Recurrent angiosarcoma of scalp with opsoclonus myoclonus syndrome: role of salvage treatment

Cutaneous angiosarcoma is a type of rare and locally aggressive malignancy requiring individualised treatment owing to paucity of randomised trials. We present the case of a middle-aged cancer survivor with locally advanced angiosarcoma of scalp managed with surgery, radiotherapy, chemotherapy and targeted therapy over a course of 6 years for two recurrences. The first recurrence was preceded by opsoclonus myoclonus syndrome, a type of paraneoplastic neurological syndrome (PNS), rarely reported in sarcomas. The second recurrence had a rapid clinical course, which led to a therapeutic dilemma of best supportive care versus active management. A trial of weekly paclitaxel was started that was continued for a total of 12 cycles with good objective clinical response. Presently, he is tolerating maintenance pazopanib well and is symptom free for 6 months. In cutaneous angiosarcoma patients, PNS may be a harbinger of recurrence and aggressive, multimodality treatment helps prolong survival.

Associations of Cutaneous Immune-Related Adverse Effects of Immunotherapy With Treatment Response in Patients With Metastatic Melanoma

Background: Dermatologic toxicity is the most common immune-related adverse effect of cancer immunotherapy. Methods: We retrospectively reviewed the health records of adult (≥18 years) melanoma patients who received ipilimumab, nivolumab, or pembrolizumab from January 1, 2011, through September 15, 2017, at Mayo Clinic. The χ2 test was used to assess the association between development of a cutaneous immune-related adverse effect and antitumoral response to the immune checkpoint inhibitors. Odds ratios were calculated with logistic regression models and were adjusted for sex and immunotherapeutic drugs. We described the various cutaneous immune-related adverse effects and assessed the response to immunotherapy (each patient’s objective clinical response was categorized as favorable [complete or partial response] or unfavorable). We then determined whether development of a cutaneous immune-related adverse effect was associated with the clinical response. Results: Of 690 melanoma patients, 232 (33.6%) had a cutaneous immune-related adverse effect. The most common effects were dermatitis (21.4%), pruritus (5.5%), and vitiligo (4.2%). Median (range) time to onset of dermatitis was 3 (0-7) weeks; lichenoid dermatitis, 12 (6-18) weeks; and vitiligo, 40 (12-96) weeks. Development of a cutaneous immune-related adverse effect was significantly associated with favorable clinical response. Conclusions: Development of cutaneous immune-related adverse effects is associated with favorable responses to nivolumab, ipilimumab, pembrolizumab, and ipilimumab plus nivolumab therapy in patients with metastatic melanoma.

Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome

Background PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. Results Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22–28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. Conclusion We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients

BackgroundThis phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors.MethodsBoth emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments.ResultsThree dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67+-activated CD8+ T cells accompanied by a decrease of B cells and the reduction of CD14Dim CD16bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients.ConclusionEmactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses.Trialregistration numberNCT02760797.

Tocilizumab in Covid-19 Interstitial Pneumonia: A Phase II Pilot Study

Background: Multiple studies have been conducted to investigate Tocilizumab in patients with cOVID-19 pneumonitis. However, published reports show conflicting results, largely due to weak retrospective designs and heterogeneity in critical methodological issues.Methods: This open-label trial was structured according to the Simon’s optimal two-stage design in order to clarify which patients could really benefit from anti-IL6 strategies and how a future randomized trial should be designed to provide reliable and unequivocal results. 46 patients received a single infusion of Tocilizumab. Inclusion criteria were: SARS-CoV2 infection diagnosed by rt-PCR, multifocal interstitial pneumonia, need of oxygen therapy (FiO2 50%) to maintain SO2 >93%, recent (within the last 24 hours) worsening of lung function. Clinical outcomes were established a priori to assess whether a patient responded to treatment. A low number of carefully chosen clinical and biological markers was measured in order to test their predictive values. Primary end point was early and sustained clinical response. Results: Twenty-one (46%) patients fulfilled pre-defined response criteria. Lower levels of IL-6 at 24 hours after tocilizumab infusion (p=0.049) and higher baseline values of PaO2/FiO2 (p=0.008) predicted a favorable clinical response. Patients not improving at 72 hours were also non-responder at day 7. 11/25 of non-responder patients were intubated and 7 died. High levels of vWF were detected in all sera, with a tendency towards higher concentrations in the non-responder group. Conclusions: Objective clinical response rate overcame the pre-defined threshold of 30%. Efficacy of tocilizumab to improve respiratory function in selected patients with severe COVID-19 pneumonitis warrants investigations in randomized trials. Trial registration: NCT 04315480

Clinical Experience with the AKT1 Inhibitor Miransertib in two Children with PIK3CA-related overgrowth syndrome

Background PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. Results Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. Conclusions We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced-stage ovarian cancer.

2 Background: This study evaluated weekly intraperitoneal (IP) GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine-cholesterol lipopolymer, with intravenous (IV) weekly taxane (T) and carboplatinum (C) every 3 weeks in epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives included objective clinical response and pathological response at interval debulking surgery (IDS). Methods: Newly diagnosed EOC patients with no prior therapies were eligible. The trial utilized a 3+3 design with dose escalation in ~30% increments at GEN-1 IP dose levels of 36 mg/m2, 47 mg/m2, 61 mg/m2, and 79 mg/m2 weekly for 8 treatments with concurrent IV T/C. Dose-limiting toxicity (DLT) was based on the first 4 doses of GEN-1 administered. Results: 18 patients were enrolled into the study and 12 of those patients received all 8 treatments with no DLTs. 14 patients underwent IDS. Most common related toxicities were Gr 1 nausea, abdominal pain and fatigue. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. Conclusions: Adding GEN-1 to T/C is safe and appears to be active in EOC patients receiving NAC. Dose limiting toxicity was not reached and further dose escalation and safety and activity is being evaluated in an ongoing phase I/II study. Clinical trial information: NCT02480374. [Table: see text]

Activity of RX-3117, an oral antimetabolite nucleoside, in subjects with advanced urothelial cancer: Preliminary results of a phase IIa study.

455 Background: RX-3117 is an oral small molecule antimetabolite that is activated by uridine cytidine kinase 2 (UCK2) which is predominantly expressed in cancer cells. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Preliminary data from an analysis of a Phase 2a clinical study of RX3117 in advanced urothelial cancer is described. Methods: In the Phase 2a study designed to evaluate safety, tolerability and efficacy, subjects were treated with oral RX-3117 (700 mg) once-daily for 5 consecutive days on and 2 days off for 3 of 4 weeks or all 4 weeks in a 28-day cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic urothelial cancer, ECOG PS of 0 to 1, normal organ function (hepatic, renal and hematology) with no limit on the number of prior therapies. The primary Phase 2a endpoints are progression free survival (PFS) and/or objective clinical response with secondary endpoints of safety, TTP, DOR and ORR. Results: As of October 5, 2018; 33 subjects were treated (23 males and 10 females, median age 67.5 years); 29 subjects were evaluable having completed more than 1 cycle of therapy or discontinued due to a related adverse event. Twenty subjects had received 3 or more prior therapies; 30 received gemcitabine/cisplatin and 25 received a checkpoint inhibitor. The most common related adverse events were anemia (G1-2%, G2-3%, G3-3%), fatigue (G1-6%, G2-3%), neutropenia (G2-2%, G3-5%, G4-2%), diarrhea (G1-4%, G2-2%), and thrombocytopenia (G2-2%, G3-3%, G4-1%). One subject had a complete response after 4 cycles of therapy and continues therapy beyond 10 cycles; 5 subjects had PFS ranging from 133 to 315 days. Conclusions: RX-3117 appears to be safe and well-tolerated in chemotherapy and immunotherapy refractory advanced urothelial cancer with acceptable toxicities. Preliminary results show anti-tumor activity in heavily pre-treated patients. Clinical trial information: NCT02030067.

Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.

5568 Background: This study evaluated weekly intraperitoneal (IP) GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, with intravenous (IV) weekly taxane (T) and carboplatinum (C) every 3 weeks in epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives included objective clinical response and pathological response at interval debulking surgery (IDB). Methods: Newly diagnosed advanced stage EOC patients being treated with NAC were eligible. The trial utilized a 3+3 design with GEN-1 IP dose levels of 36 mg/m2, 47 mg/m2, 61 mg/m2, and 79 mg/m2 weekly for 8 treatments with concurrent IV T/C. Dose-limiting toxicity (DLT) was based on the first 4 doses of GEN-1 administered. Results: To date, 13 patients have been treated on-study with 12 patients receiving all 8 treatments of IP GEN-1 with no DLTs. The most common related toxicities were Gr 1 nausea, vomiting, abdominal pain and fatigue. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. One patient did not undergo IDB while on-study due to a cancer related pulmonary embolism and severe deconditioning. This patient has since improved and will have IDB. Conclusions: Adding GEN-1 to neoadjuvant T/C is safe and appears to be active in EOC patients. We are reporting the interim findings; final results with translational data to be presented. Clinical trial information: NCT02480374. [Table: see text]

Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.

155 Background: This study evaluated weekly intraperitoneal GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, in combination with dose-dense weekly taxane (T) and carboplatinum (C) every 3 weeks in newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective of this study was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives were objective clinical response and pathological complete response at interval debulking surgery (IDB). Methods: This protocol followed a standard 3+3 design. Patients received GEN-1 at escalating dose levels from 36 mg/m2, 47 mg/m2, 61 mg/m2, to 79 mg/m2 weekly for 8 treatments with concurrent T/C. After IDB, patients did not receive further GEN-1 but continued on T/C. Patients were assessed for dose limiting toxicities (DLT) and had tumor samples at a time of diagnostic laparoscopy and IDB. Translational endpoints are yet to be analyzed. Patients are being followed for every 3 months for 2 years. Results: Fifteen patients were enrolled and 9 patients received all 8 treatments with no DLTs. The 79 mg/m2GEN-1 cohort of patients are actively being treated. Two patients were screen failures; 1 patient discontinued prior to GEN-1 administration due to port site infection. Most common related toxicities were Gr 1 nausea, fatigue, abdominal pain, and vomiting. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. One patient did not undergo IDB due to pulmonary embolism and severe deconditioning due to underlying cancer. Of the other 8 patients undergoing IDB: 3/8 had stable disease, 4/8 had partial responses (PR), and 1/8 had complete response (CR). There was 1 pathological CR, 3 micro PR, and 3 macro PR. All patients had a ≥ 89% drop in CA-125 following GEN-1. Conclusions: Adding GEN-1 to T/C is safe and appears to be active in NAC patients with newly diagnosed EOC. Updated results to be presented at meeting. Clinical trial information: NCT02480374.