Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53.

PURPOSE: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. PATIENTS AND METHODS: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days. RESULTS: Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg) and 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. CONCLUSIONS: ALRN-6924 was well tolerated and demonstrated antitumor activity.

TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer.

BACKGROUND: In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. METHODS: Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. RESULTS: Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. CONCLUSION: In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.

Changes in health-related quality of life with long-term eltrombopag treatment in adults with persistent/chronic immune thrombocytopenia: Findings from the EXTEND study.

Patients with persistent/chronic immune thrombocytopenia (cITP) have low platelet counts, increased risk of bleeding and bruising, and often suffer from reduced health-related quality of life (HRQoL). cITP treatments may either improve HRQoL by increasing platelet counts or decrease it because of side effects. The open-label EXTEND study (June 2006 to July 2015) evaluated long-term safety, tolerability, and efficacy of eltrombopag (an oral thrombopoietin-receptor-agonist) in adults with cITP who completed a previous eltrombopag ITP trial. The final results of EXTEND were published and used to assess changes in patient-reported HRQoL over time and association between HRQoL and platelet response. Four validated HRQoL instruments were administered: SF-36v2 including physical component summary (PCS) and Mental Component Summary; Motivation and Energy Inventory Short Form (MEI-SF); Fatigue Subscale of FACIT (FACIT-Fatigue); and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6). For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years. All 4 HRQoL instruments demonstrated positive mean changes from baseline over time adjusted for patient baseline characteristics and rescue therapy use, and had positive association with platelet response (platelet count ≥30 × 109 /L; ≥50 × 109 /L; and ≥50 × 109 /L and >2 times baseline). Improvements from baseline started within 3 months and persisted through 5 years of treatment for FACIT-Fatigue and FACT-Th6 (P <.05 for nearly all time points); through 2.5 years for SF-36v2 PCS and less consistently for the MEI-SF. In conclusion, in addition to eltrombopag increasing platelet counts and reducing bleeding/bruising, it also alleviated fatigue, concerns about bleeding and bruising, and improved physical function in many patients, especially responders.

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study.

In phase 2/3 trials, eltrombopag treatment of 6 months or less in patients with chronic/persistent immune thrombocytopenia (ITP) increased platelet counts and reduced bleeding. The open-label EXTEND study evaluated long-term safety and efficacy of eltrombopag in adults with ITP who had completed a previous eltrombopag study. For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years (2 days-8.76 years). Median platelet counts increased to 50 × 109/L or more by week 2 and were sustained throughout the treatment period. Overall, 259 patients (85.8%) achieved a response (platelet count ≥50 × 109/L at least once in the absence of rescue), and 133 (52%) of 257 patients achieved a continuous response of 25 weeks or longer. Responses in patients with platelet counts lower than 15 × 109/L, more previous therapies, and/or splenectomy were somewhat lower. Thirty-four (34%) of 101 patients receiving concomitant ITP medication discontinued 1 or more medication. In patients with assessments, bleeding symptoms (World Health Organization grades 1-4) decreased from 57% at baseline to 16% at 1 year. Forty-one patients (14%) withdrew because of adverse events. Hepatobiliary adverse events (n = 7), cataracts (n = 4), deep vein thrombosis (n = 3), cerebral infarction (n = 2), headache (n = 2), and myelofibrosis (n = 2) occurred in more than 1 patient; the remaining adverse events occurred only once. Rates of thromboembolic events (6%) and hepatobiliary adverse events (15%) did not increase with treatment duration past 1 year. EXTEND demonstrated that long-term use of eltrombopag was effective in maintaining platelet counts of 50 × 109/L or more and reducing bleeding in most patients with ITP of more than 6 months' duration. Important adverse events (eg, thrombosis, hepatobiliary, and bone marrow fibrosis) were infrequent. (ClinicalTrials.gov:NCT00351468).

Academic Cancer Center Phase I Program Development.

Multiple factors critical to the effectiveness of academic phase I cancer programs were assessed among 16 academic centers in the U.S. Successful cancer centers were defined as having broad phase I and I/II clinical trial portfolios, multiple investigator-initiated studies, and correlative science. The most significant elements were institutional philanthropic support, experienced clinical research managers, robust institutional basic research, institutional administrative efforts to reduce bureaucratic regulatory delays, phase I navigators to inform patients and physicians of new studies, and a large cancer center patient base. New programs may benefit from a separate stand-alone operation, but mature phase I programs work well when many of the activities are transferred to disease-oriented teams. The metrics may be useful as a rubric for new and established academic phase I programs. The Oncologist 2017;22:369-374.

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia.

We compared two dosing schedules for subcutaneous injections of a low-dose humanized anti-CD20 antibody, veltuzumab, in immune thrombocytopenia. Fifty adults with primary immune thrombocytopenia, in whom one or more lines of standard therapy had failed and who had a platelet count <30×109/L but no major bleeding, initially received escalating 80, 160, or 320 mg doses of subcutaneous veltuzumab administered twice, 2 weeks apart; the last group received once-weekly doses of 320 mg for 4 weeks. In all dose groups, injection reactions were transient and mild to moderate; there were no other safety issues. Forty-seven response-evaluable patients had 23 (49%) objective responses (platelet counts ≥30×109/L and ≥2 × baseline) including 15 (32%) complete responses (platelets ≥100×109/L). Responses (including complete responses) and bleeding reduction occurred in all dose groups and were not dose-dependent. In contrast, response duration increased progressively with total dose, reaching a median of 2.7 years with the four once-weekly 320-mg doses. Among nine responders retreated at relapse, three at higher dose levels responded again, including one patient who was retreated four times. In all dose groups, B-cell depletion occurred after the first dose until recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with dose group according to total dose administered, but terminal half-life and clearance were comparable. Human anti-veltuzumab antibody titers developed without apparent dose dependence in nine patients, of whom six responded including five who had complete responses. Subcutaneous veltuzumab was convenient, well-tolerated, and active, without causing significant safety concerns. Platelet responses and bleeding reduction occurred in all dose groups, and response durability appeared to improve with higher doses. Clinicaltrials.gov identifier: NCT00547066.

Phase II study of a novel taxane (Cabazitaxel-XRP 6258) in previously treated advanced non-small cell lung cancer (NSCLC) patients.

PURPOSE: Given the success of cabazitaxel in patients with prostate cancer who progressed after receiving prior chemotherapy, its preclinical efficacy in various cell lines and possible ability to cross blood-brain barrier, cabazitaxel was hypothesized to increase objective response rate (ORR) in second-line setting in non-small cell lung cancer (NSCLC). METHODS: This was a phase II 2-stage trial in 28 patients using two different treatment schedules (A: 20 mg/m(2) every 3 weeks intravenously and B: 8.4 mg/m(2) intravenously weekly) to determine the ORR of cabazitaxel with secondary end points including progression-free survival (PFS), safety, and overall survival (OS). RESULTS: There was one objective response in schedule B. PFS and OS of schedule A was 3 and 6 months, respectively. PFS and OS of schedule B was 3 and 13 months, respectively. The stable disease rate was higher in schedule A (SD = 69.23 %; 95 % CL 38.57, 90.90) as compared to schedule B (SD = 38.46 %; 95 % CL 13.86, 68.42), but this difference was not statistically significant (P value = 0.1156). There were two grade 5 toxicities from sepsis. Hematuria of any grade developed in greater percentage of patients (35%) as compared to previous cabazitaxel phase 3 trial and led to change in our protocol. CONCLUSIONS: Response to cabazitaxel in NSCLC was not as robust as seen in prostate cancer and not superior to currently used agents such as docetaxel, pemetrexed, and erlotinib. In absence of significant objective responses, the second stage of the study was not undertaken.

Phase I/IIa study of sequential chemotherapy regimen of bendamustine/irinotecan followed by etoposide/carboplatin in untreated patients with extensive disease small cell lung cancer (EDSCLC).

PURPOSE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS. METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome. RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis. CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.

EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-Expressing Breast Cancer.

PURPOSE: Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS: Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator's choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS: Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION: Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.

A randomized, phase II study of the anti-insulin-like growth factor receptor type 1 (IGF-1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer.

Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV(max)). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV(max) (DiSUV) greater than 20% 12-14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%-32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab.

Assessment of treatment and monitoring patterns and subsequent outcomes among patients with chronic myeloid leukemia treated with imatinib in a community setting.

INTRODUCTION: Real-world treatment and monitoring patterns have not been well documented among imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients. Thus, we evaluated these patterns and responses to imatinib in CP-CML patients. METHODS: This retrospective study, based on the Georgia Cancer Specialists' electronic medical record (EMR) system, identified CP-CML patients initiating treatment with imatinib from 01/01/2002 to 11/01/2011 who were subsequently followed for ≥6 months. RESULTS: A total of 177 patients met the study criteria. Imatinib dose modification occurred in 59 patients (33%). Rates of treatment interruption, discontinuation, and switching to another therapy were 16%, 24%, and 23%, respectively. Of 27 patients discontinuing imatinib for lack of efficacy, 9 (33%) had initial dose escalation; 26 patients (96%) eventually switched to a second-generation tyrosine kinase inhibitor. By 3 months, 168 patients remained on imatinib, of whom 96 (57%) had undergone cytogenetic and/or molecular testing. The frequency of response monitoring fluctuated over time, with rates as high as 28% for cytogenetic and 69% for molecular testing. Cumulative response rates steadily increased; 18 month rates were 47% for complete cytogenetic response and 26% for major or complete molecular response. There were no cases of progression and/or death among 38 patients who were regularly monitored for molecular response within the first 12 months of imatinib. Ten of 98 patients (10%) not regularly monitored had progressed or died. CONCLUSIONS: Almost one-third of patients initiating imatinib for CP-CML required dose modification, treatment interruption, or discontinuation. Opportunities for improved monitoring in this setting were identified. Limitations include those inherent to retrospective analyses based on EMR and the uncertain extrapolability of the results.

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

Low-dose anti-CD20 veltuzumab given intravenously or subcutaneously is active in relapsed immune thrombocytopenia: a phase I study.

Low doses of the humanized anti-CD20 monoclonal antibody, veltuzumab, were evaluated in 41 patients with immune thrombocytopenia (ITP), including 9 with ITP ≤1 year duration previously treated with steroids and/or immunoglobulins, and 32 with ITP >1 year and additional prior therapies. They received two doses of 80-320 mg veltuzumab 2 weeks apart, initially by intravenous (IV) infusion (N = 7), or later by subcutaneous (SC) injections (N = 34), with only one Grade 3 infusion reaction and no other safety issues. Thirty-eight response-assessable patients had 21 (55%) objective responses (platelet count ≥30 × 10(9) /l and ≥2 × baseline), including 11 (29%) complete responses (CRs) (platelet count ≥100 × 10(9) /l). Responses (including CRs) occurred with both IV and SC administration, at all veltuzumab dose levels, and regardless of ITP duration. Responders with ITP ≤1 year had a longer median time to relapse (14·4 months) than those with ITP >1 year (5·8 months). Three patients have maintained a response for up to 4·3 years. SC injections resulted in delayed and lower peak serum levels of veltuzumab, but B-cell depletion occurred after first administration even at the lowest doses. Eight patients, including 6 responders, developed anti-veltuzumab antibodies following treatment (human anti-veltuzumab antibody, 19·5%). Low-dose SC veltuzumab appears convenient, well-tolerated, and with promising clinical activity in relapsed ITP.(Clinicaltrials.gov identifier: NCT00547066.).

Treatment rationale and study design for a randomized, double-blind, placebo-controlled phase II study evaluating onartuzumab (MetMAb) in combination with bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal cancer.

BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin). PATIENTS AND METHODS: Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5-fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers.

Repeated short-term use of eltrombopag in patients with chronic immune thrombocytopenia (ITP).

Eltrombopag is a thrombopoietin-receptor agonist that stimulates platelet production and increases platelet counts in patients with chronic immune thrombocytopenia (ITP). This open-label, single-arm study evaluated consistency of response and safety following repeated intermittent dosing of eltrombopag 50 mg daily over 3 cycles (1 cycle = up to 6 weeks on therapy followed by up to 4 weeks off therapy). The primary endpoint was proportion of patients with a response (platelet count ≥50 × 10(9) /l and ≥2× baseline) in Cycle 1 who subsequently responded in Cycle 2 or 3. Fifty-two of 65 evaluable patients (80%) responded in Cycle 1; these responding patients comprised the primary analysis population. Of these, 45/52 (87%) responded in Cycle 2 or 3 [95% confidence interval (CI), 74-94%] and 34/48 (71%; 95% CI, 56-83%) responded in both Cycles 2 and 3. Time to response was consistent, with >50% of responders responding by Day 8 in each cycle. Bleeding rates relative to baseline decreased by approximately 50% during each treatment cycle. The frequency or severity of adverse events, most commonly headache, did not increase over successive cycles. If a chronic ITP patient not requiring consistent therapy responds to short-term eltrombopag, then subsequent courses of eltrombopag, as needed, are likely to be safe and effective.

Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study.

Patients with chronic immune thrombocytopenia may have bleeding resulting from low platelet counts. Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment lasting ≤ 6 months. This interim analysis of the ongoing open-label EXTEND (Eltrombopag eXTENded Dosing) study evaluates the safety and efficacy of eltrombopag in 299 patients treated up to 3 years. Splenectomized and nonsplenectomized patients achieved platelets ≥ 50 000/µL at least once (80% and 88%, respectively). Platelets ≥ 50 000/µL and 2 × baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks, respectively. Bleeding symptoms (World Health Organization Grades 1-4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3 years. One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45 of 69) had a sustained reduction or permanently stopped ≥ 1 concomitant treatment. Thirty-eight patients (13%) experienced ≥ 1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). No new or increased incidence of safety issues was identified. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired range.