Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. METHODS: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. RESULTS: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. CONCLUSIONS: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).

Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial.

BACKGROUND: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA. METHODS: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383. FINDINGS: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001). INTERPRETATION: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development.

Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10-5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial.

BACKGROUND: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. METHODS: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. FINDINGS: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment. INTERPRETATION: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy. FUNDING: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.

Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma.

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029.

Comparative efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) without and with daratumumab (D-VTd) in CASSIOPEIA versus VTd in PETHEMA/GEM in transplant-eligible patients with newly diagnosed multiple myeloma, using propensity score matching.

Background: Traditional bortezomib, thalidomide, and dexamethasone (VTd) regimens for patients with newly diagnosed multiple myeloma (NDMM) include doses of thalidomide up to 200 mg/day (VTd-label). Clinical practice has evolved to use a lower dose (100 mg/day) to reduce toxicity (VTd-mod), which was evaluated in the phase III CASSIOPEIA study, without or with daratumumab (D-VTd; an anti-CD38 monoclonal antibody). We used propensity score matching to compare efficacy and safety for VTd-mod and D-VTd with VTd-label. Methods: Patient-level data for VTd-mod and D-VTd from CASSIOPEIA (NCT02541383) and data for VTd-label from the PETHEMA/GEM study (NCT00461747) were analyzed. Propensity scores were estimated using logistic regression, and nearest-neighbor matching procedure was used. Outcomes included overall survival (OS), progression-free survival (PFS), time to progression (TTP), postinduction and posttransplant responses, as well as rate of treatment discontinuation and grade 3/4 peripheral neuropathy. Results: VTd-mod was noninferior to VTd-label for OS, PFS, TTP, postinduction very good partial response or better (≥VGPR) and overall response rate (ORR). VTd-mod was significantly better for posttransplant ≥VGPR and ORR versus VTd-label. VTd-mod safety was not superior to VTd-label despite the lower thalidomide dose. D-VTd was significantly better than VTd-label for OS, PFS, TTP, postinduction and posttransplant ≥VGPR and ORR, and was noninferior to VTd-label for safety outcomes. Conclusions: In transplant-eligible patients with NDMM, D-VTd had superior efficacy compared with VTd-label. Despite a lower dose of thalidomide, VTd-mod was noninferior to VTd-label for safety and was significantly better for posttransplant ≥VGPR/ORR. These data further support the first-line use of daratumumab plus VTd.

Daratumumab Plus Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma.

BACKGROUND: Combination therapy regimens containing a proteasome inhibitor, an immunomodulatory drug, and a steroid are an established standard of care for patients with newly diagnosed multiple myeloma (NDMM) regardless of transplant eligibility. Triplet regimens that include lenalidomide/dexamethasone combined with daratumumab or carfilzomib are highly active in multiple myeloma, including NDMM. The aim of this open-label, phase 1b study was to evaluate daratumumab in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd) in patients with NDMM. PATIENTS AND METHODS: Patients (n = 22), regardless of transplant eligibility, received treatment with D-KRd for up to thirteen 28-day cycles or until autologous stem cell transplant. The first daratumumab dose was administered as a split infusion (8 mg/kg on days 1 and 2 of cycle 1). The primary end point was safety and tolerability. RESULTS: A total of 10 patients discontinued treatment, most frequently because of elective autologous stem cell transplant (n = 8). The most common treatment-emergent adverse events (any grade; grade 3/4) were diarrhea (68%; 18%), lymphopenia (64%; 59%), cough (59%; 5%), and upper respiratory tract infection (55%; 0%). Stem cell collection was successful in most patients (91%). Daratumumab infusion-related reactions occurred in 9 (41%) patients, primarily during the first infusion, and were mild in severity (no grade 3/4 events). The best overall response rate was 95%, including 86% with a very good partial response or better and 67% with a complete response or better. CONCLUSION: D-KRd was well tolerated, and encouraging efficacy results support further investigation of daratumumab-based quadruplet therapies for NDMM.

Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA): health-related quality of life outcomes of a randomised, open-label, phase 3 trial.

BACKGROUND: In part 1 of the two-part CASSIOPEIA study, treatment before and after autologous haematopoietic stem-cell transplantation (HSCT) with daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) significantly improved rates of stringent complete response and progression-free survival versus bortezomib, thalidomide, and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma. METHODS: CASSIOPEIA is an ongoing randomised, open-label, active-controlled, parallel-group, phase 3 trial done at 111 academic and community practice centres in Europe. Transplantation-eligible adults with newly diagnosed multiple myeloma were randomly assigned (1:1) to D-VTd or VTd. Treatment consisted of four 28-day cycles of induction therapy before autologous HSCT and two 28-day cycles of consolidation therapy after. In this prespecified secondary analysis, patient-reported outcomes were assessed using the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire at baseline, after induction (cycle 4, day 28), and after consolidation (day 100 after autologous HSCT). The analysis was done in all patients in the intention-to-treat population with a baseline and at least one post-baseline patient-reported outcome assessment. The trial is registered at ClinicalTrials.gov (NCT02541383). FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled and randomly assigned D-VTd (n=543) or VTd (n=542). Questionnaire completion rates were high at baseline (511 [94%] of 543 in the D-VTd group vs 510 [94%] of 542 in the VTd group). Compliance rates (calculated from the number of completed surveys as a proportion of the predicted number of participants still on study treatment) were high at post-induction (431 [84%] of 513 vs 405 [80%] of 509) and post-consolidation (414 [90%] of 460 vs 386 [88%] of 438) assessments and were similar between treatment groups. Mean changes in global health status scores from baseline to post-induction were not different between the D-VTd group (3·8 [95% CI 1·6 to 6·0]) and VTd group (2·9 [0·7 to 5·1]; p=0·43), or from baseline to post-consolidation between the two groups (D-VTd group, 9·7 (95% CI 7·4 to 11·9) vs VTd group, 8·7 (6·5 to 11·0; p=0·45). Improvements from baseline in EORTC QLQ-C30 global health status and EQ-5D-5L visual analogue scale scores were observed in post-consolidation scores in both groups. Post-consolidation scores showed significantly greater mean decreases in pain (-23·3 [95% CI -26·6 to -20·0] in the D-VTd group vs -19·7 [-23·0 to -16·3] in the VTd group; p=0·042), significantly smaller reductions in cognitive functioning (-5·0 [-7·6 to -2·4] vs -7·9 [-10·6 to -5·3]; p=0·036), and significantly greater improvements in emotional functioning (13·0 [10·4 to 15·5] vs 9·5 [6·9 to 12·1]; p=0·013) and in constipation (-3·2 [-7·3 to 0·9] vs 1·8 [-2·4 to 6·0]; p=0·025) with D-VTd versus VTd. Between-group differences in change from baseline for all other scales were not significant. INTERPRETATION: D-VTd and VTd were associated with on-treatment health-related quality of life improvements from baseline in transplantation-eligible patients with newly diagnosed multiple myeloma. The significantly greater reductions in pain, less deterioration of cognitive functioning, and greater emotional functioning improvements complement the clinical benefits observed with D-VTd versus VTd, and support the addition of daratumumab to standard regimens in patients with newly diagnosed multiple myeloma. FUNDING: Intergroupe Francophone du Myélome, The Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research and Development.

The prognostic significance of patient-reported outcomes in pancreatic cancer cachexia.

Data from a clinical study of 86 pancreatic cancer patients with involuntary, significant weight loss (cachexia) were used to explore the relationship between patient-reported outcomes (PROs) and survival. In all, 28 pancreatic cancer patients with cachexia were given gemcitabine (Gemzar) plus 3 mg/kg of infliximab (Remicade), 28 were given gemcitabine plus 5 mg/kg of infliximab, and 30 were given gemcitabine plus placebo in a double-blinded, phase II, multicenter trial. PRO endpoints included scores from the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Functional Assessment of Anorexia/ Cachexia Therapy (FAACT), Brief Pain Inventory (BPI), and the Short-Form 36 general health survey (SF-36). Population mean scores at baseline indicated fatigue problems (FACIT-F), nutritional health issues (FAACT), and mild-to-moderate pain (BPI "worst pain" score). Baseline normalized SF-36 values for physical functioning, vitality, and mental health indicated substantial impairment. Baseline fatigue and physical-functioning scores predicted survival as well as, or better than, baseline Karnofsky Performance Status or hemoglobin level. A cut-point in the FACIT-F score (median < or = 30) strongly predicted mortality; patients with greater fatigue had a lower median overall survival than did those with less fatigue. These findings supported several features of an a priori clinical-benefit model. Patient-reported fatigue provided powerful prognostic information; tracking of this symptom may be useful for treatment planning and medical monitoring of advanced-stage pancreatic cancer patients with cachexia. These results must be confirmed by larger trials.

A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia.

To evaluate the safety and efficacy of infliximab administered with gemcitabine to treat cancer cachexia and to explore a functional measure of clinical benefit, investigators involved in this multicenter, phase II, placebo-controlled study randomized 89 patients with stage II-IV pancreatic cancer and cachexia to receive either placebo or 3 mg/ kg or 5 mg/kg of infliximab at weeks 0, 2, and 4 and then every 4 weeks to week 24; patients also received 1,000 mg/m2 of gemcitabine weekly from weeks 0-6 and then for 3 of every 4 weeks until their disease progressed. The primary endpoint was change in lean body mass (LBM) at 8 weeks from baseline; major secondary endpoints included overall survival, progression-free survival, Karnofsky performance status, and 6-minute walk test distance. In addition, quality of life was measured. The mean change in LBM at 8 weeks was +0.4 kg for patients receiving placebo, +0.3 kg for those receiving 3 mg/kg of infliximab, and +1.7 kg for those receiving 5 mg/kg of infliximab. No statistically significant differences in LBM or secondary endpoints were observed among the groups. Safety findings were similar in all groups. Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated with statistically significant differences in safety or efficacy when compared with placebo.

Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone.

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months-not reached) and 3.7 months (95% CI, 2.8-5.6 months), and median time on treatment 21 months (range, 2.6-37.5) and 4.9 months (range, 1.3-23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59-93) and 64% (95% CI, 43-82) of AAP-naïve and 43% (95% CI, 22-66) and 10% (95% CI, 1-30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544-51. ©2017 AACR.

Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort.

BACKGROUND: Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. OBJECTIVE: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo). INTERVENTION: Patients received 240mg/d apalutamide while continuing on androgen-deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS). RESULTS AND LIMITATIONS: A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade ≥3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data. CONCLUSIONS: In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. PATIENT SUMMARY: Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01171898.

An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma.

PURPOSE: This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL). EXPERIMENTAL DESIGN: Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics. RESULTS: Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5-8 months). Median number of cycles: 4 (range, 1-16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing). CONCLUSIONS: JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL.

Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study.

C-C chemokine ligand 2 (CCL2) stimulates tumor growth, metastasis, and angiogenesis. Carlumab, a human IgG1κ anti-CCL2 mAb, has shown antitumor activity in preclinical and clinical trials. We conducted a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel + carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Patients had advanced solid tumors for which ≥1 of these regimens was considered standard of care or for whom no other treatment options existed. Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on docetaxel (n = 15), gemcitabine (n = 12), paclitaxel or carboplatin (n = 12), or PLD (n = 14). Total serum CCL2 concentrations increased post-treatment with carlumab alone, consistent with carlumab-CCL2 binding, and continued increase in the presence of all chemotherapy regimens. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). One partial response and 18 (38 %) stable disease responses were observed. The most common drug-related grade ≥3 adverse events were docetaxel arm-neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm-neutropenia (2/12); paclitaxel + carboplatin arm-neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm-anemia (3/14) and stomatitis (2/14). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serum CCL2 or significant tumor responses were observed.