Clinical Trials

PRIMARY OBJECTIVES: I. To evaluate the proportion of confirmed response of LBH589 in patients with relapsed or refractory non-Hodgkin lymphoma.  SECONDARY OBJECTIVES: I. To describe the toxicities associated with LBH589 in patients with NHL. II. To evaluate overall survival, progression-free survival, and duration of response in patients treated with LBH589.  TERTIARY OBJECTIVES: I. To evaluate the pharmacokinetics of LBH589. II. To assess the correlation between clinical (toxicity and/or tumor response or activity) effects with the pharmacologic (pharmacokinetic/pharmacodynamic) parameters, and/or biologic (correlative laboratory) results.  OUTLINE: Patients receive oral panobinostat 3 times weekly. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.  After completion of study treatment, patients are followed up every 6 months for up to 2 years.

OBJECTIVES:

     Primary

       -  To compare the complete remission rate in patients with high-risk follicular lymphoma receiving induction therapy comprising bendamustine hydrochloride and rituximab with vs without bortezomib.

       -  To compare the 1-year post-induction disease-free survival rate in patients receiving continuation therapy comprising rituximab with vs without lenalidomide.

     Secondary

       -  To determine the 3-year progression-free survival and the 5-year overall survival of these patients.

       -  To evaluate patient-reported outcomes at baseline and during treatment to determine differences in symptom palliation, treatment-related symptoms, and overall health-related quality of life.

       -  To examine the association between baseline FLIPI information and outcome of these patients.

       -  To examine the association between baseline and end-of-treatment patient comorbidities assessed by the Cumulative Illness Rating Scale (CIRS) and outcome.

       -  To create an image and tissue bank including serial PET/CT scans, diagnostic paraffin-embedded tissue, germline DNA, and serial blood and bone marrow samples sufficient to support proposed and future studies of tumor and host characteristics that may predict for clinical outcome, including treatment arm effects, and enhance existing prognostic indices. (exploratory)

     OUTLINE: Patients are stratified according to FLIPI-1score (1 or 2 vs 3 vs 4 or 5) and GELF tumor burden (low vs high). Patients are randomized to 1 of 3 treatment arms.

       -  Arm I: Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

     Beginning 4 weeks after the completion of induction therapy, patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

       -  Arm II: Patients receive rituximab IV on day 1; bortezomib IV on days 1, 4, 8, and 11; and bendamustine hydrochloride IV over 1 hour on days 1 and 4. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

     Beginning 4 weeks after the completion of induction therapy, patients receive rituximab as in arm I.

       -  Arm III: Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

     Immediately after completing induction therapy, patients receive oral lenalidomide on days 1-21. Treatment repeats every 4 weeks for 13 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

     Quality of life (including fatigue, neurotoxicity, anxiety, and depression) is assessed by questionnaire at baseline and periodically during study therapy.

     Blood, bone marrow, and tissue samples may be collected periodically for correlative studies and for a repository.

     After completion of study therapy, patients are followed up periodically for 15 years.

OBJECTIVES:

     Primary

       -  To assess tumor response in patients with relapsed or refractory low-grade follicular lymphoma (grade I or II), mantle cell lymphoma, or lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) treated with rituximab, cyclophosphamide, bortezomib, and dexamethasone.

     Secondary

       -  To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure in patients treated with this regimen.

       -  To describe the adverse event profile (as assessed by NCI CTCAE version 3.0) of this regimen in these patients.

       -  To evaluate the quality of life, in terms of patient-reported neurotoxicity, in patients treated with this regimen.

     OUTLINE: Patients receive rituximab IV on day 1, bortezomib IV on days 1, 4, 8, and 11, and oral cyclophosphamide and oral dexamethasone on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

     Patients complete a quality of life questionnaire (FACT/GOG neurotoxicity questionnaire, version 4.0) at baseline, on day 1 of courses 3, 6, and 9, and at the completion of study treatment.

     After completion of study treatment, patients are followed every 3-6 months for up to 5 years.

This study will be a Phase I, open-label, non-randomized, dose-finding trial conducted at multiple clinical centers. The study is designed to determine the safety, tolerability and PK of TKM-080301 in adult patients with solid tumors or lymphomas that are refractory to standard therapy or for whom there is no standard therapy.

OBJECTIVES:

     Primary

       -  To determine the maximum tolerated dose of lenalidomide when given in combination with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in patients with newly diagnosed stage II-IV diffuse large cell or grade 3 follicular B-cell lymphoma. (Phase I)

       -  To assess the efficacy of this regimen, in terms of event-free survival and response rate, in these patients. (Phase II)

       -  To assess the safety of this regimen in these patients. (Phase II)

     Secondary

       -  To assess the host immune function at baseline and after treatment and correlate these parameters with tumor response and event-free survival.

     OUTLINE: This is a multicenter, phase I dose-escalation study of lenalidomide followed by a phase II study.

       -  Phase I: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, oral prednisone on days 1-5, and oral lenalidomide on days 1-10. Patients also receive pegfilgrastim subcutaneously on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

       -  Phase II: Patients receive lenalidomide at the maximum tolerated dose determined in phase I and rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone, and pegfilgrastim as in phase I.

     Blood is collected at baseline, before course 3, and after completion of study treatment for translational research studies. Research studies include immune function and cytokine analysis, T- and B- quantitative lymphocyte analysis, and single nucleotide polymorphism analysis.

     After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 3 years.

PRIMARY OBJECTIVES: I. To establish the maximum tolerated dose of RAD001 and lenalidomide in subjects with relapsed/refractory Non-Hodgkin Lymphoma or Hodgkin Lymphoma. (Phase I) II. To assess tumor response to RAD001 and lenalidomide in subjects with relapsed/refractory Non-Hodgkin Lymphoma or Hodgkin Lymphoma. (Phase II) SECONDARY OBJECTIVES: I. To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure of subjects receiving RAD001 and lenalidomide. II. To describe the adverse event profile (using CTCAE CTEP Active Version) of RAD001 and lenalidomide. OUTLINE: Patients receive oral everolimus once daily and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

PRIMARY OBJECTIVES:

     I. To evaluate in a Phase II study a preliminary estimate of the complete response (CR) rate of a new chemotherapy regimen involving Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP) alternating with Pralatrexate (P) as front line therapy for patients with Stage II, III and IV Peripheral T-Cell NHL not otherwise specified (NOS), Anaplastic large cell lymphoma (ALK negative), Angioimmunoblastic T-cell lymphoma, Enteropathy associated T-cell lymphoma, Hepatosplenic gamma delta T-cell lymphoma followed by an optional stem cell transplant with high dose chemotherapy and Autologous stem cell transplant.

     SECONDARY OBJECTIVES:

     I. To evaluate partial response (PR). II. To evaluate overall response (CR+PR). III. To evaluate the safety and tolerability of the regimen. IV. To assess the 2 year event free survival (EFS) and overall survival (OS) using this regimen.

     V. To assess the percentage of patients who intended to receive transplant versus those who actually proceeded with transplant.

     VI. To evaluate the ability to collect peripheral blood stem cells after this regimen.

     OUTLINE:

     Patients receive cyclophosphamide intravenously (IV) and vincristine sulfate IV on day 1, etoposide IV on days 1-3 or orally (PO) once daily (QD) on days 2-3, and prednisone PO QD on days 1-5 (CEOP administration). Patients also receive pralatrexate IV over 3-5 minutes on days 15, 22, and 29 (P administration). Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

     Patients with CR or PR, per investigators discretion, may then undergo hematopoietic stem cell collection and administration of standard preparative regimen followed by hematopoietic stem cell transplantation.

     After completion of study treatment, patients are followed up for 2 years (transplant patients) or periodically.

Ascenta Therapeutics, Inc. is conducting a clinical trial of the compound Debio 1143 (AT-406), a small molecule second mitochondria-derived activator of caspase C (Smac) mimetic.  In vivo and in vitro studies have demonstrated that Debio 1143 (AT-406) induces cell death in several tumor models by inhibiting XIAP (X linked IAP), cIAP-1 (cellular IAP-1) and cIAP-2 (cellular IAP-2), thus releasing initiator and effector caspases to promote apoptosis.  This protocol is a Phase I, dose-escalation, open-label, multi-center study conducted in patients with advanced solid tumors and lymphomas to evaluate the safety, tolerability and pharmacology of Debio 1143 (AT-406) in humans when administered orally.

OBJECTIVES:

     Primary

       -  To determine whether the addition of bortezomib (RBV) to an induction regimen of rituximab-bendamustine hydrochloride (RB) improves progression-free survival (PFS) compared to RB alone in patients ≥ 60 years of age with previously untreated mantle cell lymphoma.

       -  To determine whether the addition of lenalidomide to a consolidation regimen of rituximab following an induction regimen of RB or RBV improves PFS compared to consolidation rituximab alone in this patient population.

     Secondary

       -  To determine whether the addition of bortezomib to induction therapy improves the positron emission tomography (PET)-documented complete response (CR) rate compared to RB alone.

       -  To determine the objective response rate (ORR) for RB and RBV.

       -  Among patients who do not have PET-documented CR at the end of induction, to determine whether the addition of lenalidomide to consolidation therapy improves CR and ORR compared with rituximab alone.

       -  To determine overall survival (OS) in the treatment arms.

       -  To determine safety, with attention to the addition of bortezomib in the induction regimen and lenalidomide-rituximab (LR) as consolidation therapy.

       -  To collect paraffin-embedded tissue for creation of tissue microarray.

       -  To collect and bank serum and blood mononuclear cells for future studies.

       -  To collect formalin-fixed paraffin-embedded (FFPE) tissue to analyze potential prognostic factors (Ki-67 proliferation index by immunohistochemistry and correlation with proposed 5-gene set of proliferation markers analyzed by RNA PCR; SOX 11 expression by immunohistochemistry; and Micro-RNA levels by microarray).

       -  Using patient-reported outcomes data, to determine the extent and severity of neuropathy associated with the addition of bortezomib to induction treatment.

       -  Using patient-reported outcomes data, to determine the extent and severity of fatigue associated with the addition of lenalidomide to consolidation treatment.

       -  To evaluate the effects of the addition of bortezomib and lenalidomide on patient-reported health-related quality of life.

       -  To evaluate the effects of bortezomib-related neuropathy on patient-reported health-related quality of life.

       -  To evaluate the response of lymphoma-specific symptoms to treatment.

       -  Using longitudinal patient-reported outcomes data, to describe the trajectory of lymphoma symptoms, neuropathy, fatigue, and overall health-related quality of life prior to, during, and following treatment among older adults with MCL.

     Tertiary

       -  To assess the proportion of patients up and down staging when fludeoxyglucose F 18- (FDG) PET/CT is added to standard Ann Arbor staging.

       -  To assess the ability of pre-treatment FDG-PET/CT (SUVmax) to predict response rate and PFS.

       -  Among patients with interim (post-cycle 3) FDG-PET/CT imaging, to assess the correlation of interim FDG-PET/CT imaging with response rate and PFS both during induction and consolidation therapy.

       -  To assess standard FDG-PET/CT metrics including SUVmax, tumor metabolic burden, total tumor burden, and association with pathology features (blastoid variant vs other, and Ki67) in the setting of MCL.

       -  To assess differences in overall and CR rates when using Deauville vs International Harmonization Project FDG-PET/CT interpretation criteria.

       -  To determine whether there is a correlation between FDG-PET/CT response and residual disease assessment by molecular and/or flow cytometric techniques.

       -  To determine whether the number of malignant cells in circulation predict the number of cells in marrow.

       -  To determine whether the number of malignant cells in circulation/in marrow at the end of induction correlate with CR and 2-year PFS.

       -  To determine whether there is a higher rate of minimal residual disease (MRD) negativity among patients randomized to RBV as compared with RB, and among patients treated with LR maintenance compared with rituximab.

       -  To compare the two methods of MRD detection - molecular techniques and flow cytometry - as prognostic markers for outcome.

     OUTLINE: This is a multicenter study. Patients are stratified according to mantle cell lymphoma International Prognostic Index risk score (low vs intermediate vs high). Patients are randomized to 1 of 4 treatment arms.

       -  Arm A: Patients receive induction therapy comprising rituximab IV on day 1 and bendamustine hydrochloride IV over 60 minutes on days 1-2. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

            -  Arm E: Patients receive consolidation therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

       -  Arm B: Patients receive induction therapy comprising bortezomib IV or subcutaneously (SC) on days 1, 4, 8, and 11 and rituximab and bendamustine hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

            -  Arm F: Patients receive consolidation therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

       -  Arm C: Patients receive induction therapy comprising rituximab and bendamustine hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

            -  Arm G: Patients receive consolidation therapy comprising lenalidomide orally (PO) daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

       -  Arm D: Patients receive bortezomib, rituximab, and bendamustine hydrochloride as patients in arm B. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

            -  Arm H: Patients receive consolidation therapy comprising lenalidomide PO daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

     Patients may undergo blood and bone marrow sample collection at baseline and during treatment for correlative studies.

     Patients complete the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym), the FACT/GOG-Neurotoxicity scale (FACT/GOG-Ntx), FACT-Fatigue, and FACT-General questionnaires at baseline and periodically during study and follow up.

     After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years.

This is a phase 3, randomized, 2-arm, open-label, international trial evaluating alisertib compared with single-agent treatment, as selected by the investigator from the offered options of pralatrexate or gemcitabine or romidepsin, in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Note: romidepsin will not be used as a single-agent comparator in countries that do not permit its use at this time.