Minor Response Research Articles

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

Two -Year Follow-up Data of Phase II Study of Tirabrutinib, a Second-Generation Bruton's Tyrosine Kinase Inhibitor, in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström's Macroglobulinemiatwo -Year Follow-up Data of Phase II Study of Tirabrutinib, a Second-Generation Bruton's Tyrosine Kinase Inhibitor, in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström's Macroglobulinemia

Two -Year Follow-up Data of Phase II Study of Tirabrutinib, a Second-Generation Bruton's Tyrosine Kinase Inhibitor, in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström's Macroglobulinemiatwo -Year Follow-up Data of Phase II Study of Tirabrutinib, a Second-Generation Bruton's Tyrosine Kinase Inhibitor, in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström's Macroglobulinemia

Duration of Objective Responses for Patients with Indolent Non-Hodgkin Lymphoma Discontinuing Treatment before Progression: Analysis from the Phase III Chronos-3 Trial Comparing Copanlisib Plus Rituximab with Placebo Plus Rituximab

Duration of Objective Responses for Patients with Indolent Non-Hodgkin Lymphoma Discontinuing Treatment before Progression: Analysis from the Phase III Chronos-3 Trial Comparing Copanlisib Plus Rituximab with Placebo Plus Rituximab

Depilatory creams increase the number of hair follicles, and dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-β in mouse skin.

Besides using for hair removal, depilatory agents have been considered to be used as a penetration enhancer for transepidermal drug delivery. To examine the effect in hair follicles (HFs), two commercially available depilatory creams were tested on the dorsal skin of mice to monitor the effect deep into the skin structure. Fifteen male BALB/c mice were used in this study. Depilatory creams were applied to the dorsal skin of the same animal using shaved and untouched treatments as controls to minimize individual differences. Skin samples were collected at three days, one week and two weeks (n = 5 for each) after the treatment, and subjected for hematoxylin-eosin staining, and immunohistochemical analysis for proinflammatory cytokines. The morphological examination showed an increase in the thickness of epidermal layer of the depilatory cream-treated skin at early time points and in the subcutis at two weeks. Depilatory cream promoted entry of anagen phase and increased the number of hair follicles in the subcutis at one and two weeks. Immunohistochemistry showed elevated percentages of dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-β. Shaving process increased the thickness of epidermis and dermis as depilatory creams did, but did neither induce the expression of proinflammatory cytokines in the dermal fibroblasts nor the number of HFs. The results suggested that the commercially available depilatory creams caused a transient minor inflammatory response of the skin and increased the levels of cytokines that might subsequently affect hair growth.

Comparison between three decellularization protocol whit SDS in swine esophagus: a future option in veterinary medicine

Disease such as megaesophagus and esophagitis does not have a cure. Esophagitis has treatments depending on it’s degree, while megaesophagus has a palliative treatment, which can be recommended euthanasia in cases of a poor prognosis, cases that the esophagus transplant could be at use, although it is not described in literature. In this perspective the regenerative medicine have techniques of a bioengineering of tissues, creating a minor immune response in transplants, as it removes the organ’s genetic material, preserving the extra cellular matrix (ECM). Different protocols have been evaluated for swine esophagus decellularization, using sodium dodecyl sulphate (SDS) in concentrations 0,5%, 1,0% and 1,5% for seven days, analysing the remaining EMC integrity. It has been concluded that the material in 0,5% of SDS showed more integrity of the remaining EMC compared to the other concentrations, demonstrating that it is the best biological scaffold for future medical applications.

Association of Delayed Surgery With Oncologic Long-term Outcomes in Patients With Locally Advanced Rectal Cancer Not Responding to Preoperative Chemoradiation

Extending the interval between the end of neoadjuvant chemoradiotherapy (CRT) and surgery may enhance tumor response in patients with locally advanced rectal cancer. However, data on the association of delaying surgery with long-term outcome in patients who had a minor or poor response are lacking. To assess a large series of patients who had minor or no tumor response to CRT and the association of shorter or longer waiting times between CRT and surgery with short- and long-term outcomes. This is a multicenter retrospective cohort study. Data from 1701 consecutive patients with rectal cancer treated in 12 Italian referral centers were analyzed for colorectal surgery between January 2000 and December 2014. Patients with a minor or null tumor response (ypT stage of 2 to 3 or ypN positive) stage greater than 0 to neoadjuvant CRT were selected for the study. The data were analyzed between March and July 2020. Patients who had a minor or null tumor response were divided into 2 groups according to the wait time between neoadjuvant therapy end and surgery. Differences in surgical and oncological outcomes between these 2 groups were explored. The primary outcomes were overall and disease-free survival between the 2 groups. Of a total of 1064 patients, 654 (61.5%) were male, and the median (IQR) age was 64 (55-71) years. A total of 579 patients (54.4%) had a shorter wait time (8 weeks or less) 485 patients (45.6%) had a longer wait time (greater than 8 weeks). A longer waiting time before surgery was associated with worse 5- and 10-year overall survival rates (67.6% [95% CI, 63.1%-71.7%] vs 80.3% [95% CI, 76.5%-83.6%] at 5 years; 40.1% [95% CI, 33.5%-46.5%] vs 57.8% [95% CI, 52.1%-63.0%] at 10 years; P < .001). Also, delayed surgery was associated with worse 5- and 10-year disease-free survival (59.6% [95% CI, 54.9%-63.9%] vs 72.0% [95% CI, 67.9%-75.7%] at 5 years; 36.2% [95% CI, 29.9%-42.4%] vs 53.9% [95% CI, 48.5%-59.1%] at 10 years; P < .001). At multivariate analysis, a longer waiting time was associated with an augmented risk of death (hazard ratio, 1.84; 95% CI, 1.50-2.26; P < .001) and death/recurrence (hazard ratio, 1.69; 95% CI, 1.39-2.04; P < .001). In this cohort study, a longer interval before surgery after completing neoadjuvant CRT was associated with worse overall and disease-free survival in tumors with a poor pathological response to preoperative CRT. Based on these findings, patients who do not respond well to CRT should be identified early after the end of CRT and undergo surgery without delay.

SYST-04. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY

Abstract BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

Indatuximab ravtansine plus dexamethasone with lenalidomide or pomalidomide in relapsed or refractory multiple myeloma: a multicentre, phase 1/2a study

Indatuximab ravtansine (BT062) is an antibody-drug conjugate that binds to CD138 and synergistically enhances the antitumor activity of lenalidomide in preclinical models of multiple myeloma. This phase 1/2a study was done to determine the safety, activity, and pharmacokinetics of indatuximab ravtansine in combination with immunomodulatory drugs in patients with relapsed or refractory multiple myeloma. This open-label, phase 1/2a study took place at nine hospital sites in the USA. Eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and ECOG performance status or Zubrod score of 2 or below. Patients who received indatuximab ravtansine with lenalidomide and dexamethasone (indatuximab ravtansine plus lenalidomide) had failure of at least one previous therapy. Patients treated with indatuximab ravtansine with pomalidomide and dexamethasone (indatuximab ravtansine plus pomalidomide) had failure of at least two previous therapies (including lenalidomide and bortezomib) and had progressive disease on or within 60 days of completion of their last treatment. In phase 1, patients received indatuximab ravtansine intravenously on days 1, 8, and 15 of each 28-day cycle in escalating dose levels of 80 mg/m2, 100 mg/m2, and 120 mg/m2, with lenalidomide (25 mg; days 1 to 21 every 28 days orally) and dexamethasone (20-40 mg; days 1, 8, 15, and 22 every 28 days). In phase 2, the recommended phase 2 dose of indatuximab ravtansine was given to an expanded cohort of patients in combination with lenalidomide and dexamethasone. The protocol was amended to allow additional patients to be treated with indatuximab ravtansine plus pomalidomide (4 mg; days 1 to 21 every 28 days orally) and dexamethasone, in a more heavily pretreated patient population than in the indatuximab ravtansine plus lenalidomide group. The phase 1 primary endpoint was to determine the dose-limiting toxicities and the maximum tolerated dose (recommended phase 2 dose) of indatuximab ravtansine, and the phase 2 primary endpoint was to describe the objective response rate (ORR; partial response or better) and clinical benefit response (ORR plus minor response). All patients were analysed for safety and all patients with post-treatment response assessments were analysed for activity. This study is registered with ClinicalTrials.gov, number NCT01638936, and is complete. 64 (86%) of 74 screened patients were enrolled between July 3, 2012, and June 30, 2015. 47 (73%) patients received indatuximab ravtansine plus lenalidomide (median follow-up 24·2 months [IQR 19·9-45·4]) and 17 (27%) received indatuximab ravtansine plus pomalidomide (24·1 months [17·7-36·7]). The maximum tolerated dose of indatuximab ravtansine plus lenalidomide was 100 mg/m2, and defined as the recommended phase 2 dose for indatuximab ravtansine plus pomalidomide. An objective response for indatuximab ravtansine plus lenalidomide was observed in 33 (71·7%) of 46 patients and in 12 (70·6%) of 17 patients in the indatuximab ravtansine plus pomalidomide group. The clinical benefit response for indatuximab ravtansine plus lenalidomide was 85% (39 of 46 patients) and for indatuximab ravtansine plus pomalidomide it was 88% (15 of 17 patients). The most common grade 3-4 adverse events in both groups were neutropenia (14 [22%] of 64 patients), anaemia (10 [16%]), and thrombocytopenia (seven [11%]). Treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 35 (55%) of the 64 patients. Five (8%) patients with a TEAE had a fatal outcome; none was reported as related to indatuximab ravtansine. Indatuximab ravtansine in combination with immunomodulatory drugs shows preliminary antitumor activity, is tolerated, and could be further evaluated in patients with relapsed or refractory multiple myeloma. Biotest AG.

963MO Naxitamab for the treatment of refractory/relapsed high-risk neuroblastoma (HR NB): Updated efficacy and safety data from the international, multicenter phase II trial 201

Patients with HR NB (∼50% of patients with NB at initial diagnosis) and limited or no response to initial therapy have poor outcomes, and residual disease can drive relapse. Naxitamab is a GD2-binding monoclonal antibody, recently approved in the US in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) for the treatment of relapsed/refractory (R/R) HR NB in the bone and/or bone marrow (BM) in patients ≥1 year of age with a partial response, minor response, or stable disease to prior therapy.

Prevalence of Allergic Reactions After Pfizer-BioNTech COVID-19 Vaccination Among Adults With High Allergy Risk

Allergic reactions among some individuals who received the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine discourage patients with allergic conditions from receiving this vaccine and physicians from recommending the vaccine. To describe the assessment and immunization of highly allergic individuals with the BNT162b2 vaccine. In a prospective cohort study from December 27, 2020, to February 22, 2021, 8102 patients with allergies who applied to the COVID 19 vaccine referral center at the Sheba Medical Center underwent risk assessment using an algorithm that included a detailed questionnaire. High-risk patients (n = 429) were considered "highly allergic" and were immunized under medical supervision. Pfizer-BioNTech (BNT162b2) COVID-19 vaccine. Allergic and anaphylactic reactions after the first and second doses of BNT162b2 vaccine among highly allergic patients. Of the 429 individuals who applied to the COVID-19 referral center and were defined as highly allergic, 304 (70.9%) were women and the mean (SD) age was 52 (16) years. This highly allergic group was referred to receive immunization under medical supervision. After the first dose of the BNT162b2 vaccine, 420 patients (97.9%) had no immediate allergic event, 6 (1.4%) developed minor allergic responses, and 3 (0.7%) had anaphylactic reactions. During the study period, 218 highly allergic patients (50.8%) received the second BNT162b2 vaccine dose, of which 214 (98.2%) had no allergic reactions and 4 patients (1.8%) had minor allergic reactions. Other immediate and late reactions were comparable with those seen in the general population, except for delayed itch and skin eruption, which were more common among allergic patients. The rate of allergic reactions to BNT162b2 vaccine, is higher among patients with allergies, particularly among a subgroup with a history of high-risk allergies. This study suggests that most patients with a history of allergic diseases and, particularly, highly allergic patients can be safely immunized by using an algorithm that can be implemented in different medical facilities and includes a referral center, a risk assessment questionnaire, and a setting for immunization under medical supervision of highly allergic patients. Further studies are required to define more specific risk factors for allergic reactions to the BNT162b2 vaccine.

The stress response in Atlantic salmon (Salmo salar L.): identification and functional characterization of the corticotropin-releasing factor (crf) paralogs

Corticotropin-Releasing Factor (CRF) is one of the main mediators of the Hypothalamic-Pituitary–Interrenal (HPI) axis to stress response. In Atlantic salmon, a comparative understanding of the crf1 paralogs role in the stress response is still incomplete. Our database searches have identified four crf1 genes in Atlantic salmon, named crf1a1, crf1a2, crf1b1 and crf1b2. Brain distribution analysis revealed that the four crf1 paralogs were widely distributed, and particularly abundant in the telencephalon, midbrain, and hypothalamus of Atlantic salmon post-smolts. To increase the knowledge on crf1-mediated response to stress, Atlantic salmon post-smolts were exposed to either repeated chasing, hypoxia or a combination of chasing and hypoxia for eight days, followed by a novel-acute stressor, confinement. Cortisol, glucose, lactate, and creatinine levels were used as markers for the stress response.The crf1 paralogs mRNA abundance showed to be dependent on the stress exposure regime. Both crf1 mRNA levels in the telencephalon and crf1a1 mRNA levels in the hypothalamus showed similar response profiles to the serum cortisol levels, i.e., increasing levels during the first 24 h after stress exposure followed by a decline during the eight-day exposure. The similar trend between crf1 and cortisol disappeared once exposed to the novel-acute stressor. There was a minor response to stress for both crf1b1 and crf1b2 in the hypothalamus, while no changes at mRNA level were observed in the hypothalamic crf1a2 under the different stress conditions. No or weak relationship was found between the crf1 paralogs mRNA expression and the other serum stress-indicators analysed. In summary, our data provide novel insights on the dynamic of the HPI axis activation in Atlantic salmon, and thus underline the involvement of the crf1 paralogs as additional factors in the regulation of the stress response in this species. Likewise, the data highlight the importance of analysing all crf1 paralogues response to a stress-condition, in particular in this premature knowledge stage of their functionality. Further analysis and a more detailed time-point series will help to elucidate the response of the HPI axis and the link of crf1 paralogs in the stress response mechanism.

Sensitivity of Photosynthesis to Warming in Two Similar Species of the Aquatic Angiosperm Ruppia from Tropical and Temperate Habitats

Climate change-related events, such as marine heatwaves, are increasing seawater temperatures, thereby putting pressure on marine biota. The cosmopolitan distribution and significant contribution to marine primary production by the genus Ruppia makes them interesting organisms to study thermal tolerance and local adaptation. In this study, we investigated the photosynthetic responses in Ruppia to the predicted future warming in two contrasting bioregions, temperate Sweden and tropical Thailand. Through DNA barcoding, specimens were determined to Ruppia cirrhosa for Sweden and Ruppia maritima for Thailand. Photosynthetic responses were assessed using pulse amplitude-modulated fluorometry, firstly in short time incubations at 18, 23, 28, and 33 °C in the Swedish set-up and 28, 33, 38, and 43 °C in the Thai set-up. Subsequent experiments were conducted to compare the short time effects to longer, five-day incubations in 28 °C for Swedish plants and 40 °C for Thai plants. Swedish R. cirrhosa displayed minor response, while Thai R. maritima was more sensitive to both direct and prolonged temperature stress with a drastic decrease in the photosynthetic parameters leading to mortality. The results indicate that in predicted warming scenarios, Swedish R. cirrhosa may sustain an efficient photosynthesis and potentially outcompete more heat-sensitive species. However, populations of the similar R. maritima in tropical environments may suffer a decline as their productivity will be highly reduced.

Uncoupling Thermotolerance and Growth Performance in Chinook Salmon: Blood Biochemistry and Immune Capacity.

Ocean warming and extreme sea surface temperature anomalies are threatening wild and domesticated fish stocks in various regions. Understanding mechanisms for thermotolerance and processes associated with divergent growth performance is key to the future success of aquaculture and fisheries management. Herein, we exposed Chinook salmon (Oncorhynchus tshawytscha) to environmentally relevant water temperatures (19–20 °C) approaching their upper physiological limit for three months and sought to identify blood biomarkers associated with thermal stress and resilience. In parallel, blood biochemical associations with growth performance were also investigated. Temperature stress-activated leukocyte apoptosis induced a minor immune response, and influenced blood ion profiles indicative of osmoregulatory perturbation, regardless of how well fish grew. Conversely, fish displaying poor growth performance irrespective of temperature exhibited numerous biomarker shifts including haematology indices, cellular-based enzyme activities, and blood clinical chemistries associated with malnutrition and disturbances in energy metabolism, endocrine functioning, immunocompetence, redox status, and osmoregulation. Findings provide insight into mechanisms of stress tolerance and compromised growth potential. Biochemical phenotypes associated with growth performance and health can potentially be used to improve selective breeding strategies.

Flexible Chemiresistive Cyclohexanone Sensors Based on Single-Walled Carbon Nanotube-Polymer Composites.

We report a chemiresistive cyclohexanone sensor on a flexible substrate based on single-walled carbon nanotubes (SWCNTs) functionalized with thiourea (TU) derivatives. A wrapper polymer containing both 4-vinylpyridine (4VP) groups and azide groups (P(4VP-VBAz)) was employed to obtain a homogeneous SWCNT dispersion via noncovalent functionalization of SWCNTs. The P(4VP-VBAz)-SWCNT composite dispersion was then spray-coated onto an organosilanized flexible poly(ethylene terephthalate) (PET) film to achieve immobilizing quaternization between the pyridyl groups from the polymer and the functional PET substrate, thereby surface anchoring SWCNTs. Subsequent surface functionalization was performed to incorporate a TU selector into the composites, resulting in P(Q4VP-VBTU)-SWCNT, for the detection of cyclohexanone via hydrogen bonding interactions. An increase in conductance was observed as a result of the hydrogen-bonded complex with cyclohexanone resulting in a higher hole density and/or mobility in SWCNTs. As a result, a sensor device fabricated with P(Q4VP-VBTU)-SWCNT composites exhibited chemiresistive responses (ΔG/G0) of 7.9 ± 0.6% in N2 (RH 0.1%) and 4.7 ± 0.4% in air (RH 5%), respectively, upon exposure to 200 ppm cyclohexanone. Selective cyclohexanone detection was achieved with minor responses (ΔG/G0 < 1.4% at 500 ppm) toward interfering volatile organic compounds (VOC). analytes. We demonstrate a robust sensing platform using the polymer-SWCNT composites on a flexible PET substrate for potential application in wearable sensors.

Single-Agent Oral Vinorelbine in the Treatment of Pediatric Progressive Optic Pathway Glioma: A Single Institutional Experience

Purpose: The vinca alkaloids’ activity against pediatric low-grade glioma (PLGG) is well established. The goal of the present study is to describe our experience with oral vinorelbine in patients with progressive optic pathway glioma (OPG), not only regarding the clinical response, but also the cost benefit using an oral medication. Methods: Patients under 21 years of age with unresectable and/or progressive OPG were eligible. Oral vinorelbine was administered at a dose of 90mg/m2 daily on days 0, 8 and 22, in a scheme of 4 weekly cycles for a total of 18 cycles (54 doses). Results: From 2013 to 2018, sixteen patients were enrolled onto the study, with a median age of 9,1 years (range 4,6-17,8y). The most common histology was pilocytic astrocytoma (88,8%). Best response to chemotherapy was reviewed with a response rate (complete, partial, or minor response) of 30% for the patients treated exclusively with the oral drug. Five-year event-free survival (EFS) rate was 43.4%. Six patients had to change to intravenous vinorelbine due to gastrointestinal toxicity, vomiting grade III. None of the patients showed neurotoxicity. The total cost including drug acquisition, administration and toxicity management was lower with the oral formulation comparing to IV one. Conclusion: Single-agent oral vinorelbine seems to have some clinical activity in the management of recurrent or refractory pediatric OPG, being an interesting and cost-effective option, minding that gastrointestinal toxicity may be limiting and a combination of antiemetics should be considered in this treatment regimen.

Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenström macroglobulinemia

AbstractMYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.

A rate-dependent constitutive model incorporated in two-dimensional PolyFEM for Galfenol sensors

A micromechanical model with rate effects is developed to constitute the nonlinear hysteresis sensor behaviour of Galfenol and embedded into a numerical framework, the polygonal finite element method. The model stems from the domain rotation events taking place at microlevel in response to the external magnetomechanical loads. The internal variables of the model to represent the material state at any instant are the volume fraction of the domains, and their evolution equations are derived using thermodynamic principles. Inter-domain effects within each grain are accounted in the form of back fields that act as hardening or softening parameters. The constitutive model is extended further to include the rate effects and then incorporated into a hybrid-magnetomechanical-formulation with Voronoi-based-discretization to study the behaviour of Galfenol. The Voronoi discretizations closely resemble the microstructure of Galfenol with each finite element specifying a random grain in the polycrystalline Galfenol. The developed framework is shown to simulate the major and minor loop sensor responses of the material with rate effects under complex loading conditions.

Phase 2 Trial Of Single Agent MLN9708 In Patients With Relapsed Multiple Myeloma Not Refractory To Bortezomib

BackgroundProteasome inhibitors have become an important part of myeloma therapy along with the IMiDS, but both approved drugs require parenteral administration. An orally bioavailable proteasome inhibitor will significantly enhance the ability to incorporate this class of drugs in majority of patients, and increase the ability to develop oral combinations. MLN9708 is an orally bioavailable proteasome inhibitor, that has been shown to have activity in relapsed MM, and in combination with lenalidomide has been effective for newly diagnosed MM. However, the vast majority of patients in the prior trial had relapsed after bortezomib or was refractory to bortezomib. We designed this trial to evaluate the single agent activity of MLN9708 in patients with limited exposure to bortezomib who were not refractory to that agent. Patients and methodsWe designed a phase 2 trial of MLN9708, used a single agent, in patients with relapsed myeloma who had received none or less than 6 cycles of a bortezomib based regimen as part of their prior treatment. MLN9708 was given at a flat dose of 5.5 mg once weekly for three out of four weeks. Dexamethasone (20 mg on the day of and the day after MLN) was added for lack of a minor response by end of Cycle 2 or lack of a partial response by end of Cycle 4 or if there was disease progression at any time. Responses were assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. The primary endpoint of this study is the proportion of confirmed responses with single agent MLN9708. ResultsThirty-three patients were enrolled, and one patient was considered ineligible and excluded from all analysis. The median age was 69 years and 53% were male. The median duration from diagnosis was 57 mos (range 14 mos to 12.3 years) and patients had a median of 2 prior therapies (range 1-7). Prior therapies included IMiDs (88%), bortezomib (28%) and stem cell transplant (59%). At the time of data cutoff, 75% of patients had not progressed and all but 2 (94%) were alive, with a median follow up of 7 months. Nearly half (47%) are still on therapy; reasons for drug discontinuation were disease progression (8), refusal (5) and adverse event (3). Overall, 184 cycles of treatment were delivered, with a dose reduction required for 15 (8%) cycles. A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 18 (56%) and 6 (19%) patients, respectively; there were no deaths on study. The most common adverse events observed included thrombocytopenia, fatigue, nausea, and diarrhea. Peripheral neuropathy possibly related to the drug was seen in 6 patients (grade 1) and 2 patients (grade 2), respectively. Dexamethasone was initiated in 19 (59%) patients, 16 for not reaching the desired response and 3 for progression. Response (>=PR) to single agent was seen in 5 patients within 4 cycles of therapy including 3 patients with PR and 2 patients with a stringent CR. Six additional patients who had either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34% (11/32). The median event free survival was 12.4 months and 6 month overall survival was 96%. The patient disposition by addition of dexamethasone is shown in the figure. [Display omitted] [Display omitted] ConclusionsMLN9708 as a single agent results in a 16% PR or better after 4 cycles of therapy. RR improved to 34% with the addition of dexamethasone in patients not responding to single agent MLN9708. This includes 2 patients with a sCR on single agent MLN9708. We anticipate the response rate and response depth to improve with nearly half of the patients still remaining on therapy. Disclosures:Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding. Lacy:Celgene Corporation: Research Funding. Gertz:Celgene: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding.

Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab

Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab