- To assess the efficacy and safety of the combination of rituximab, cladribine, and temsirolimus in patients with newly diagnosed mantle cell lymphoma.
- To determine the maximum tolerated dose of temsirolimus combined with a fixed dose and schedule of rituximab and cladribine in these patients. (Phase I)
- To assess the efficacy of this regimen, in terms of proportion of complete responses in these patients. (Phase II)
- To assess other measures of efficacy of this regimen, including progression-free survival, duration of response, and overall survival of these patients.
- To assess the toxicity profile of this regimen in these patients.
- To assess efficacy using traditional lymphoma parameters and absolute lymphocyte count.
- To assess metabolic markers (i.e., hyperglycemia and hyperlipidemia) as markers of mTOR inhibition using the glucose and lipid measurements being performed in the clinical laboratory as part of routine care for these patients.
- To correlate response in these patients with serum free light chains, single nucleotide polymorphisms in host immune genes, vitamin D metabolites, and PI3K pathway member expression.
OUTLINE: This is a phase I, dose-escalation study of temsirolimus followed by a phase II study.
Patients receive rituximab IV on day 1 and cladribine IV over 2 hours on days 1-5. Patients then receive temsirolimus IV over 30 minutes on day 1; on days 1 and 15; on days 1, 8, and 15; or on days 1, 8, 15, and 22*. Patients also receive filgrastim (G-CSF) subcutaneously (SC) on days 6-15 or pegfilgrastim SC on day 6. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
NOTE: *Patients enrolled in phase II receive temsirolimus at the maximum tolerated dose determined in phase I following a fixed schedule in a 28-day course.
Blood and tissue samples are collected at baseline and after course 2 for laboratory correlative studies. Samples are analyzed for serum free light chains, single nucleotide polymorphisms in host immune genes, vitamin D metabolites by liquid chromatography/tandem mass spectrometry, clinical metabolic markers (i.e., hyperglycemia or hyperlipidemia) as markers of mTOR inhibition, and PI3K pathway member expression.
After completion of study treatment, patients are followed periodically for up to 5 years.
- Histologically confirmed mantle cell lymphoma
- Newly diagnosed disease
- Excisional biopsy or adequate core needle biopsies allowed
- Tumor must be cyclin D-1 positive by IHC or have evidence of a t(11;14) translocation by FISH or cytogenetics
- Measurable or assessable disease, defined as ≥ 1 of the following:
- A lymph node or tumor mass that is ≥ 2.0 cm in ≥ 1 dimension by PET/CT, CT, MRI, or plain radiograph imaging
- Enlarged spleen that is palpable ≥ 3 cm below the left costal margin
- Diffuse infiltration of an organ (e.g., stomach, bone marrow, peripheral blood, liver, lungs, or bowel) by lymphoma without a discrete mass (assessable only disease)
- No known CNS involvement
- ECOG performance status 0-3
- Life expectancy ≥ 12 weeks
- ANC ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Serum creatinine ≤ 2.0 mg/dL
- Serum total bilirubin (or direct bilirubin if total is abnormal) normal with or without secondary liver involvement
- SGOT ≤ 3 times upper limit of normal (ULN) (≤ 5 times ULN if there is liver involvement)
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 12 months after completion of study treatment
- Willing to return to NCCTG enrolling institution for follow-up
- Willing to provide blood and tissue specimens as required by the protocol
- Willing to abstain from eating grapefruit or drinking grapefruit juice
- No active or uncontrolled infection
- No cardiac conditions, including any of the following:
- Uncontrolled high blood pressure
- Unstable angina
- Active congestive heart failure
- Myocardial infarction within the past 6 months
- Serious uncontrolled cardiac arrhythmia
- No medical or psychiatric conditions which, in the opinion of the investigator, make the patient a poor risk for participation
- No known HIV positivity
- No other malignancy within the past 5 years except carcinoma in situ of the cervix, resected basal cell or squamous cell carcinoma of the skin, or prostate cancer that is in remission following a radical retropubic prostatectomy or radiation therapy
- No known hypersensitivity to rituximab or its components, or to murine proteins
PRIOR CONCURRENT THERAPY:
- No prior therapy for mantle cell non-Hodgkin lymphoma, including radiation therapy
- Patients may have undergone a splenectomy for diagnosis, cytopenia, or systematic splenomegaly
- No prior mTOR inhibitor
- At least 7 days since prior and no concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, phenobarbital, or primidone)
- At least 7 days since prior and no concurrent potent CYP3A4 inducer (e.g., rifampin, glucocorticoids at greater than adrenal replacement levels, or St. John's wort)
- At least 7 days since prior and no concurrent strong CYP3A4 inhibitors
- No planned autologous or allogeneic stem cell transplantation as part of initial therapy
- No concurrent combination anti-retroviral therapy for HIV-positive patients
- No other specific, concurrent treatment for prior cancer (other than hormonal therapy)
- No concurrent glucocorticoid steroids or other immunosuppressive therapies
- Concurrent corticosteroids allowed for treatment of adrenal insufficiency, acute allergic reactions, or as N078D 27 prophylaxis for infusion-related adverse events
- No other concurrent investigational agent that would be considered treatment for the primary neoplasm
Last updated: 06/17/2012
NCT ID: NCT00787969