bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of erlotinib monotherpay in patients with previously treated advanced non-small cell lung cancer (NSCLC) without EGFR gene mutation who have never/light smoking history: NEJ006/TCOG0903.
Authors: Ishii Yoshiki , Maemondo Makoto , Okudera Koichi , Takamura Kei , Demura Yoshiki , Kobayashi Kunihiko , Morikawa Naoto , Gemma Akihiko , Ishimoto Osamu , Harada Masao , Miura Satoru , Fujita Yuka , Usui Kazuhiro , Saijo Yasuo ,   North East Japan
Published: March 2020

7561

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated good response in NSCLC harboring EGFR gene mutation. However, survival benefit from erlotinib was observed also in NSCLC patients with wild type (wt) EGFR gene in subsets of several phase III trials. Additionally, smoking status could be a predictive factor of erlotinib efficacy, This study aimed to evaluate the efficacy of erlotinib in Japanese NSCLC patients with wt-EGFR and find a biomarker that predicts the efficacy of erlotinib other than EGFR gene mutation. Methods: The primary endpoint was an objective response rate. Secondary endpoints included disease control rate, overall survival, and safety. Advanced NSCLC patients without EGFR gene mutation who had received one to three prior chemotherapy regimens and who had never smoked or light smoked (Brinkman Index: less than200) were eligible in this study. EGFR gene status was evaluated by the PNA-LNA PCR clamp method. Erlotinib was administered daily (150mg/day) until disease progression or unacceptable toxicities. Results: Forty seven patients were enrolled between March 2010 and November 2011. One patient was excluded for evaluation because having mutation of EGFR. Efficacy and safety were evaluated among 46 patients. Best responses were PR 7 (15.2%), SD 12 (26.1%), PD 26 (46.4%), NE 1 (2.2%). Response rate and disease control rate were 15.2% (95%CI: 4.9-25.5%) and 41.3 % (95%CI 27.1-55.5%) respectively. Grade 3 or 4 adverse events were anorexia (4), skin rash (2), neutropenia (1), leukopenia (1), anemia (2), elevation of AST/ALT (1), rectal ulcer (1), and cerebral infarction (1).Two patients suffered grade 3 interstitial lung disease. Conclusions: This is the first report to evaluate Erlotinib efficacy in selected NSCLC who do not possess EGFR gene mutation. Erlotinib showed significant anti-tumor activity in pretreated never or light smoked Japanese NSCLC patients without EGFR gene mutation. The results of biomakr analysis will be presented at the meeting.
Phase II study of amrubicin (AMR) for patients (pts) with non-small cell lung cancer (NSCLC) as third-line or fourth-line chemotherapy: Hokkaido Lung Cancer Clinical Study Group trial (HOT) 0901.
Authors: Harada Toshiyuki , Ito Kenichiro , Takamura Kei , Kikuchi Eiki , Oizumi Satoshi , Kuda Tomoya , Sugawara Shunichi , Maemondo Makoto , Fujita Yuka , Kinoshita Ichiro , Inoue Akira , Hommura Fumihiro , Katsuura Yutaka , Akita Hirotoshi , Isobe Hiroshi , Nishimura Masaharu ,   Hokkaido Lung Cancer Clinical Study Group
Published: March 2020

7571

Background: Although an increasing number of NSCLC pts receive third-line chemotherapy with the established benefit of second-line chemotherapy, the role of cytotoxic agent in this setting has not yet been well defined prospectively. AMR, third-generation synthetic anthracycline agent, has found favorable clinical activity and acceptable toxicity for NSCLC as well as small cell lung cancer. This prospective trial was conducted to evaluate the efficacy and safety of AMR for NSCLC pts as third-line or fourth-line chemotherapy. Methods: Eligible pts had a performance status 0 to 2, failure of second-line or third-line chemotherapy, and adequate organ function. Pts received AMR 35 mg/m2 intravenously on days 1-3 every 3 weeks. The primary endpoint was disease control rate (DCR: CR + PR + SD). Secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate (CR + PR), and toxicity profile. The estimated accrual was 37 pts to confirm a DCR of 50% as desirable target level and a DCR of 30 % as uninteresting with alpha = 0.05 and beta = 0.20. Results: From August 2009 to May 2011, 41 pts were enrolled from 10 institutions. Patient characteristics were: male/female 29/12; median age 66 (range 43–74); performance status 0/1/2 16/24/1; adenocarcinoma/squamous cell carcinoma/large cell carcinoma/not other specified 30/8/2/1; EGFR mutation positive/negative/unknown 7/26/8; treatment lines 3rd/4th 26/15. The median number of treatment cycles was 2 (range 1-9). The objective responses were CR 0, PR 4, SD 22, PD 14, and NE 1, giving a DCR of 61.0% (95% CI, 46.0-75.9%). Overall response rate was 9.8% (95% CI, 0.6-18.8%). Median PFS was 2.6 months, whereas median survival time was not reached. Grade 3/4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Grade 3/4 non-hematological toxicities were anorexia (12%), nausea (10%), and pneumonitis (2%). No treatment-related death was observed. Conclusions: AMR shows significant clinical activity with acceptable toxicities as third-line or fourth-line chemotherapyfor advanced NSCLC.
Cutaneous toxicity secondary to erlotinib therapy in patients with non-small cell lung cancer in the NCIC CTG BR.21 study: Time course and correlation with survival.
Authors: Perez-Soler Roman , Leon Larry , Wojtowicz-Praga Slawomir
Published: March 2020

7573

Background: Cutaneous rash often develops in erlotinib-treated patients (pts) and is thought to be associated with improved response and survival. This analysis focuses on incidence, severity, and time course of skin rash secondary to erlotinib, as well as the correlation between rash development and overall survival (OS) in pts in the NCIC CTG BR.21 (NCT00036647) trial. Methods: Pts with stage IIIB or IV non–small cell lung cancer (NSCLC) who had failed first- or second-line chemotherapy were randomized 2:1 to erlotinib or placebo. Cutaneous toxicity was graded per NCI CTC v2.0 and managed at the discretion of the treating investigator. This retrospective analysis used a landmark approach, dividing pts into rash and no-rash groups, by the appearance of rash by week 10. Results: A total of 366 of 488 erlotinib-treated pts (75%) and 40 of 243 placebo-treated pts (16%) developed rash at any time point. Of the former, 75% of rash episodes occurred by week 2. The incidence of grades 1 and 2 rash peaked at week 3; grade 3 rash peaked at week 5. The erlotinib dose was reduced in 48 pts (10%) due to rash. In most erlotinib-treated pts with rash, severity decreased or plateaued over time (Table). Some 311 erlotinib-treated pts (rash group) developed rash by week 10. Median OS in the erlotinib-treated rash (n=311) and no-rash (n=65) groups were 37.4 and 11.1 weeks, respectively (hazard ratio=0.51 [95% confidence interval, 0.38–0.68]; P<.0001). Baseline factors significantly associated with prolonged OS in the rash population included race (Asian vs white), number of affected organs (<3 vs ≥3), and smoking status (never vs ever). Conclusions: For most pts, rash secondary to erlotinib presented within the first 2 weeks, peaked during weeks 3–5, decreased thereafter, and did not necessitate dose reduction, thus supporting SATURN results (Perez-Soler, ASCO 2011, abst. 7610). Development of rash by week 10 of erlotinib therapy was associated with significantly improved OS. [Table: see text]
Frequency of anaplastic lymphoma kinase (ALK) positive tumors among African American non-small cell lung cancer (NSCLC) patients.
Authors: Gadgeel Shirish M. , Cote Michele L , Bepler Gerold , Murphy Valerie , Malysa Agnes , Wozniak Antoinette J. , Sukari Ammar , Schwartz Ann G.
Published: March 2020

7593

Background: ALK gene rearrangement is a recently identified molecular alteration in the tumors of a small proportion of NSCLC patients. Previous reports have shown that the rate of EGFR gene mutations may vary in NSCLC patients of different ethnic background. It is unclear if similar differences exist with regards to ALK positivity. We analyzed ALK expression in tumors of AA NSCLC patients and also assessed the epidemiologic features and outcomes of these patients, as well as the occurrence of known oncogene mutations. Methods: We identified 260 tumor tissues of AA NSCLC patients, enrolled on several epidemiologic studies conducted at our institution. Immunohistochemistry, using the anti-Alk D5F3 antibody (Cell Signaling Technology) was used to visualize ALK expression. Fifty-three of these tumors also underwent mutation analysis using the OncoCarta Panel V1 (Sequenom) to evaluate 238 mutations in 19 oncogenes. Results: Of the 260 tumors analyzed, 6 (2.3%, 95% CI- 0.5-4.1%) were ALK positive. All ALK positive patients had adenocarcinoma histology (6/157) while no patients with other NSCLC histologies were ALK positive, p=0.04. There was no difference in the rate of positivity based on sex, 1% (1/99) in males versus 3.1% (5/161) in females, p=0.27. Consistent with prior studies, patients with ALK positive tumors were slightly younger (median age 56 years vs 61 years, p = 0.27) and the positive rate was higher in never smokers 11% (2/18) than in ever smokers 1.6%, p=0.06. There was no correlation of ALK positivity with the stage of the disease at diagnosis. The survival of ALK positive and negative patients, adjusted for age, sex and stage, was similar (HR=0.77; 95% CI 0.19-3.13). Fifty-three tumors have been assessed for oncogene mutations in addition to ALK expression. Of these, 2 (3.8%) were ALK positive and neither of these tumors carried other tested mutations such as EGFR, Kras, PIK3 or AKT. Conclusions: The rate of ALK positive tumors among African-American NSCLC patients is similar to the general population and the demographic features of ALK positive AA patients is also similar to the general ALK positive NSCLC patient population.
Insulin-like growth factor 1 (IGF-1R) protein expression (PE) and gene copy number (GCN) for discrimination of response and outcome to figitumumab in NSCLC.
Authors: Wynes Murry W. , Ekman Simon , Reyna Asuncion Bernadette , Dziadziuszko Rafal , Glisson Bonnie S. , Wistuba Ignacio I. , Hirsch Fred R.
Published: March 2020

7597

Background: Early clinical data suggested figitumumab (F), an anti-IGF-1R antibody, had clinical activity in several tumor types. However, two phase III studies, A4021016 carboplatin/paclitaxel (CP) +/- F in 1st line treatment or A4021018 erlotinib (E) +/- F in 2nd line therapy for patients with advanced NSCLC, were closed prematurely due to futility. Neither study used biomarker driven selection criteria. The aim of this study was to retrospectively examine the phase III specimens in order to determine if IGF-1R PE or GCN could discriminate response and/or outcome to F. Methods: IGF-1R PE was determined by immunohistochemistry (IHC) and the tumor specimens were scored using the H-score method (0-300) with separate enumeration of membranous and cytoplasmic components and then combination of these scores. GCN was evaluated by bright field silver in situ hybridization (SISH) with recording the average copy number for 50 tumor cells. Results: IHC was evaluable in 25 CP+F, 20 CP, 27 E+F and 26 E specimens whereas SISH was evaluable in 24, 17, 21 and 22 specimens, respectively. Median PE for membrane, cytoplasm and both in A4021016 were 130, 110 and 120 and in A4021018 they were 135, 140 and 140. Median GCN was 1.88 and 1.98 for A4021016 and A4021018, respectively. There were no significant differences in PE or GCN between treatment arms within each study. Neither PE nor GCN were able to discriminate between response/non-response or disease control/progression in either study. Likewise, neither study showed a significant difference in OS or PFS when using the median cut-points for either PE or GCN. Conclusions: Neither IGF1R PE or GCN were able to discriminate response or outcome in the limited quantity of specimens available from two studies that examined the IGF-1R targeted therapy figitumumab.
Clinical presentation of hepatotoxicity-associated crizotinib in ALK-positive (ALK+) advanced non-small cell lung cancer (NSCLC).
Authors: Schnell Patrick , Safferman Allan Zachary , Bartlett Cynthia Huang , Tang Yiyun , Wilner Keith D.
Published: March 2020

7598

Background: Severe hepatotoxicity has been observed with most receptor tyrosine kinase inhibitors. Crizotinib, a first-in-class oral inhibitor of ALK, was recently FDA approved for the treatment (tx) of advanced (ALK+) NSCLC. We provide a review of hepatotoxicity in the crizotinib clinical development program. Methods: Relevant tx-emergent adverse event (AE) reports from 2 pooled single-arm trials in patients (pts) with ALK+ NSCLC who received crizotinib 250 mg BID (n=588) up to Jun 2011 were reviewed. Five reports of severe hepatotoxicity received through Dec 13, 2011 were also evaluated. Results: Incidence of elevation in ALT and AST lab values by CTCAE grade are shown in the table. Additionally, 16 all-grade (7 grade 3 or 4) cases of pertinent hepatic events have been reported. Transaminase elevations generally occurred in the first 2 months of tx and were usually reversible. Pts usually resumed tx at a lower dose without recurrence; however, 4 (<1%) required permanent discontinuation from tx. Five (<1%) cases of severe, potentially drug-related hepatotoxicity (2 fatal) were reported through Dec 13, 2011, with an estimated exposure of 1400 pts. Pts presented with fatigue, nausea, anorexia, weakness, and abdominal pain. Time from starting crizotinib to onset of hepatotoxicity was <6 weeks in 4 cases, while significant transaminase elevation was observed after 6 months in the fifth case. Significant hepatic metastases and abnormal enzymes at baseline were present in 1 (fatal) case, while baseline transaminases were normal in 3 cases, or just above the upper limit of normal in 1 case. Conclusions: Crizotinib is uncommonly associated with severe hepatotoxicity and was reported in <1% of pts. Nausea, malaise, decreased appetite, vomiting, and abdominal pain may indicate hepatic toxicity. ALT and total bilirubin should be monitored monthly and as clinically indicated. Discontinuation of crizotinib is recommended when severe drug-induced hepatic toxicity is suspected or diagnosed. [Table: see text]
Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): Potential implications for management.
Authors: Otterson Gregory Alan , Riely Gregory J. , Shaw Alice Tsang , Crinò Lucio , Kim Dong-Wan , Martins Renato , Salgia Ravi , Zhou Caicun , Solomon Benjamin J. , Wilner Keith D. , Polli Anna , Tang Yiyun , Bartlett Cynthia Huang , Ou Sai-Hong Ignatius
Published: March 2020

7600

Background: Crizotinib is a first-in-class oral ALK inhibitor for the treatment (tx) of advanced ALK-positive (ALK+) NSCLC. Dramatic and prolonged responses to crizotinib are common, but pts do experience PD. Methods: Clinical characteristics of ALK+ NSCLC pts enrolled onto two multicenter, single arm trials of crizotinib (A8081001, PROFILE 1005) with investigator-defined PD who were allowed to continue crizotinib if, in the investigator’s opinion, there was reasonable evidence of ongoing clinical benefit were assessed. A period of ≥2 wks was chosen as a reasonable minimum duration of post-PD crizotinib tx. Results: As of 1 June 2011, 146 pts (A8081001, n=61, PROFILE 1005, n=85) had PD. PD was observed in new lesions only (1 organ site, n=62; >1 organ site, n=18), target ± new lesions (≥ 1 organ site, n=55), clinical PD (n=9), and no site assessment (n=2). Most common new lesions in single organ sites were brain (brain MRI not mandatory; n=25), liver (n=20), bone (n=4), and kidney (n=1). Of the 146 pts, 78 (53%) received crizotinib post-PD for at least 2 wks, 91% of whom had ECOG PS 0 or 1 at PD. In these 78 pts, PD was observed in new lesions only (1 organ site, n=39; >1 organ site, n=4), target ± new lesions (≥ 1 organ site, n=29), and clinical PD (n=6); the most common sites for single organ PD were brain (n=20), liver (n=9), and other (n=10). Best response before PD (% CR/PR, SD, PD) was 62/27/12 in the 78 pts who received ≥2 weeks’ tx post-PD and 31/37/32 in the 68 pts who received <2 weeks’ tx post-PD or discontinued. Median duration of crizotinib tx post-PD (n=78) was 10 weeks (range 2–84). 20 pts with PD in brain only (concurrent local tx or radiation permitted) continue to receive crizotinib (range 3–82 weeks post-PD). Conclusions: Following initial crizotinib tx, PD most commonly occurred at a single organ site in ALK+ NSCLC pts. The majority of pts receiving crizotinib post-PD had good PS, and tended to have single-site PD (most often the brain or liver), and a prior response on crizotinib. Given these observations, pts may be able to continue with crizotinib for a period of time following clinical or documented progression.
Impact of disease progression (DP) date determination method on post progression survival (PPS) and DP metrics in advanced lung cancer.
Authors: Mandrekar Sumithra J. , Foster Nathan R. , Qi Yingwei , Dy Grace K. , Jatoi Aminah , Molina Julian R. , Jett James R. , Stella Philip J. , Schild Steven E. , Adjei Alex A. ,   Alliance (North Central Cancer Treatment Group)
Published: March 2020

7605

Background: Overall survival (OS) can be partitioned into progression-free survival (PFS) and PPS. PPS helps to understand trial results, especially when PFS and OS data on trial treatment effects are discordant. At ASCO 2011, we reported that the magnitude of difference in the PFS estimates using different DP date methods was large enough to alter trial conclusions. Here, we investigate the impact of the DP date method on 1) PPS estimates, and 2) predictive utility of DP metrics on subsequent OS (SOS). Methods: Individual patient (pt) data from 14 trials were pooled. DP date was determined using: reported progression date (RPD) (method 1, M1), one day after last progression-free (PF) scan (M2), and midpoint between last PF scan and RPD (M3). PPS was estimated using the method of Kaplan-Meier for the 3 DP date methods. A flexible landmark analysis at 2, 4, and 6 months (mos) using Cox proportional hazards model was used to assess the impact of DP status (progression versus no-progression) on SOS (using M1, M2, or M3). Results: Among NSCLC (SCLC), 87% (91%) of pts reported DP. As expected, the PPS estimates were the lowest for RPD, highest for M2, and in-between for M3 (a direct consequence of the DP date method); with no difference by arm for the randomized trials. Regardless of the DP date method, patients who were progression-free had improved SOS (NSCLC: Hazard ratio, HR<=0.33; p < 0.0001; SCLC: HR<=0.48; p < 0.002) at each landmark time point, with comparable concordance index (SCLC: 0.57-0.65; NSCLC: 0.63-0.67), i.e., ability to discriminate patients with different SOS outcomes. Conclusions: While the DP date methods do not impact the predictive utility of the DP metrics, they significantly impact PPS estimates. The translation of a significant treatment effect on PFS to an effect on OS is influenced by PPS (longer PPS dilutes effect on OS). Standards for declaring DP date are thus critical to trial design and for trial go/no-go decisions. [Table: see text]
A pooled analysis of 1,144 patients with HIV-associated lymphoma: Assessment of lymphoma-, HIV-, and treatment-specific factors on clinical outcomes.
Authors: Barta Stefan K. , Xue Xiaonan , Tamari Roni , Lee Jeanette Y , Mounier Nicolas , Kaplan Lawrence D. , Ribera Josep-Maria , Spina Michele , Weiss Rudolf , Galicier Lionel , Boue Francois , Wilson Wyndham Hopkins , Wyen Christoph , Navarro Jose-Tomas , Dunleavy Kieron , Little Richard F. , Ratner Lee , Morgades Mireia , Garcia Olga , Sparano Joseph A.
Published: March 2020

8005

Background: Non-Hodgkin Lymphoma (NHL) remains the most common malignancy in patients with HIV. Outcomes have significantly improved over the last decade, but there is no accepted consensus regarding the optimal initial therapeutic approach. Our objective was to assess the effects of clinical factors on response and survival. Methods: We performed a systematic review to search for prospective clinical phase II or III trials that assessed therapeutic interventions for HIV-associated NHL and assembled individual patient data from 16 trials published between 2000 and 2011 including 1144 patients (median N=62/trial, range 17-195). Treatment factors included type of chemotherapy (CHOP, N=642; EPOCH, N=178; CDE, N=191; intensive regimens, N=155) and rituximab use (N=542). Endpoints included complete response (CR), progression-free survival (PFS), and overall survival (OS). We used logistic regression and Cox proportional hazard models adjusted for age, sex, age-adjusted International Prognostic Index (IPI), baseline CD4 count, baseline HIV viral load, use of concurrent antiretroviral therapy, and histology. Odds ratios (OR) > 1 for CR denote improved CR, and hazard ratios (HR) < 1 indicate reduced risk of progression or death. Results: Among the lymphoma- and HIV-specific covariates evaluated, only a higher IPI score was associated with inferior CR rate, PFS and OS (p<0.001). Rituximab was associated with a higher CR rate (OR 1.75; p=0.017), better PFS (HR 0.39, p<0.001) and OS (HR 0.39, p<0.001); patients with a higher baseline CD4 count benefited more from rituximab (HR for OS 0.57 if baseline CD4 count ≥100/ul vs. <100/ul; p<0.001). For all histologies, initial therapy with the EPOCH regimen resulted in a better CR rate (OR 1.78, p=0.039), PFS (HR 0.61, p=0.032) and OS (HR 0.47, p<0.001) when compared to CHOP. Conclusions: In this pooled analysis including 1144 patients with HIV-associated NHL, the addition of rituximab to chemotherapy was associated with significantly improved CR rate, PFS, and OS, specifically for patients with a baseline CD4 count ≥100/uL. Treatment with infusional EPOCH was also more effective than CHOP.
R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL).
Authors: Federico Massimo , Luminari Stefano , Dondi Alessandra , Sacchi Stefano , Franco Vito , Pileri Stefano , Lombardo Marco , Rossi Giuseppe , Arcaini Luca , Chisesi Teodoro , Petrini Mario , Galimberti Sara , Vitolo Umberto , Di Raimondo Francesco , Rigacci Luigi , Carella Angelo Michele , Angrilli Francesco , Freilone Roberto , Ferreri Andres , Brugiatelli Maura
Published: March 2020

8006

Background: The optimal chemotherapy regimen for patients with advanced, active follicular lymphoma (FL) has not been established yet. We conducted a randomized trial comparing R-CVP with R-CHOP and R-FM. Methods: Previously untreated patients with advanced FL were randomly assigned to receive 8 doses of rituximab associated to 8 cycles of CVP, or 6 cycles of CHOP or FM (fludarabine 25 mg/m2 day 1-3, mitoxantrone 10 mg/m2 day 1). No maintenance therapy was allowed. The principal study end point was Time to Treatment Failure (TTF). Events in TTF were failure of induction therapy, progressive or relapse disease and death from any causes. In order to show a hazard ratio between each experimental arms and standard arm of 0.53 we planned to accrue 534 patients (178 per arm) with 4 years of accrual and 1 year of follow-up. Statistical tests were two-sided with an alpha error of 0.05, adjusted by Bonferroni for multiple arm comparison, and power of 90%. Results: Between March 2006 and September 2010, 534 patients were enrolled; 30 were subsequently excluded due to violation of inclusion criteria. Median patient age was 56 years (range 30-75), 63% of patients had stage IV disease, 37% had 3-5 FLIPI and 27% 3-5 FLIPI2 scores. At the end of induction treatment the overall response rate (CR+ PR) for the whole group was 91% (p=0.247). After a median follow-up of 34 months 208 events for TTF were recorded; 3-year TTF was 46%, 64% and 61% for patients treated with R-CVP, R-CHOP and R-FM respectively (R-CHOP vs R-CVP p=0.007; R-FM vs R-CVP p=0.021; R-FM vs R-CHOP p=0.969). The 3-year overall survival rate (OS) was 98%, 95% and 93% for R-CVP, R-CHOP and R-FM group, respectively (P=NS). Patients treated with R-FM had a higher rate of g III-IV neutropenia (64% vs 28% R-CVP, p<0.001; and vs 50% R-CHOP, p=0.015). During follow-up second malignancies were registered as late events in 23 patients (2%, 3% and 8% in R-CVP, R-CHOP and R-FM, respectively). Conclusions: This trial showed that R-CVP was associated with an inferior 3-year TTF and PFS compared with R-FM and R-CHOP. OS was similar among study arms but R-FM showed a higher rate of secondary tumors.
A phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma.
Authors: Mikhael Joseph , Reeder Craig B. , Libby Edward N. , Costa Luciano , Mayo Angela , Bergsagel P. Leif , Buadi Francis , Pirooz Nicholas , Lubben Jade Marie , Dueck Amylou C. , Stewart A. Keith
Published: March 2020

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]
PANORAMA 2: A phase II study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma.
Authors: Alsina Melissa , Schlossman Robert L. , Weber Donna M. , Coutre Steven E. , Lonial Sagar , Gasparetto Cristina , Warsi Ghulam , Ondovik Michael S. , Mukhopadhyay Sutapa , Paley Carole S. , Richardson Paul Gerard Guy
Published: March 2020

8012

Background: Patients (pts) with multiple myeloma (MM) refractory to bortezomib (BTZ) and an immunomodulatory drug have limited treatment options and a poor prognosis. In a phase I study of pts with relapsed or relapsed/refractory MM treated with panobinostat (PAN) + BTZ, clinical responses were observed overall and in pts with BTZ-refractory disease. We report results in PANORAMA 2, a trial in relapsed and BTZ-refractory pts. Methods: PANORAMA 2 is a single-arm, phase II study of PAN + BTZ + dexamethasone (Dex) in pts with relapsed and BTZ-refractory MM. Treatment phase 1 (TP1) consists of eight 3-week cycles of oral PAN + intravenous BTZ + oral Dex. Pts demonstrating clinical benefit enter treatment phase 2 (TP2) which consists of four 6-week cycles of PAN + BTZ + Dex. The primary endpoint is overall response (≥ partial response [PR]) in TP1. Results: Fifty-five pts with BTZ-refractory MM were enrolled with 10 pts ongoing and 28 in follow-up. The median age was 61 years (range 41-88 years). Pts were heavily pretreated: the median number of prior regimens was 4 (range 2-11), and most pts (64%) received prior autologous stem cell transplant. Twenty-seven (49%) and 36 (65%) pts had BTZ and Dex in their most recent prior line of therapy, respectively. Eighteen pts achieved ≥ PR for an overall response rate of 33% (1 near complete response and 17 PR), and 13 pts achieved MR for a clinical benefit rate of 56%. Three pts achieved a VGPR. Eighteen pts completed TP1 and entered TP2, and 2 have completed ≥ 12 cycles. Common adverse events (AEs) of any grade included thrombocytopenia (66%), fatigue (64%), diarrhea (62%), nausea (58%), dyspnea (40%), anemia (38%), decreased appetite (36%), and dizziness (36%). Common grade 3/4 AEs included thrombocytopenia (58%), fatigue (17%), anemia (15%), pneumonia (15%), neutropenia (13%), and diarrhea (13%). Only 1 pt (2%) experienced grade 3/4 peripheral neuropathy. Conclusions: PAN synergizes with BTZ in recapturing responses in heavily pretreated, BTZ-refractory MM pts. The combination of PAN and BTZ is a promising treatment for pts with BTZ-refractory MM that is generally well tolerated, with several pts receiving therapy long term.
Phase II, randomized, double blind, placebo-controlled study comparing siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/refractory multiple myeloma.
Authors: Orlowski Robert Z. , Gercheva Liana , Williams Cathy , Sutherland Heather J , Robak Tadeusz , Masszi Tamás , Goranova-Marinova Vesselina , Dimopoulos Meletios A. , Cavenagh James D. , Spicka Ivan , Maiolino Angelo , Suvorov Alexander , Blade Joan , Samoilova Olga S , Van De Velde Helgi , Bandekar Rajesh , Kranenburg Britte , Xie Hong , Rossi Jean-Francois
Published: March 2020

8018^

Background: Preclinical studies of siltuximab (S), a chimeric anti-IL-6 mAb, in combination with bortezomib (B) indicate an additive to synergistic effect in multiple myeloma (MM) cell lines. This randomized study evaluated the safety and efficacy of S+B compared with placebo (plc)+B in pts with relapsed/refractory MM after 1−3 prior tx lines, measurable disease but no prior B exposure. Methods: 286 pts were randomized 1:1 to S+B: B+plc. S 6 mg/kg or plc was given IV q2w. B 1.3 mg/m2 was given IV on d 1, 4, 8, 11, 22, 25, 29, 32 for a max of 4 of 42-d cycles and then reduced to q1w for 35-d cycles. B was stopped for pts with PD/intolerability, and high dose oral dexamethasone (dex) 40 mg could then be started qd on d 1−4, 9−12, 17−20 for a max of 4 of 28-d cycles and on d 1−4 of subsequent cycles until PD, while S/plc continued. Primary endpoint was PFS by EBMT criteria censored at the start of dex/subsequent tx. Secondary endpoints included overall response rate (ORR), OS, and safety before dex. Results: 142 and 144 pts received S+B and B+plc, respectively. Baseline demographics and disease characteristics were well balanced across S+B and B+plc, except for age (median 64 vs. 61 yrs) and myeloma type (IgG 65 vs. 71%, IgA 27 vs. 20%). Median tx duration was 5.1 mo in both grps. Median PFS was 8.1 mo in S+B and 7.6 mo in B+plc (HR 0.869, p = 0.345). ORR (CR+PR) was 55% in pts on S+B and 47% on B+plc (p = 0.213); CR rates were 11 and 7% (p = 0.342), respectively. With 24.5 mo median follow up, median OS was 30.8 mo for S+B and 36.9 mo for B+plc (HR 1.353 for S+B, p = 0.103). Fewer pts on S+B than B+plc moved to dex (23 vs. 31%) and had subsequent SCT (5 vs. 11%). Gr ≥3 AEs occurred in 91% on S+B and 74% on B+plc. Common gr ≥3 AEs in S+B were neutropenia (49%), thrombocytopenia (48%), leukopenia (14%). SAEs occurred in 29% on S+B and 24% on B+plc. Death occurred within 30 d of last study agent administration pre-dex in 8% on S+B and 5% on B+plc. Conclusions: The combination of S+B had higher response rates but did not prolong survival compared with B+plc. A negative survival trend heavily influenced by differences in dex and SCT rescue was noted. S+B appears to be generally well tolerated but had a higher incidence of hematologic AEs.
A multicenter phase II study of bendamustine with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Authors: Ogura Michinori , Ando Kiyoshi , Niitsu Nozomi , Kim Seok Jin , Ohmachi Ken , Takahashi Naoki , Uchida Toshiki , Takahashi Naoto , Uike Naokuni , Eom Hyeon Seok , Chae Yee Soo , Terauchi Takashi , Tateishi Ukihide , Tatsumi Mitsuaki , Kim Won Seog , Suh Cheolwon , Tobinai Kensei ,   Japanese and Korean Bendamustine Lymphoma Study Group
Published: March 2020

8023

Background: Effective salvage therapies are needed in patients (pts) with relapsed/refractory DLBCL after R-CHOP. Therapy with bendamustine plus rituximab (B-R) was well tolerated and effective in the preceding phase I study in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, including DLBCL. This phase II study assessed the efficacy and safety of B-R in pts with relapsed/refractory DLBCL. Methods: Pts with histologically confirmed DLBCL (excluding transformed disease) and 1-3 prior therapies received rituximab 375 mg/m2 IV on day 1 and bendamustine 120 mg/m2 IV on days 2 and 3 of each 21-day cycle, for up to 6 cycles. Recovery of neutrophil count to ≥1,000/mm3 and platelet count to ≥75,000/mm3 were required prior to the start of each cycle; treatment delays >2 weeks resulted in discontinuation. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and safety. Results: A total of 63 pts were enrolled; data from 59 pts were available. Median age was 67 (range, 36-75) years with 37 pts over 65 years. The majority of pts (64.4%) had 1 prior therapy; 57 pts (96.6%) were previously treated with rituximab-containing combination chemotherapy and 8 (13.6%) had prior auto-PBSCT. Pts received a median of 4 (range, 1-6) treatment cycles. Sixteen (27.1%) pts completed 6 treatment cycles; most common reasons for early discontinuation were disease progression (n=15) and failure to meet criteria to start the next cycle (n=13). Among 59 pts evaluable for response, ORR was 62.7% with a 37.3% CR rate. The median PFS was 200 days (95% CI, 109-410). Most common grade 3/4 adverse events (AEs) included CD4 lymphocytes decreased (66.1%), neutropenia (54.2%), and thrombocytopenia (10.2%). Four (6.8%) pts discontinued due to serious AEs (cytomegalovirus infection, infection, pneumonia, and pneumonia/respiratory failure). Conclusions: B-R demonstrated promising activity in pts with relapsed/refractory DLBCL. Toxicity was primarily hematologic and generally manageable. These results suggest that B-R is a promising salvage regimen for pts with relapsed/refractory DLBCL after R-CHOP.
A multicenter phase II study of vorinostat in patients (pts) with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell lymphoma (MCL).
Authors: Ando Kiyoshi , Ogura Michinori , Suzuki Tatsuya , Ishizawa Kenichi , Oh Sung Yong , Kim Won Seog , Tanaka Yoshinobu , Shimamoto Takashi , Tobinai Kensei
Published: March 2020

8029

Background: Most pts with indolent B-NHL relapse even after rituximab-containing chemotherapy. Vorinostat is an orally active histone deacetylase (HDAC) inhibitor, and is under investigation as monotherapy or in combination regimens in various hematologic malignancies. It has been reported that the histone acetyltransferase genes (EP300 and CREBBP) are frequently mutated in NHL, suggesting the potential usefulness of HDAC inhibitors in its treatment. Methods: We conducted a phase 2 study to investigate the efficacy, safety and tolerability of vorinostat in pts with indolent B-NHL or MCL with the overall response rate (ORR) against follicular lymphoma (FL) as the primary endpoint. The primary hypothesis was to demonstrate the efficacy in FL pts as measured by the ORR. Assuming the true ORR with vorinostat of 50% and without vorinostat of less than 25%, 39 pts will provide 90% power to demonstrate an ORR>25%. Vorinostat was administered at the dose of 200 mg BID for 14 consecutive days in a 21-day cycle. The ORR and PFS were determined by an independent review panel in the Full Analysis Set (FAS) population. Results: A total of 56 pts with a median age of 60 years (range: 33 - 75) were enrolled, and 50 of them (39 with FL, 11 with other subtypes of indolent B-NHL or MCL) were included in the FAS population. The number of prior therapeutic regimens was 2 (range: 1 - 4) and 41 pts have previously received rituximab-based regimens.. The percentages of pts with FLIPI at low risk, intermediate risk and high risk were 41%, 39%, and 21%, respectively. The ORR in 39 pts with FL was 49% (95% CI: 32, 65), and the pre-specified statistical success criterion was met. The median PFS in 39 pts with FL was 17.5 months (range: 2, 22+), especially the median PFS in 19 responders with FL has not yet been reached. The major toxicities were hematologic and gastrointestinal ones, which were reversible and manageable. Grade 3/4 infection was observed in 2%. Conclusions: This phase 2 study demonstrated that oral vorinostat is an agent with sustained antitumor activity in pts with relapsed or refractory indolent B-NHL, with acceptable safety profiles, warranting further investigations.
Phase Ib trial of AVL-292, a covalent inhibitor of Bruton's tyrosine kinase (Btk), in chronic lymphocytic leukemia (CLL) and B-non-Hodgkin lymphoma (B-NHL).
Authors: Brown Jennifer R. , Sharman Jeff Porter , Harb Wael A. , Kelly Kevin R. , Schreeder Marshall T. , Sweetenham John W. , Barr Paul M. , Foran James M. , Gabrilove Janice Lynn , Kipps Thomas J. , Ma Shuo , O'Brien Susan Mary , Evans Erica , Lounsbury Heather , Silver Bruce A. , Singh Juswinder , Stiede Kathryn , Westlin William , Witowski Steven , Mahadevan Daruka
Published: March 2020

8032

Background: Btk supports activation, survival, and proliferation of malignant B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 < 0.5nM), selective small molecule covalent inhibitor of Btk. Methods: Patients (pts) with previously treated CLL or B-NHL were administered AVL-292 in escalating cohorts of 125, 250, or 400 mg po QD using a 3+3 design in continuous 28 day cycles until progressive disease (PD) or toxicity. Key objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292 was assessed by covalent probe assay in peripheral blood mononuclear cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at 400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4 B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2 marginal zone (MZL)). Median time on treatment is 65 days, range 28-158. Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or grade 4 adverse events (AEs) have occurred and MTD has not been reached. Most frequent AEs reported include transient diarrhea, rash/skin infection, URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients have stable disease (SD) with median 28% decrease from baseline lymph node measurement (range 3-40% decrease). Six of 8 pts with CLL experienced increased ALC in cycle 1: median increase 89.5% (range 50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1 not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose levels ≥ 250 mg. Multiple dose PK exposure (AUClast) was linear with no accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was achieved with ≥ 250 mg QD and PK was predictable with no accumulation. Dose escalation is ongoing and MTD cohort expansion is planned.
Response rates to single-agent carfilzomib in patients refractory or intolerant to both bortezomib and immunomodulators in trial PX-171-003-A1.
Authors: Siegel David Samuel DiCapua , Martin Thomas , Singhal Seema , Wang Michael , Vij Ravi , Jakubowiak Andrzej J. , Jagannath Sundar , Lonial Sagar , Kukreti Vishal , Bahlis Nizar J. , Alsina Melissa , Chanan-Khan Asher Alban Akmal , Buadi Francis , Reu Frederic J. , Somlo George , Kunkel Lori A. , Rajangam Kanya , Chang Yu-Lin , Orlowski Robert Z. , Stewart A. Keith ,   Myeloma Research Consortium (MMRC)
Published: March 2020

8035

Background: Patients (pts) with relapsed and refractory multiple myeloma (RR MM) who are refractory or intolerant to both bortezomib (BTZ) and immunomodulators (IMiDs; thalidomide [Thal] or lenalidomide [Len]) (ie, “double-refractory/intolerant”), have few therapeutic options and a poor prognosis. Carfilzomib (CFZ), a next generation proteasome inhibitor (PI), has shown durable single-agent activity in clinical studies including 003-A1, an open-label, single-arm phase 2b trial in RR MM. The present analysis describes clinical activity in pts from 003-A1 with double-refractory/intolerant disease and in other groups of clinical interest including pts with disease refractory to all 5 approved classes of anti-MM tx (alkylators, anthracyclines, corticosteroids, IMiDs, and PIs) in clinical use (“refractory to all approved tx”). Methods: Pts from 003-A1 with double-refractory/intolerant disease were analyzed, as were pts with disease refractory to all approved tx. CFZ was given on days 1, 2, 8, 9, 15, 16 of 28-day cycles (C), (20 mg/m2 in C1; 27 mg/m2 in C2–12). Primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival, and safety. Results: The study ORR was 22.9% with median DOR of 7.8 mo (N=266). 228 pts (86%) with double-refractory/intolerant disease had ORRs of 20.6% and a median DOR of 7.4 mo. Conclusions: Single-agent CFZ demonstrated clinically meaningful, durable responses in pts with double-refractory/intolerant MM or disease refractory to all 5 approved classes of tx. The ORRs across groups of clinical interest were generally consistent with results for the entire study population. These results are notable for a next-generation PI and demonstrate the activity of single-agent CFZ in pts with advanced stage MM. [Table: see text]
Risk factors for development of second primary malignancies (SPM) after autologous stem cell transplant (ASCT) for multiple myeloma.
Authors: Krishnan Amrita Y. , Mei Matthew , Sun Canlan , Berano-Teh Jennifer , Forman Stephen J. , Htut Myo , Kang Tongjun , Karanes Chatchada , Sahebi Firoozeh , Somlo George , Bhatia Smita
Published: March 2020

8038

Background: Studies from the CALGB and IFM have suggested an increased incidence of SPM post ASCT in patients on lenalidomide maintenance. Patients with MM as well as patients post ASCT are inherently at higher risk of SPM. Therefore, assessment of risk factors associated with SPM would be useful in therapeutic decisions re preASCT therapy and post ASCTmaintenance. Methods: We conducted a retrospective cohort study of 841 consecutive MM patients who underwent at least one ASCT at City of Hope from 1989 to 2009. Sixty cases with 70 SPMs were identified. A nested case-control study was also conducted to understand the role of therapeutic exposures associated with SPMs. Controls were MM patients post ASCT matched by year of HCT (±5 years). Results: The median length of follow up was 3.3 yrs. (range 0.3-19.9). Median age at ASCT was 56 yrs (range 18-77). 62% had received a single autologous HCT, 27% tandem autologous HCT, 11% had received multiple HCTs (72 had a second allogeneic HCT)). The overall cumulative incidence of any SPM was 7.4% at 5 years and 15.9% at 10 years; the cumulative incidence of SPMs for patients >55 years approached 21.9% at 10 years. The cumulative incidence of MDS/AML was 1.8% and of solid tumors was 13.0%. Factors examined included age, race, sex, number and individual therapeutic exposures ( pre-ASCT, conditioning, and post-ASCT), disease status at ASCT. Multivariate Cox regression analysis revealed non-Hispanic whites (RR=2.4, 95% CI, 1.2-4.6, p=0.01) and older age (>55) at diagnosis of MM (RR=2.3, 95% CI, 1.3-4.1, p=0.004) to be associated with an increased risk of developing SPMs. Only cumulative thalidomide exposure (both pre-ASCT and post-ASCT) demonstrated a trend toward a positive association (OR=3.5, 95% CI, 0.6-19.4, p=0.15). Six patients (3 cases and 3 controls) were exposed to lenalidomide prior to development of SPM (OR=1.0, 95% CI, 0.14-7.10). Conclusions: This single institution analysis identified non-hispanic whites and older age to be associated with increased risk of developing SPM in pts post ASCT for MM. The trend towards increased risk with thalidomide exposure may be suggestive of a class effect from IMIDs that is not restricted to lenalidomide alone.
Efficacy of alemtuzumab (ALZ) in combination with dose-adjusted EPOCH (DA-EPOCH) in untreated nodal peripheral T-cell lymphoma (PTCL).
Authors: Grant Cliona , Dunleavy Kieron , Janik John E. , Shovlin Margaret , Steinberg Seth M. , D'Amore Francesco , Stetler-Stevenson Maryalice , Pittaluga Stefania , Jaffe Elaine S. , Wilson Wyndham Hopkins
Published: March 2020

8051

Background: The survival of patients (pts) with PTCL (excluding ALCL) is disappointing following anthracycline-based therapy and novel approaches are needed. In diffuse large B-cell lymphoma, the addition of anti-CD20 therapy to CHOP has significantly improved outcome and we investigated if in PTCL, adding ALZ – which targets CD52, expressed on most PTCLs – was feasible and improved outcome. Methods: This was a single-center phase I/II trial of ALZ, in combination with DA-EPOCH in patients with treatment-naïve CD52+ PTCL. The MTD of 30 mg ALZ was combined with DA-EPOCH for phase II evaluation resulting in an intention-to-treat population (ITTP) of 30 pts. Results: Patient (n=30) characteristics: median (range) age 50 (17-77); M:F 1:1; Stage III/IV 27 (90%); IPI ≥2 22 (73%). Histologies: ATLL 11 (37%), PTCL NOS 6 (20%), AITL 5 (16%), Hepatosplenic 3 (10%), Peripheral T NK cell 2 (7%), Other 3 (10%). At 67 months median follow-up, 11 patients were alive, 10 disease-free. Median overall (OS) and event-free survivals (EFS) were 15.4 and 6.7 months respectively. Outcome was substantially better for pts with ‘nodal’ (AITL, PTCL-NOS, Other) compared to ‘non-nodal’ (ATLL and ‘extranodal’ histologies) PTCL subtypes. 3-year OS for the two groups was 58.3% and 27.8% respectively (p=0.082); 3-yrs EFS was 50% (median 27.0 months) and 22.2% (median: 5 months) respectively (p=0.041). Half of the ‘nodal’ PTCL pts had sustained long-term complete remissions demonstrated by a plateau in the EFS curve at 27 months. There were 3 treatment related deaths: 2 from neutropenic sepsis; 1 from toxoplasma. Other toxicities included CMV and BK virus reactivation in 53% and 30% respectively. Febrile neutropenia was seen in 20% and grade 4 thrombocytopenia in 12 % of cycles. Conclusions: Although it has significant infectious toxicity, ALZ 30mg and DA-EPOCHin untreated PTCL is feasible and associated with a long-term favorable outcome in nodal but not extranodal or leukemic PTCL. A phase III study of ALZ 30mg with anthracycline-based therapy is ongoing and we await the results with interest.