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Purpose: Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial. Patients and Methods: Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc. Results: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25–7.20 months)/9.9 (6.74–12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06–23.49 months)]. Overall response rate (95% CI) was 18% (8.6%–31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 Conclusions: The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.

Introduction: Multicenter, phase I study of concurrent and delayed nivolumab plus nab-paclitaxel/carboplatin in advanced non-small cell lung cancer (NSCLC). Methods: Chemotherapy-naive patients with advanced NSCLC (ineligible for potentially curative radiation or surgery) received nab-paclitaxel 100 mg/m2 (days 1, 8, 15) and carboplatin area under the curve 6 (day 1) intravenously every 21 days (first 4 cycles); nivolumab 5 mg/kg was administered intravenously (day 15) beginning in cycle 1 (concurrent) or cycle 3 (delayed) in separate cohorts and continued beyond the 4 chemotherapy cycles. The primary objective was to assess safety. Secondary objectives were to assess tolerability and explore antitumor activity. Results: All 32 patients received chemotherapy; 20 of 22 and 6 of 10 patients also received concurrent or delayed nivolumab, respectively. No dose-limiting toxicities were reported in the concurrent cohort; 1 dose-limiting toxicity was reported in the delayed cohort. In the concurrent cohort, 20 patients (91%) had ≥1 grade 3/4 treatment-emergent adverse event (TEAE), and 7 (32%) discontinued treatment due to TEAEs. In the delayed cohort, all patients had ≥1 grade 3/4 TEAE, and 2 (20%) discontinued due to TEAEs. The median progression-free and overall survival, respectively, were 10.5 and 29.3 months in the concurrent cohort and 4.1 and 8.2 months in the delayed cohort. Conclusions: The safety profile of the combination was consistent with that of individual agents and generally similar in the 2 cohorts. Efficacy outcomes in the concurrent cohort, but not in the delayed cohort, were encouraging and support the rationale for concurrent administration of nivolumab with nab-paclitaxel/carboplatin for the treatment of advanced NSCLC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02309177.

298 Background: Chemotherapy may work synergistically with immune checkpoint inhibitors by increasing tumor antigen exposure. This 2-part phase I study assessed safety and efficacy of Nivo + nab-P + Gem in APC. Methods: Treatment-naive patients (pts) with APC (locally advanced or metastatic) received nab-P 125 mg/m2 + Gem 1000 mg/m2 on d 1, 8, and 15 + Nivo 3 mg/kg on d 1 and 15 of each 28-d cycle until disease progression (PD), unacceptable toxicity, or withdrawal. Pts could continue Nivo alone beyond initial PD. Part 1 assessed dose-limiting toxicities (DLTs) and determined the recommended Part 2 dose; Part 2 (expansion phase) further assessed safety. The primary endpoints were DLTs (Part 1) and safety and tolerability (Parts 1 and 2). Key secondary endpoints were response rates, progression-free survival (PFS), and overall survival (OS). Results: As of July 13, 2018, 50 pts with APC were treated: 6 in Part 1; 44 in Part 2. The median age was 67.5 years; 56% were male; 62% had an ECOG PS 1. Of 40 pts with available data, 12 (24%) had ≥ 1% and 6 (12%) had ≥ 5% PD-L1 expression at baseline (data missing for 10 pts). The median follow-up was 11.3 mo. In Part 1, 1 DLT (hepatitis, as evidenced by grade 3 elevated liver function tests; suspected to be related to nab-P + Gem) was reported. In Parts 1 and 2, 48 pts (96%) had ≥ 1 grade 3/4 TEAE; 7 (14%) discontinued treatment due to a TEAE. Most common (> 10%) grade 3/4 TEAEs of special interest were anemia (36%), neutropenia (36%), gastrointestinal events (24%), hepatic toxicity (22%), peripheral neuropathy (16%), thrombocytopenia (12%), and colitis (12%). One grade 5 TEAE, respiratory failure (most likely pneumonitis), was reported. The table shows treatment responses. Of 7 pts (14%) who continued Nivo beyond initial PD, 4 achieved disease control. The median PFS was 5.5 mo (6-mo PFS rate, 47%). The median OS was 9.9 mo (6-mo OS rate, 73%). Conclusions: Combining Nivo with nab-P + Gem is feasible in pts with APC: 1 DLT was reported, and no unexpected safety signals were detected. Clinical trial information: NCT02309177. [Table: see text]

Twelve patients with Waldenstrom's macroglobulinemia (WM) underwent treatment with the nonmyelosuppressive combination regimen BLT-D: clarithomycin (Biaxin [BXN], Abbott Laboratories, Abbott Park, IL) 500 mg orally twice daily, low-dose thalidomide (THAL) 50 mg orally escalated to 200 mg daily, and dexamethasone (DXM) 40 mg orally once weekly all with modification for toxicity. Omeprazole (correction of omepraxole) 20 mgm orally twice daily for 2 days with the DXM, and enteric-coated aspirin 81 mg orally daily were also administered. Twelve patients have been evaluated. All had previously received at least one purine analogue or alkylating agent. Five had a reduction in either leukocytes and/or platelets prior to treatment, of which three were disease-related. Median age was 62 years. All patients received a minimum of 6 weeks of therapy. Of the 12 patients, 10 had a significant response (83%) consisting of three near complete, three major, four partial, and two minor responses. Four of five had restoration of reduced blood counts. Two with minor responses did not receive sufficient dose escalation due to toxicity. Median time on therapy was 7 months (range, 3 to 28 months). Patients were removed from therapy primarily due to neurotoxicity. Drug resistance occurred in three patients, with one transformation to large cell lymphoma. Toxicity was as follows: gastrointestinal (primarily constipation), 42%; neurological, 100%; endocrine, 42%, and thrombotic, 8%. Most toxicities were World Health Organization (WHO) grade 1 or 2; however, neurological toxicity was more prominent and severe in WM patients than in myeloma. BLT-D is effective in WM. Because of its toxicity, predominantly neurological, BLT-D may best serve as an induction regimen or to "rescue" patients with refractory disease or disease-related low counts.

Multiple myeloma (MM) is a malignant clonal proliferation of plasma cells characterized by the excessive production of a single immunoglobulin protein isotype. In the year 2000, approximately 13,800 new cases of MM were diagnosed in the United States. This accounts for approximately 1% of all malignancies and 10% of hematologic malignancies. Over the past decades, the incidence of MM has been steadily increasing. It is twice as common in African-Americans as in the white population and it usually occurs in older individuals with a median age of 69 years. Although a number of potential risk factors have been suggested for myeloma, including radiation exposure, genetic predisposition, chronic antigenic stimulation such as rheumatoid arthritis and certain bacterial and viral infections, as well as certain occupational exposures, the etiology of this disease remains unknown.

We report the results of a dose-intense chemotherapy regimen designed to rapidly induce remissions in patients with advanced multiple myeloma (MM). Patients received VAD for 3-6 cycles depending on response kinetics. This was followed by three sequential cycles of cyclophosphamide (CTX) at 3 g/m2 every 15 days with G-CSF support. 71% of these patients had stage IIIa, 23% had renal failure. The median age was 58, median beta-2 microglobulin 4.6 and median albumin was 3.5, indicating poor prognosis. Of 35 patients, 66% achieved a complete response (CR) (SWOG). Six patients (18%) had a partial response. Fifty percent of the patients with renal failure recovered their kidney function. High-dose CTX contributed to tumor-mass reduction particularly in patients presenting with high-tumor burden. Tumor-mass reduction following three pulses of dexamethasone (4 days each) is significantly higher than with one pulse (p < 0.005). While high beta-2 microglobulin and LDH levels (p < 0.05) were associated with poor outcome, patients who responded faster to chemotherapy had a longer survival (p = 0.005). We conclude that this regimen is safe and effective. A rapid response may be useful in selecting patients who may benefit from further high dose chemotherapy and stem cell support.

Adjunctive anti-bone resorption therapy has become an important part of multiple myeloma (MM) treatment. Currently, no definite evidence exists that this therapy increases survival. We examined a cohort of 13 of 167 patients (8%) treated with the M-2 protocol who received adjuvant gallium nitrate (GN) treatment for osteolysis, and then compared the outcome of these patients to all individuals treated with the M-2 regimen. The stage at diagnosis was IA in two patients, IIIA in 10 patients and IIIB in one. Median age at diagnosis was 51 years (range 35-73). Median (range) of entry data were: paraprotein level: 6000mg/dl (3058-8675); beta2M: 2.7mg/l, (1.2-9.6); LDH: 166U/l (142-237); hemoglobin: 10.2 g/dl (8.3-12.6); albumin: 3.7 g/dl (2.5-5.0); calcium: 10.0 mg/dl (8.3-14.5); creatinine: 1.2 mg/dl (0.7-2.7). Median survival in these patients was 87+ months from time of diagnosis compared with 48 months for all other patients treated on the M-2 protocol. We identified a subgroup of patients with remarkably prolonged survival who had received M-2 chemotherapy and GN. Survival in this group markedly exceeds expectations for patients with advanced stage disease and poor prognostic features. The administration of GN may have a positive impact on survival either by decreasing skeletal complications or through a direct action of GN on the complex cytokine network involved in the proliferation of the malignant myeloma cell.

Multiple myeloma remains incurable. Despite the pursuit of various chemotherapeutic approaches, little improvement in outcome has been made in the last 30 years. Thalidomide, dexamethasone, and clarithromycin are oral, nonmyelosuppressive agents, each with reported single agent activity against myeloma. We evaluated a regimen of clarithromycin (Biaxin), low-dose thalidomide and dexamethasone (BLT-D) in patients with previously untreated or treated multiple myeloma or Waldenström's macroglobulinemia. Patients were initially given clarithromycin 500 mg twice daily, thalidomide 50-200 mg daily, and dexamethasone 40 mg weekly until disease progression. Minimum response was defined as50% reduction in monoclonal immunoglobulin or light chain levels in serum or urine. Response, toxicity, and survival were determined on an evaluable and/or intent-to-treat basis. Of the 50 patients available for analysis, 92% remain alive and 64% remain on treatment with a median and mean duration of treatment of 7 and 8 months, respectively. Overall, 93% of evaluable patients responded to BLT-D, including 13% complete remissions, 40% near complete responses, 13% major responses, and 27% partial responses. Minimal drug resistance was initially encountered. Neurotoxicity, although usually mild to moderate, was the primary reason for treatment discontinuation. Only four patients died, including three sudden deaths in patients with severe cardiopulmonary disease. It appears that BLT-D is a highly effective, nonmyelosuppressive regimen for myeloma. Caution should be exercised when using thalidomide, alone or in combination, in patients with a preexisting tendency to thromboses, severe cardiopulmonary disease, or neurologic dysfunction.

Revlimid® (R) or lenalidomide is the leading clinical compound in a new group of drugs called IMiD®s, which have immunomodulatory properties. In contrast with thalidomide (T) R has significantly less neurological toxicity. Several phase I and II trials with R showed promising results in relapsed/refractory MM. Our group demonstrated that Bi augments tumor mass reduction and improves responses in patients (pts) receiving low-dose T and/or D. We report the initial results of a phase II trial exploring the combination of Bi plus R plus D (BiRD) in newly diagnosed MM. Methods: The trial is designed to accrue 35 pts. Thus far 28 pts have been accrued between Nov. 2004 and Aug. 2005 of which 22 pts (13 male and 9 female) are eligible for evaluation. R is given orally (po) at a dose of 25 mg daily on days 1–21 of a 28-day cycle. D is given po at a dose of 40 mg once weekly. Bi is given po at 500 mg twice daily. All pts also receive low dose aspirin (ASA)(81mg) once daily as thrombosis prophylaxis, prophylactic sulfamethoxazole/trimethoprim, and a proton pump inhibitor. Responses are defined according to the EBMTR. In addition, the category of near-CR (nCR) is defined as a CR with a positive immunofixation. A minimum of 2 cycles is required for response assessment; all pts are assessed on an intent-to-treat basis. Results: Pt characteristics are as follows: median age of 62 years (range 36–77), hemoglobin of 11.4g/dL (range 7.2–15.1), platelets of 247k/uL (range 51–526), β2m of 4.0mg/L (range 0.8–5.1), CRP of 1.0mg/dL (range 0.3–8.4), creatinine of 1.3mg/dL (range 0.5–3.1), albumin of 3.6g/dL (range 2.3–4.9), and calcium of 8.9mg/dL (range 6.9–11.2). Conventional cytogenetics was normal in all pts; FISH abnormalities are as follows: trisomy 11 (2 pts), tetrasomy 11 (1 pt), del13q14(5 pts), t(4,14)(1pt), t(11,14)(2 pts). 52% of the pts are stage IIIa, 13% are stage IIIb, 35% are stage IIa. Responses are summarized in the table below. Of the 22 evaluable pts, 21(95%) have achieved an objective response (>PR) within 1–2 months of Rx with the remaining pt continues to respond. Nearly one third of pts have achieved either a CR(6/22) or a nCR(1/22-continuing on Rx). The remaining 14 pts(63%) achieved a PR. Of those pts who achieved a PR, 6/14 pts(43%) had >90% reduction in the initial paraprotein, while 12/14 pts(86%) had >75% decrement. 5 pts are now off study (3 pts in CR going to PBSCT and 2 due to toxicities). So far 15 pts have experienced grade ≥3 adverse events. These include, anemia(4.5%), neutropenia(4.5%), thrombocytopenia(4.5%), increased liver enzymes(4.5%), anxiety(4.5%), insomnia(9%), tremors(4.5%), hyperglycemia(4.5%), syncope(4.5%), Stevens Johnson’s(4.5%) and colonic perforation(4.5%). DVT occurred in 3(13.6%) patients, all off ASA, of which 2 (9%) had an associated PE, one of whom died. No grade 4 toxicities have been otherwise observed. Three pts have undergone successful stem cell harvest of which one has undergone transplantation with melphalan 200. Engraftment was successful by day 12. Conclusions: BiRD is highly effective and safe in the initial Rx of MM. Stem cell harvest is not impaired after BiRD induction. Supported in part by the LLS SCOR grant and K23CA109260-01 | | # of Pts | % | |:---------------- | -------- | ---- | | Total | 22 | 100 | | Overall Response | 21 | 95 | | CR | 6 | 27.3 | | n-CR | 1 | 4.5 | | PR | 14 | 63.6 | | SD | 1 | 4.5 | Response Evaluation