Reeder, Craig B.

Abstract Background: Lenalidomide (Revlimid®) has demonstrated activity with manageable side effects in relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). In the initial pilot study, response to lenalidomide was associated with low tumor burden, long duration from prior rituximab and high absolute lymphocyte count. Aims: To confirm the activity and safety of lenalidomide monotherapy in patients with relapsed/refractory aggressive NHL in an international setting and Determine whether predictors of response identified in the previous study were valid. Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test were conducted to investigate and characterize associations of prognostic variables with response. Results: Eighteen patients who received lenalidomide were eligible for response assessment as of May 15, 2007. The median age was 66 (43–81) and 17 were male. Histology was diffuse large B-cell lymphoma [DLBCL] (n=11), mantle cell lymphoma [MCL] (n=5) and transformed (n=2). Median time from diagnosis was 2 (0.4–12) years and median number of prior treatment regimens was 3 (1–13). Four patients (22%) exhibited an objective partial response including 2/11(18%) DLBCL and 2/5 (40%) MCL. Five patients had stable disease. Lenalidomide response was associated with low disease burden (29% for < 50 cm2v 0% for ≥ 50 cm2), time from last rituximab to lenalidomide treatment (36% for ≥ 230 days v 0% for < 230 days) and absolute lymphocyte count [ALC] (33% for ≥ 0.6×109/L v 0% < 0.6×109/L). Patients with favorable values for these three prognostic factors (N = 7) had a 57% response rate (compared with a 0% response rate for patients with unfavorable values (N = 11; P = 0.01). Grade 4 adverse events were neutropenia (22%) and thrombocytopenia (11%). Most common Grade 3 adverse events were fatigue (17%), thrombocytopenia (11%) and leukopenia (11%). Conclusion: Lenalidomide has activity in relapsed/refractory aggressive NHL with a favorable safety profile. Initial results from this ongoing study are confirming that patients with low tumor burden, long duration from prior rituximab, and high ALC are more likely to respond.

Abstract Introduction Antisense oligonucleotides are used to inhibit messenger RNA function and inhibit protein translation. Bcl-2 expression proteins have been implicated in mediating resistance to apoptotic cell death in Waldenstrom Macroglobulinemia (WM). Oblimersen sodium is a specific inhibitor of Bcl-2 expression and has shown activity in multiple myeloma and in Waldenstrom cell lines. The in vitro data led to the development of a phase I study for WM patients with relapsed or refractory disease. Materials and Methods Eligible patients had symptomatic WM who had failed prior cytotoxic chemotherapy. All patients had to have one of the following: a hemoglobin <11 g/dL, a platelet count <100,000/uL, bulky lymphadenopathy, or hyperviscosity syndrome. As a phase I study, the primary end point was toxicity assessment, but all patients were assessed for response, using monoclonal protein levels. Patients were enrolled and evaluated in cohorts of three. Drug was administered as a 24-hour continuous infusion for 7 days every 21 days, with intrapatient dose escalation each subsequent cycle beginning at 3 mg/kg/day up to a maximum of 7 mg/kg/day days 1–7 for a maximum of 8 cycles. Results To date 9 patients have been accrued, six at dose level one and three patients at dose level two. Data is available for the first six entered. Five women and 1 man have been accrued with a median age of 74.5 years, ranging from 58 to 81. Four patients had relapsed from prior therapy, 2 were refractory. Three had a history of transfusions. The median number of prior regimens was 4 (range 2–7). One patient had a dose-limiting toxicity on the first cycle of therapy, which was grade 3 fatigue and anorexia, and the dose for this patient was reduced. Two patients had non-hematologic grade 3 toxicity, possibly related to therapy. Five out of six patients on dose level one had grade 3 or greater hematologic toxicity. These toxicities occurred after cycle 1 was completed, during the toxicity observation period and were not considered dose limiting toxicities influencing dose escalation. Three patients required dose reductions in subsequent cycles. To date one patient has had a partial response with her serum M spike falling from 3.6 to 1.1 g/dL. Her quantitative IgM fell from 6,000 mg/dL to 1,000 mg/dL(figure). Conclusion Oblimersen was well tolerated at the first dose level in patients with WM. Hematologic toxicity is frequent in this cohort with heavily involved bone marrows when the dose was escalated during successive cycles. Dose reductions with subsequent cycles were frequently required. Evaluation of the maximum tolerated dose continues. Data on response for this dose level is promising, where efficacy will be fully evaluated in the phase II portion of this trial. Figure Figure

Abstract Background: mTOR inhibition has produced responses in mantle cell lymphoma as well as other non-Hodgkin lymphomas. This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in simultaneous two-stage phase II lymphoma studies, including one arm involving Hodgkin lymphoma. The goals were to learn the toxicity profile and to assess the anti-tumor response. A total of 17 patients with Hodgkin lymphoma were enrolled in the uncommon arm at completion of enrollment. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12, with a possible extension in responders) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. Results: The median age of the 17 pts with Hodgkin lymphoma was 37 yrs (range: 27–68), with a median of 6 (range, 4–14) prior therapies. Fourteen pts (82.4%) had a prior stem cell transplant (SCT). Pts completed a median of 6 (range, 1–13) cycles of therapy. Fifteen of 17 patients were evaluable for response as of this analysis. The overall response rate was 47% (7/15), all partial responses. Ten patients are continuing on study while 6 have gone off due to disease progression and 1 due to other reasons. Common grade 3 adverse events (AEs) include thrombocytopenia (5 pts), anemia (5 pts) and alkaline phosphatase elevation (1 pts). 1 patient was reported to have grade 4 neutropenia. Conclusions: Oral everolimus has promising activity with acceptable toxicity in Hodgkin lymphoma. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens for Hodgkin lymphoma.

TPS7570 Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced B cell non-Hodgkin lymphoma (B-NHL). Developed by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies. We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using IHC, mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry, and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients will be randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered and open to participation to members of ETCTN and EDDOP. Clinical trial information: NCT03038672.

8514 Background: MLN9708 is an investigational, orally bioavailable, potent, reversible, specific inhibitor of the 20S proteasome that has demonstrated antitumor activity in in vivo models of MM. We report safety, activity and pharmacokinetics (PK) of weekly oral MLN9708 in a phase 1 trial in patients (pts) with relapsed and/or refractory MM after full enrollment (NCT00963820). Methods: Pts received MLN9708 (days 1, 8, 15; 28-day cycles) at 0.24–3.95 mg/m2 (dose-escalation phase) and at the MTD, 2.97 mg/m2, in relapsed and refractory (RR), bortezomib (btz)-relapsed, PI-naïve, and prior carfilzomib (CZ) expansion cohorts. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Response was assessed by IMWG uniform criteria. Results: 60 pts (33 male, median age 64 yrs [40–79]) were enrolled, 32 in the dose-escalation phase and 31 to the expansion cohorts (11 RR, 10 btz-relapsed, 6 PI-naïve, 4 CZ; 2 RR and 1 btz-relapsed pts included from MTD dose-escalation cohort). Median time from MM diagnosis was 4.9 yrs (1.5–18.8). Median number of prior regimens was 6 (2–18), including btz, lenalidomide, thalidomide, and CZ in 83%, 95%, 52%, and 13%, respectively; 76% were refractory to last therapy (17% btz-refractory). At data cut-off (Nov 29, 2012) pts had received a median of 2 cycles (1–11); 5 pts remained on treatment. All-grade/grade ≥3 drug-related AEs were seen in 83%/52% of pts; common drug-related grade ≥3 AEs were thrombocytopenia (33%), diarrhea, neutropenia (17%), decreased appetite, fatigue, and lymphopenia (8%). 6 pts (10%) had drug-related PN (no grade ≥3). 5 pts discontinued due to drug-related AEs; 1 pt died on study due to an unrelated AE. By investigator assessment in 41 evaluable pts, responses included1 VGPR, 5 PR, 1 MR, and 15 with SD. MLN9708 was rapidly absorbed, with a terminal half-life of 4–12 days (supporting weekly dosing) and a proportional increase in plasma AUC with dose (0.8–3.95 mg/m2). PK data were similar across expansion cohorts. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows activity in this heavily pretreated population with prior exposure to immunomodulatory drugs and btz. Clinical trial information: NCT00963820.

8053 Background: Lenalidomide (LEN) is an immunomodulatory agent that has shown significant single-agent anti-lymphoma activity in patients with relapsed disease and in combination may enhance the efficacy of rituximab by various mechanisms. There is limited data on the role of LEN in combination regimens for treatment-naïve patients. This phase II single arm trial was designed to evaluate tumor response, toxicity (AE) and survival with a combination of LEN, rituximab, cyclophosphamide (CTX) and dexamethasone (DEX) (LR-CD) in symptomatic untreated patients with low grade B-cell non-Hodgkin lymphoma. Methods: Eligibility required age ≥18, ECOG PS ≤2, confirmed diagnosis of low-grade B-cell lymphoma (FL1-2, SLL, MZL or LPL/WM), measurable nodes ≥2cm or IgM ≥400mg/dL(LPL/WM), ANC ≥1400/mm3, platelets ≥100,000/mm3, creatinine ≤2mg/dL, signed informed consent and in need of therapy. Treatment consisted of IV rituximab 375mg/m2 D1, oral LEN 20mg D1-21, CTX 250mg/m2 D1, 8, 15, DEX 40mg D1, 8, 15, 22 and ASA 325 mg daily in a 28 day cycle. Treatment continued 2 cycles beyond best response (max 12). Toxicity was assessed by NCI CTCAE v3.0. Results: 28 patients have enrolled at Mayo Clinic with 25 evaluable for toxicity and 21 for response: Median age 65(43-83), 72% male, FL 24%, MZL 28%, LPL/WM 38%, and SLL 4%. Median number of cycles given was 5. Overall response in 21 patients with response data is 95% (95% CI 76-100%) with 19% CR (95% CI 5-42%), and 76% PR (confirmed and unconfirmed, 95% CI 53-92%). The ORR in 8 patients with LPL/WM with response data was 88%, all PR (95% CI 47-100%). At a median f/u of 14.7 months 96% are alive without progression. 1 death (unrelated) occurred 7.7 months after completing 12 cycles of treatment. The most common grade ≥3 AEs were neutropenia (37.5%), leukopenia (16.7%), anemia (12.5%) and fatigue (12.5%). Conclusions: The combination LR-CD with the novel agent LEN is feasible, well tolerated and produces high response rates in symptomatic patients with low grade B-cell NHL. Toxicities are manageable and similar to reported data of single agent LEN.

8043 Background: The mammalian target of rapamycin (mTOR) signal pathway controls cell proliferation and survival. The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus (TORC1 inhibitor) in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 x 106/L, a neutrophil count ≥1,000 x 106/L. Patients received everolimus 10 mg PO daily. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 60 pts were treated. The median age was 64 years (range, 43-85). The median number of prior therapies was 3 (range, 1-11). All but two patients (97%) had received prior rituximab based therapy and 64% of patients had received prior alkylator based therapies. The overall response rate (complete response CR+ partial response PR+ minimal response MR) was 73% (95% CI: 60-84%), with a PR of 50% and 23% MR. The median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) for the entire study population is 28 months (mos), (95% CI: 18-not reached (NR)), 22 mos (95% CI: 12 0-NR), and 55 mos (95% CI: 55-NR), respectively. The estimated PFS at 12 and 24 months is 62% (95%CI: 51-75%), and 48% (95%CI: 37-63%), respectively. The 30 patients who achieved a PR responded after a median of 2 months (range, 1-26) of treatment. The median duration of response (DR) for these patients has not yet been reached and 19 of these patients remain in response after a median follow up of 31 months (range, 3-54). All but two patients had a decrease in their serum IgM. Grade 3 or higher related toxicities were observed in 67% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 5% of patients. Dose reductions due to toxicity occurred in 63% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 73% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient population.

8010 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target with favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM). Here we used carfilzomib as the center of a 4 drug induction regimen designed for MM patients pre stem cell transplant (SCT). Methods: We conducted a phase I safety run in 6 patients with no DLT observed before expanding to phase II. The phase II regimen is shown below. Treatment was for 4 cycles with expected SCT post induction. For the phase II portion of this trial, the primary endpoint is the proportion of patients who have ≥ very good partial response to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: Twenty seven patients were enrolled. Median age was 65 (range 27-74). ORR for evaluable patients (n=17) at phase II dosing is 100%: CR 35%, VGPR 48%, PR 18% after 4 cycles of CYCLONE. Grade 3 toxicity was reported in 52% of patients and 14% experienced a grade 4 toxicity. Grade 3/4 toxicities occurring in >5% of patients included fatigue, neutropenia, lymphopenia, thromboembolism, myopathy. Toxicities of any grade seen in >20% of patients included fatigue, constipation, lethargy, thrombocytopenia, somnolence, creatinine increased, malaise. Four patients (20%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. All patients are alive. All patients advancing to SCT successfully collected stem cells. One patient with t(4;14) disease who was not transplanted has progressed. 94% remain progression free. Conclusions: The 4 drug CYCLONE regimen has remarkable efficacy (83% ≥VGPR) and manageable toxicity in newly diagnosed patients with multiple myeloma. Especially notable was the low incidence of neuropathy and depth of response (CR 35%) after only 4 cycles. Given the relative lack of toxicity an extension of this regimen at higher doses of carfilzomib (20/45mg/m2) has been initiated. [Table: see text]

8034 Background: Phase 1 studies are evaluating IV and oral dosing of the reversible proteasome inhibitor MLN9708 in multiple tumor types. We report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary responses with weekly oral MLN9708 in pts with relapsed/refractory MM (NCT00963820). Methods: Pts aged ≥18 yrs received MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor (PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation phase (0.24–3.95 mg/m2) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and median number of prior lines of therapy was 3.5 (range 1-13), including 92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 2 cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs) and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97 mg/m2. Overall, 69% of pts had drug-related AEs, and 28% had related grade ≥3 AEs, including thrombocytopenia (17%), diarrhea (11%), nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 2 pts discontinued due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2, 1 had a PR at 2.97 mg/m2, and 8 have achieved SD durable for up to 9.5 mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2), Tmax of 0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active hydrolysis product). There was a trend for a dose-dependent increase in whole blood 20S proteasome inhibition. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows early signs of antitumor activity.

AbstractBackground: Patients with multiple myeloma often have Bence Jones proteins composed of free monoclonal light chains of the κ or λ type in their urine. Usually, these light chains exist as monomeric or dimeric forms, but rarely, larger molecules, such as tetramers, have been reported in the serum.Methods and Results: We report the presence of trimeric complexes of λ light chain dimers in a patient who was diagnosed with a free λ light chain multiple myeloma 2 years earlier and subsequently underwent a stem cell transplant. Recently, the patient presented with a large serum M-spike (23 g/L) by protein electrophoresis. The spike consisted of monoclonal λ light chains without a heavy chain. The urine contained only 8 mg of λ light chain in a 24-h specimen. Quantitative analysis of the serum and urinary free light chains (FLCs) indicated the probability of larger aggregates of FLCs. Size-exclusion chromatography, electrophoresis, analytical ultracentrifugation, and mass spectrometric studies of the serum revealed almost exclusively the presence of trimolecular aggregates of λ light chain dimers without other multimeric species.Conclusion: Monoclonal λ light chains may present as hexameric aggregates that cannot be cleared by renal excretion.