN Cancer Research Group
Verification Date
September 2021