Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials.

Lenalidomide-RCHOP (R2-CHOP21) has been shown to be safe and effective in patients with untreated diffuse large B-cell lymphoma (DLBCL). The aim of this analysis is to report long-term outcome and toxicities in newly diagnosed DLBCL patients who received R2-CHOP21 in two independent phase 2 trials, conducted by Mayo Clinic (MC) and Fondazione Italiana Linfomi (FIL). All patients received R-CHOP21 plus lenalidomide. Long-term progression-free survival (PFS), time to progression (TTP), overall survival (OS) and late toxicities and second tumors were analyzed. Hundred and twelve patients (63 MC, 49 FIL) were included. Median age was 69 years, 88% were stage III-IV. At a median follow-up of 5.1 years, 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%; according to cell of origin (COO): 5y-PFS 52.8% vs 64.5%, 5y-TTP 61.6% vs 69.6% and 5y-OS 68.6% vs 74.1% in germinal center (GCB) vs non-GCB respectively. Four patients experienced grade 4-5 late toxicities. Grade ≤ 3 toxicities were infections (N = 4), thrombosis (N = 1) and neuropathy (N = 3). Seven seconds tumors were observed. Long-term follow-up demonstrates that R2-CHOP21 efficacy was maintained with high rates of PFS, TTP, and OS. Lenalidomide appears to mitigate the negative prognosis of non-GCB phenotype. Incidence of therapy-related secondary malignancies and late toxicities were low.

Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial.

Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.

A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma.

This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). In a 3+3 trial design, 30 patients received rituximab 250 mg/m2 with indium-111 ibritumomab tiuxetan (111In-Zevalin) for dosimetry (day -22); rituximab 250 mg/m2 with escalating doses of 90Y-Zevalin (day -14); melphalan 100 mg/m2 (days -2,-1) followed by ASCT (day 0) and sargramostim (GM-CSF, day 0) until neutrophil engraftment. Each patient's 111In-Zevalin dosimetry data were used to calculate the dose of 90Y-Zevalin (in mCi) to deliver 10, 12, 14, 16, 18 or 20 Gy to the liver. Dose limiting toxicities were seen in 3 patients. The overall response rate was 73% (22/30) with stringent complete response in 2 patients; complete response, 5; very good partial response, 12; and partial response, 3. The median PFS was 16.5 months and the median overall survival was 63.4 months. In MM, the MTD of 90Y-Zevalin with HDM is 18 Gy to the liver. The addition of radiation with novel delivery methods such as radioimmunotherapy combined with standard transplant regimens warrants further study.

Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma.

MV-NIS is an Edmonston lineage oncolytic measles virus expressing the human sodium iodide symporter-a means for monitoring by non-invasive imaging of radioiodine. Patients with relapsed, refractory myeloma who had explored all other treatment options were eligible for this Phase I trial. Cohort 1 was treated with intravenous MV-NIS, and Cohort 2 received cyclophosphamide 2 days prior to MV-NIS. Thirty-two patients were treated. Cohort 1 initially enrolled to four dose levels without reaching maximum tolerated dose (MTD) and subsequently to two higher dose levels when improved virus manufacture technology made it possible. MTD was not reached in Cohort 1, and TCID50 1011 is the dose being used in a Phase II trial of single agent MV-NIS. Grade 3-4 adverse events in both cohorts at all dose levels were: neutropenia (n=9); leukocyte count decreased (n=5); thrombocytopenia (n=2); and CD4 lymphocytes decreased, anemia and lymphopenia (each n=1). MV-N RNA sequences were amplified from gargle specimens, blood and urine. 123I scans were positive in eight patients. One patient achieved a complete response; transient drops in serum free light chains were seen in other patients. MV-NIS is capable of replicating before being cleared by the immune system. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated myeloma.

Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma.

We analyzed the utility of Revised International staging system (RISS) in an unselected cohort of newly diagnosed multiple myeloma (NDMM; cohort 1), and relapsed/refractory multiple myeloma (RRMM; cohort 2) patients. Cohort 1 included 1900 patients seen within 90 days of diagnosis, from 2005 to 2015, while cohort 2 had 887 patients enrolled in 23 clinical trials at Mayo Clinic. The overall survival (OS) and progression-free survival (PFS) was calculated from the time since diagnosis or trial registration. The median estimated follow up was 5 and 2.3 years for Cohorts 1 and 2, respectively. Among 1067 patients evaluable in Cohort 1, the median OS and PFS was 10 and 2.8 years for RISS stage I, 6 and 2.7 years for RISS stage II and 2.6 and 1.3 years for RISS stage III (P<0.0001). Among 456 patients evaluable in Cohort 2, the median OS and PFS was 4.3 and 1.1 years for RISS stage I, 2 and 0.5 years for RISS stage II and 0.8 and 0.2 years for RISS stage III (P<0.0001). In conclusions, RISS gives a better differentiation of NDMM as well as RRMM patients into three survival subgroups and should be used to stratify patients in future clinical trials.

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.

This phase 2 trial was designed to evaluate ixazomib, an orally bioavailable proteasome inhibitor, in patients with myeloma who have limited prior exposure to bortezomib. Thirty-three patients with relapsed multiple myeloma were enrolled. Ixazomib was given at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a median of two prior therapies (range 1-7). A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 19 (59%) and 6 (19%) patients, respectively. The most common adverse events were thrombocytopenia, fatigue, nausea and diarrhea. Dexamethasone was initiated in 22 (67%) patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) to single agent was seen in five patients within four cycles of therapy including three patients with PR, one patient with complete response (CR) and one patient with stringent CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34%.

Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma.

BACKGROUND: We conducted this trial to determine the maximum tolerated dose (MTD) of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma. PATIENTS AND METHODS: A standard phase I cohort of three study design was utilized. The fixed doses of rituximab and cladribine were 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. There were five planned temsirolimus i.v. dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1, 8 and 15; and 25 mg days 1, 8, 15, and 22. RESULTS: Seventeen patients were treated: three each at levels 1-4 and five at dose level 5. The median age was 75 years (52-86 years). Mantle Cell International Prognostic Index (MIPI) scores were low in 6% (1), intermediate in 59% (10), and high in 35% (6) of patients. Five patients were treated at level 5 without dose limiting toxicity. Hematologic toxicity was frequent: grade 3 anemia in 12%, grade 3 thrombocytopenia in 41%, grade 4 thrombocytopenia in 24%, grade 3 neutropenia in 6%, and grade 4 neutropenia in 18% of patients. The overall response rate (ORR) was 94% with 53% complete response and 41% partial response. The median progression-free survival was 18.7 months. CONCLUSIONS: Temsirolimus 25 mg i.v. weekly may be safely added to rituximab and cladribine at 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. CLINICALTRIALSGOV IDENTIFIER: NCT00787969.

Phase 2 trial of intravenously administered plerixafor for stem cell mobilization in patients with multiple myeloma following lenalidomide-based initial therapy.

Initial therapy of multiple myeloma with lenalidomide-based regimens can compromise stem cell collection, which can be overcome with the addition of plerixafor. Plerixafor is typically given subcutaneously (SQ), with collection ∼11 h later for maximum yield. Intravenous administration may allow more rapid and predictable mobilization. This trial was designed to assess the efficacy and feasibility of IV plerixafor in patients receiving initial therapy with a lenalidomide-based regimen. Patients received G-CSF at 10 µg/kg/day for 4 days followed by IV plerixafor at 0.24 mg/kg/dose starting on day 5; plerixafor was administered early in the morning with apheresis 4-5 h later. Thirty-eight (97%) patients collected at least 3 × 10(6) CD34+ cells/kg within 2 days of apheresis. The median CD34+ cells/kg after 1 day of collection was 3.9 × 10(6) (range: 0.7-9.2) and after 2 days of collection was 6.99 × 10(6) (range: 1.1-16.5). There were no grade 3 or 4 non-hematological adverse events, and one patient experienced grade 4 thrombocytopenia. The most common adverse events were nausea, diarrhea and abdominal bloating. IV plerixafor is an effective strategy for mobilization with low failure rate and is well tolerated. It offers flexibility with a schedule of early-morning infusion followed by apheresis later in the day.

Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study.

Lenalidomide was shown to have significant single-agent activity in relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase I trial to establish the maximum tolerated dose of lenalidomide that could be combined with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone). Eligible patients were adults with newly diagnosed, untreated CD20 positive diffuse large cell or follicular grade III NHL. Patients received oral lenalidomide on days 1-10 with standard dose R-CHOP every 21 days. All patients received pegfilgrastim on day 2 of the cycle and aspirin prophylaxis. The lenalidomide dose levels tested were 15, 20 and 25 mg. A total of 24 patients were enrolled. The median age was 65 (35-82) years and 54% were over 60 years. Three patients received 15 mg, 3 received 20 mg and 18 received 25 mg of lenalidomide. No dose limiting toxicity was found, and 25 mg on days 1-10 is the recommended dose for phase II. The incidence of grade IV neutropenia and thrombocytopenia was 67% and 21%, respectively. Febrile neutropenia was rare (4%) and there were no toxic deaths. The overall response rate was 100% with a complete response rate of 77%. Lenalidomide at the dose of 25 mg/day administered on days 1 to 10 of 21-day cycle can be safely combined with R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma.

A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma.

The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20-41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant.

Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531).

Nanoparticle albumin-bound (nab)-paclitaxel has better efficacy and practically eliminates the risk of hypersensitivity reactions associated with solvent-based paclitaxel. We studied weekly nab-paclitaxel and gemcitabine combination in an open-label one-stage, phase II trial in patients with previously untreated metastatic breast cancer (MBC). Nab-paclitaxel (125 mg/m(2)) and gemcitabine (1000 mg/m(2)) were administered on days 1 and 8 of a 21-day cycle until disease progression. Fifty patients were enrolled. Forty (80%) had visceral organ involvement and 30 (60%) had >or= 3 sites of metastases. Four (8%) and 21 (42%) patients had complete and partial responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median duration of response was 6.9 months [95% confidence interval (CI) 5.7, not reached], median progression-free survival (PFS) 7.9 months (95% CI 5.4-10 months), and median overall survival (OS) was not reached. PFS and OS at 6 months were 60% (95% CI 48% to 76%) and 92% (95% CI 85% to 100%), respectively. Therapy was well tolerated. Neutropenia was commonest toxicity (42% and 12% grades 3 and 4 neutropenia). Only one patient developed febrile neutropenia. Significant activity and favorable toxicity profile provides a basis for considering this regimen for further evaluation in phase III trials or in combination with biologic agents.

The proteolysis-inducing factor: in search of its clinical relevance in patients with metastatic gastric/esophageal cancer.

The proteolysis-inducing factor is a putative mediator of cancer-associated weight loss. The goal of this study was to examine for the first time: (i) its prevalence in patients with metastatic gastric/esophageal cancer; and (ii) whether it possibly correlated with weight loss and anorexia and whether it predicted tumor response and patient survival. This study recruited 41 patients as part of a phase II therapeutic, chemotherapy protocol for patients with metastatic gastric/esophageal cancer. Patient eligibility criteria were designed to select a group of patients who would tolerate treatment with the drugs capecitabine and oxaliplatin. Urine for assaying the proteolysis-inducing factor was obtained at registration and then 6 weeks later. Patients completed the FACT-E questionnaire every 6 weeks and had their weights checked at the same interval. Patients were followed prospectively for tumor response and patient survival. Twenty-three (56%) patients had the proteolysis-inducing factor in their urine at registration, and 18 (64%) had it at 6 weeks. There was no statistically significant correlation between the presence of the proteolysis-inducing factor and weight loss or between its presence and anorexia. Moreover, there was no evidence that the presence of the proteolysis-inducing factor in urine was able to predict tumor response or patient survival. The proteolysis-inducing factor in urine does not appear to be tied to weight loss, anorexia, tumor response, or patient survival in the clinical setting of metastatic gastric/esophageal cancer.