Oral Everolimus Research Articles

Angiomiolipoma renal y complejo esclerosis tuberosa: resultados a largo plazo en seguridad y eficacia de terapia con everolimus

IntroductionRenal angiomyolipoma is a frequent manifestation of Tuberous Sclerosis Complex (TSC), for which everolimus therapy has been recently established as a novel non-invasive therapeutic option. As there are limited real life and long-term data, the analysis of our experience provides added value in terms of safety and efficacy. Material and methodsDescriptive analysis of our experience in patients with giant bilateral renal angiomyolipomas, in the context of TSC, treated with 10 mg oral everolimus daily, during a median of 71.5 months. We evaluated the following parameters: response rate and duration, reduction of kidney size and lesions, prevention of complications and presentation of toxicity and its cause. ResultsWe confirm the effectiveness of treatment in 4 young patients, with multiple, bilateral angiomyolipomas of a median of 12 (5-19) cm maximum diameter, from June 2013 to date, after continuous reduction in lesion size, a decrease of 30% of the volume in 75% at six months and 50% in half of the subjects at two years, still showing drug response. Absence of complications such as bleeding or glomerular filtration rate decline in the long term, with a favorable safety profile, without interruptions and with mild-moderate, non-cumulative adverse effects, mostly within the first year of treatment. ConclusionEverolimus is a safe and effective therapeutic option for renal angiomyolipoma and various manifestations of TSC, which has been reproduced in real life with six years of follow-up.

Can peritoneal carcinomatosis of colorectal origin be treated with or everolimus or in combination with capecitabine? Preliminary results

Background: We wanted to evaluate the effectiveness of oral everolimus alone and in combination with capecitabine treatment on colorectal cancer-induced peritoneal carcinomatosis animal model. Methods: Caco-2 colon adenocarcinoma cells were injected intraperitoneally to BALB/cOlaHsd-Foxn1nu mice to establish peritoneal carcinomatosis. Mice were divided into four groups (everolimus, everolimus plus capecitabine, capecitabine, control group) with 2 mice in each group. Treatment was initiated 5 days after inoculation of Caco-2 cells. 7.5 mg/kg everolimus was administered orally every 2 days. 2.1 mmol/kg capecitabine was administered orally every 5 days a week. 22 days after inoculation of Caco-2 cells, mice were sacrificed. Results: The mean weight of the tumor was 25 ± 7.07 mg in the control group (n=2); 0.7 ± 0.7 mg in the everolimus group (n=2); 0.28 ± 0.36 mg in the capecitabine group; 0.48 ± 0.07 mg in the everolimus plus capecitabine group. Conclusion: Tumor samples excised from BALB/cOlaHsd-Foxn1nu mice revealed that everolimus alone, and in combination with capecitabine suppressed tumor growth. However, a comparison of tumor weights revealed no statistically significant difference within the four groups (p=0.227). To reach statistically significant data, the sample size should be increased.

Clinical analysis of everolimus in the treatment of metastatic renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and accounts for approximately 3% of all malignancies. Metastatic RCC (mRCC) is not sensitive to traditional radiotherapy and chemotherapy, therefore targeted therapy has become an important treatment option. In this study, the second-line targeted drug everolimus (Afinitor), a mammalian target of rapamycin (mTOR) inhibitor, was investigated for its clinical efficacy and adverse events in mRCC after failure of first-line targeted therapy, such as sorafenib, sunitinib or pazopanib. A total of 21 patients with mRCC who had been treated with surgery or other therapies such as tyrosine kinase inhibitors (TKIs) were given oral everolimus (10 mg/day) until disease progression. Clinical efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) 2 months after therapy, including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The adverse events were observed, and timely treatment was provided. Everolimus extended progression-free survival (PFS) in mRCC patients from 4 to 8 months (median 6.3 months). There were 3 patients with PR, 12 with SD, and 6 with PD, and the disease control rate (DCR) was 15/21 (71.4%). Common adverse events included stomatitis, rash, and pneumonitis. This study provides further support that everolimus is still an important option in mRCC treatment after failure of first-line targeted therapy. However, clinical studies are still needed to further improve its therapeutic efficacy.

The Effect of Everolimus on Subependymal Giant Cell Astrocytoma (SEGA) in Children with Tuberous Sclerosis Complex.

Objective:Subependymal Giant Cell Astrocytomas (SEGAs) are slow-growing glioneuronal tumors typically found around the ventricles of the brain, particularly near the foramen of Monro in 15%-20% of patients with tuberous sclerosis complex (TSC). Surgical resection is the standard treatment for these symptomatic tumors. The mTOR inhibitor everolimus can be regarded as an alternative treatment for SEGAs due to the complications of surgery. The present study primarily aimed to specify the effect of everolimus on SEGA volume change before and after treatment. The secondary objective was to determine the effect of this drug on renal angiomyolipoma (AML), skin lesions, and seizures in TSC patients. Materials & Methods:This pre- and post-treatment clinical trial was performed on 14 children (eight females and six males with a mean age of 10 years) previously diagnosed with TSC based on the diagnostic criteria. The subjects received oral everolimus at a dose of 3 mg/m2 for at least six months. Results:Half of the patients had more than 30% of volume loss in SEGA, and in 28.5% of them, a ≥ 50% reduction in SEGA volume was observed (P=0.01). Moreover, 92.9% of the patients had a ≥ 50% decrease in the frequency of seizures (P=0.000). The response rate in AML and skin lesions was 14.2% and 50%, respectively. Conclusion:Everolimus significantly reduced the seizure frequency and SEGA volume in the subjects; hence, it can be used as a potential alternative treatment for symptomatic SEGA in TSC patients.

GCT-25. INNOVATIVE, INTENSIVE IRRADIATION-AVOIDING/MINIMIZING CHEMOTHERAPY FOR HIGH-RISK PRIMARY CENTRAL NERVOUS SYSTEM (CNS) MIXED MALIGNANT GERM CELL TUMORS (HR-MMGCT): A PILOT STUDY AND PROPOSED MULTI-NATIONAL PROSPECTIVE TRIAL

BACKGROUNDAbout one-third of children with primary CNS MMGCT experience incomplete responses to initial induction chemotherapy prior to irradiation, many of whom will subsequently relapse. Such high-risk patients are variably defined as having initial alpha-fetoprotein (AFP) elevations exceeding 1,000ng/mL, predominant histopathologies of malignant non-germinomatous GCT and incomplete responses to induction chemotherapy. Drugs targeting GCT-specific molecular markers have been identified for non-germinomatous GCT elements but have yet to be incorporated into prospective clinical trials. Four children with clearly identified HR-MMGCT characteristics have been treated on an innovative pilot regimen incorporating intensified chemotherapy and molecularly targeted agents, with avoidance or minimization of irradiation.METHODSFour children (two with pure suprasellar embryonal carcinoma (EC) - one with Down syndrome and the other with pre-diagnosis cognitive dysfunction; one with initial serum AFP exceeding 7,000ng/mL and yolk sac tumor (YST)+EC+Teratoma pathology; one with initial serum AFP exceeding 1,000ng/mL) were treated with 3 cycles of “standard” induction chemotherapy (ACNS1123), followed by 1–3 transplant cycles (thiotepa/carboplatin) each with complete radiographic and tumor marker responses. Two children with pure EC subsequently received six cycles of brentuximab-vedotin without irradiation and remain disease-free off therapy for 2–4 years. One child with YST+EC+Teratoma has subsequently received reduced dose craniospinal irradiation and pineal region boost, and will receive oral everolimus, erlotinib, palbocyclib and intravenous brentuximab-vedotin. The fourth child with YST+MT will commence everolimus, erlotinib and palbocyclib without irradiation.CONCLUSIONThis treatment strategy for HR-MMGCT patients provides preliminary tolerance and response data justifying extension to a multi-center trial.

CTNI-52. PHASE II STUDY OF EVEROLIMUS (AFINITOR®) FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA

Abstract Preclinical studies suggested that the mTOR signaling pathway could be a potential therapeutic target in childhood ependymomas. As a result, a phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis that inhibition of the mTOR pathway would result in tumor responses for children with recurrent and/or progressive ependymoma. Eleven patients [sex: 4 females (36.4%); median age: 8 years (range: 2 – 15 years); race: 9 white and 2 other; prior therapies: median 6 (range: 3 – 9)] were enrolled on the study. The primary tumor location for 10 participants was the posterior fossa; the primary location of the remaining tumor was the cervical spine. All patients were treated with oral everolimus 4.5 mg/m2/day (each cycle = 28 days) that was titrated to achieve serum trough levels of 5 – 15 ng/mL. Overall, everolimus was well tolerated; adverse events were grade 1 – 2 and consistent with its previously established safety profile in children. No objective tumor responses were observed. All patients discontinued therapy due to tumor progression after a median of 2 cycles of therapy (1 cycle = 2; 2 cycles = 6; 3, 4, and 8 cycles = 1 each). This study does not support the use of everolimus for children with recurrent or progressive ependymoma.

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma

Background: Facial angiofibromas may be present since early childhood in individuals with tuberous sclerosis complex (TSC), causing substantial cosmetic disfigurement. Current therapies are partially effective, but they are uncomfortable, produce scarring, and are especially expensive. Objective: The aim of the present study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas. Methods: This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus. Results: Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11–44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004). Conclusion: Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC.

Abstract B08: Improved tumor penetration, antitumor activity, and survival of ABI-009 (nab-sirolimus) versus oral rapamycin and everolimus and investigation of mTOR pathway inhibition

Abstract Background: mTOR pathway is a key regulator of cell survival and proliferation and has been implicated in various indications, including oncology, hematology, and cardiovascular, metabolic, and central nervous system diseases. ABI-009, a novel mTOR inhibitor, is an intravenously (IV) administered nanoparticle form of albumin-bound sirolimus. ABI-009 is in a registrational clinical study for perivascular epithelioid cell carcinoma (PEComa), and also studied as combination or single agent in phase 1, 1/2, and 2 studies in neuroendocrine tumors, bladder cancer, glioblastoma, soft-tissue sarcomas, colorectal cancer, childhood cancers, as well as pulmonary arterial hypertension and epilepsy. ABI-009 has a distinct PK profile vs. oral mTOR inhibitors, and it is hypothesized that albumin binding to sirolimus may improve drug penetration and thus efficacy. This xenograft study was conducted to evaluate the antitumor activity, tissue penetration, and mTOR inhibition of ABI-009 vs. equal doses of oral mTOR inhibitors at clinically relevant doses. Methods: Athymic mice were injected with UMUC3 bladder cancer cells subcutaneously into both flanks. Upon development of tumors, ABI-009, oral rapamycin and everolimus were administered at equal weekly doses of 15 mg/kg, n = 5 each group: ABI-009 IV at 7.5 mg/kg, 2x /wk; rapamycin and everolimus PO at 3 mg/kg/day, 5 days /wk; saline IV at 10 ml/kg, 3x /wk. Body weights, tumor measurements, and clinical signs were recorded 3x /wk for up to 5 wks of treatment. Tumor and blood drug concentrations were also obtained (tumor: D1 1h and 24h, D4 1h, D7; blood: D4 1h, D7). Markers for mTOR pathway activation (pS6, p4EBP1) will also be analyzed. Results: The tumor growth inhibition (TGI) was 69.6% with ABI-009, significantly greater vs. oral rapamycin (TGI 24.3%; p &amp;lt; 0.00001) and oral everolimus (TGI 36.2%; p = 0.0023). The median OS was also significantly longer with ABI-009 (not reached) vs. rapamycin (21 days; p &amp;lt; 0.05) and everolimus (19 days; p &amp;lt; 0.05). There was no statistically significant difference in body weight between the control and treatment groups. Tumor and blood drug concentrations with ABI-009 IV were significantly higher than rapamycin and everolimus at all time points tested. Tumor AUC with ABI-009 IV over 1 week were significantly higher vs. rapamycin (43 fold) and everolimus (12 fold) (p &amp;lt; 0.0001). The higher tumor distribution with ABI-009 IV correlated with greater antitumor activity and longer animal survival. mTOR pathway inhibition in tissues is being assessed. Conclusions: This study demonstrated significantly greater antitumor activity and prolonged survival at clinically relevant doses with ABI-009 vs. equal weekly dosing of oral mTOR inhibitors, rapamycin and everolimus. The increased efficacy of ABI-009 over the oral mTOR inhibitors may be the result of increased drug exposure and tumor penetration. The lack of significant weight loss indicated acceptable toxicity at the doses studied in each group. These findings warrant further study in the clinical setting. Citation Format: Anita N. Schmid, Shawn Hou, Berta Grigorian, Neil P. Desai. Improved tumor penetration, antitumor activity, and survival of ABI-009 (nab-sirolimus) versus oral rapamycin and everolimus and investigation of mTOR pathway inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B08.

Preemptive HLA Antibody Screening Prior to Episodic Transplant Renal Biopsy Enables Early Diagnosis and Therapeutic Response in Asymptomatic Chronically Active Antibody-Related Rejection: A Case Report

Common management of renal transplant recipients includes episodic renal biopsy based on clinical findings such as an increase in proteinuria or serum creatinine. When antibody-related rejection is suspected from the renal biopsy, subsequent testing for donor-specific antibodies (DSAs) is performed. We instead performed preemptive screening of asymptomatic post–renal transplant recipients for DSAs prior to renal biopsy. In this case, a 30-year-old woman with a secondary transplant was positive for 61 anti-HLA antibodies of class I and class II, among which DQ2 was a DSA with a mean fluorescence index of 2039. The patient had a living kidney transplant 9 years earlier. She had never been diagnosed with rejection, her serum creatinine was around 1.0 mg/dL, and her proteinuria was negative. Following the positive DSA result, a renal biopsy was performed, and she was diagnosed as C4d-negative chronic-active antibody-mediated rejection (CAABMR) with a Banff score of cg1b, (g + ptc) ≥ 2, and C4d 0. Intravenous steroid pulse, deoxyspagarin, antithymocyte globulin, rituximab, and oral everolimus were administrated. The treatment resulted in a gradual decrease in the DSA, which became negative 1 year later. The patient’s serum creatinine remains around 1.0 mg/dL, and proteinuria remains negative. Treatments for advanced CAABMR are often expensive and ineffective. Our present case suggests that early detection and treatment through preemptive HLA antibody screening could improve the prognosis of renal transplants.

Abstract 348: ABI-009 (nab-Sirolimus) improves tumor accumulation and antitumor activity over oral mTOR inhibitors

Abstract Background: mTOR pathway has been implicated in cell survival and proliferation and is an attractive target for cancer therapy. ABI-009 (nab-sirolimus) is an injectable nanoparticle form of human albumin-bound sirolimus with a mean particle size of approximately 100 nm developed with a proprietary nanoparticle albumin-bound (nab®) technology. ABI-009 is currently in phase 1 and 2 clinical studies for the treatment of multiple cancer types, including bladder cancer, soft-tissue sarcomas, neuroendocrine tumors, colorectal cancer, glioblastoma, and various childhood cancers, and a registrational phase 2 study for malignant perivascular epithelioid cell carcinoma (PEComa). In nonclinical and clinical studies, ABI-009 demonstrated a PK profile distinct from oral mTOR inhibitors. This study compared the antitumor activity, tissue penetration, and pharmacodynamics of ABI-009 with equal doses of oral mTOR inhibitors at clinically relevant doses in a mouse tumor xenograft model. Methods: Athymic mice bearing subcutaneous UMUC3 bladder cancer xenografts were treated with saline, ABI-009 (IV, 7.5 mg/kg, 2x/wk), sirolimus and everolimus (PO, 3 mg/kg/day, 5 days/wk). Body weights, tumor measurements, and clinical signs were recorded 3x/wk for up to 5 wks. Tumor and blood sirolimus concentrations were also obtained (tumor: D1 1h and 24h, D4 1h, D7; blood: D4 1h, D7). Markers for mTOR pathway activation (pS6, p4EBP1) will also be analyzed. Results: Overall, all treatments were well tolerated with no significant body weight loss in any group. ABI-009 IV resulted in significantly higher sirolimus concentrations in the tumor compared with oral mTOR inhibitors at all time points tested. Tumor AUC with ABI-009 IV over 1 week were significantly higher vs equal weekly dose of oral sirolimus (43 fold) and everolimus (12 fold) (p &amp;lt; 0.0001). The enhanced tumor drug delivery by ABI-009 corresponded with significantly greater tumor growth inhibition (TGI: ABI-009 69.6% vs oral sirolimus 24.3%, p &amp;lt; 0.00001; vs oral everolimus 36.2%, p = 0.0023) and longer animal survival (median OS: ABI-009 not reached vs oral sirolimus 21 days, p &amp;lt; 0.05; vs oral everolimus 19 days, p &amp;lt; 0.05). mTOR pathway inhibition in tissues is being assessed. Conclusions: Compared with equal weekly dose of oral mTOR inhibitors, ABI-009 at clinically relevant dose of administered IV demonstrated significantly greater tumor drug delivery, stronger antitumor activity, and prolonged animal survival. These advantages observed in this nonclinical study support the clinical investigation of ABI-009 in numerous oncology indications. Citation Format: Shihe Hou, Anita Schmid, Neil Desai. ABI-009 (nab-Sirolimus) improves tumor accumulation and antitumor activity over oral mTOR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 348.

Abstract CT067: A Phase I study of Fosbretabulin in combination with everolimus in neuroendocrine tumors (Grades 1-3) that have progressed after at least one prior regimen for metastatic disease

Abstract Background: Based on the SEER database, the incidence of gastroenteropancreatic neuroendocrine tumors (GEPNETs) has risen six-fold in the last four decades. At present, more than 150,000 GEPNET patients exist in the United States. Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs) and has shown activity as a single agent in ovarian cancer and GEPNETs. Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D) and safety data in metastatic GEPNET patients was conducted. Method: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance with the treatment regimen. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients that include increased abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. Only one patient had radiologic progression at the first q 3 monthly CT scan of chest, abdomen, and pelvis. A detailed table with all grade toxicities will be presented at the meeting. Conclusion: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. ClinicalTrials.gov Identifier: NCT0301429 Citation Format: Aman Chauhan, Susanne Arnold, John Wu, Stacey Slone, Emily Dressler, Heather Flynn, Val Adams, Heidi Weiss, Lowell Anthony. A Phase I study of Fosbretabulin in combination with everolimus in neuroendocrine tumors (Grades 1-3) that have progressed after at least one prior regimen for metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT067.

PS1240 EVEROLIMUS WITH DHAP (DEXAMETHASONE, HIGH‐DOSE ARAC, CISPLATINUM) IN PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA: A RANDOMIZED, PLACEBO‐CONTROLLED PHASE I/II TRIAL (HD‐R3I)

Background:Induction chemotherapy followed by BEAM high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSC transplant) is standard of care for transplant‐eligible patients with relapsed or refractory classical Hodgkin lymphoma (rrHL). However, approx. 50% of patients relapse and therefore, this strategy must be improved.Aims:As response to induction therapy is predictive of the outcome after HDCT, this trial aimed at improving the response to induction therapy by adding oral everolimus to time‐intensified standard DHAP (Ever‐DHAP).Methods:We included patients with histologically confirmed rrHL aged 18–60 years in this phase I/II trial. Dosage of everolimus was pre‐determined in the phase I part with 10 mg/day in parallel to DHAP for 14 days within each of two cycles. The phase II part started as a randomized controlled trial comparing 50 patients in the everolimus group to 50 patients in a placebo group. The primary endpoint of the phase II part was the CT‐based complete remission (CR‐) rate after two cycles of Ever‐DHAP. This CR‐rate would be expected to be ≥ 40% if adding everolimus was effective. Secondary endpoints of the trial were PET‐based CR‐rate after two cycles of induction, progression‐free and overall survival as well as time to recovery, adverse events, duration of induction therapy, discontinuation rates and rates of successful PBSC collection. The trial was registered at ClinicalTrials.gov with ID NCT01453504.Results:From 7/2014 to 3/2018 we recruited a total of 59 patients in the phase II part. Because of poor recruitment the placebo group was closed in 9/2015 after 9 patients were randomized. Of 50 patients in the everolimus group 2 did not start therapy; 3 additional patients discontinued Ever‐DHAP because of toxicity. Nine patients (20%) and 13 patients (28%) needed dose reductions in the first and second cycle of Ever‐DHAP, respectively. A delayed recovery &gt;14 days was observed in 2 patients (5%) in cycle 1 and in 6 patients (13%) in cycle 2. CTCAE grade IV toxicities occurred in 39 patients (95%) and 27 patients (75%) in cycle 1 and 2, respectively. All grade IV‐toxicities were hematological toxicities. Apheresis needed 1 day in 35 (80%) of the Ever‐DHAP patients and 2 days in 8 patients (18%). PBSC collection was successful in 38/42 documented patients receiving Ever‐DHAP (91%). After two cycles of therapy we observed a CT‐based CR in 12/45 patients of the everolimus group (27%) and in 2/9 patients of the placebo group (22%). A PET‐based CR was achieved by 22/39 patients of the everolimus group (56%) and by 2/8 patients of the placebo group (25%). In the everolimus group 2 patients had progressive disease (4%) and 3 died (7%, not related to Ever‐DHAP). Final results and additional analyses will be presented.Summary/Conclusion:With a CT‐based CR‐rate of 27% after two cycles of everolimus plus DHAP (PET‐based CR‐rate 56%), the trial did not meet the primary endpoint. Adding everolimus to time‐intensified DHAP is feasible, however, everolimus plus DHAP failed to show an improved efficacy.

Clinical efficacy and toxicity data on phase I study of fosbretabulin in combination with everolimus in neuroendocrine tumors.

4114 Background: Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs). Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D), safety data and early clinical efficacy in metastatic GEPNET patients was conducted. Methods: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. RECIST 1.1 was used to evaluate radiological responses at 3 month. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had &gt; 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Conclusions: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Clinical trial information: NCT0301429.

Induction Therapy with Everolimus in Combination with DHAP (Dexamethasone, High-Dose AraC, Cisplatinum) in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma: A Randomized, Placebo-Controlled Phase I/II Trial (HD-R3i)

Introduction: Induction chemotherapy followed by BEAM high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSC transplant) is standard of care for transplant-eligible patients with relapsed or refractory classical Hodgkin lymphoma (rrHL). However, approx. 50% of patients relapse and therefore, this strategy must be improved. As response to induction therapy is predictive of the outcome after HDCT, this trial aimed at improving the response to induction therapy by adding oral everolimus to time-intensified standard DHAP (Ever-DHAP).Methods: We included patients with histologically confirmed rrHL aged 18-60 years in this phase I/II trial. Dosage of everolimus was pre-determined in the phase I part with 10 mg/day given parallel to DHAP for 14 days within each of two cycles. The phase II part started as a randomized controlled trial comparing 50 patients in the everolimus group to 50 patients in a placebo group. The primary endpoint of the phase II part was the CT-based complete remission (CR-) rate after two cycles of Ever-DHAP. This CR-rate would be expected to be ≥ 40% if adding everolimus was effective. Secondary efficacy endpoints of the trial were PET-based CR-rate after two cycles of induction, progression-free and overall survival. Secondary feasibility endpoints were time to recovery, CTC-based adverse events, duration of induction therapy, discontinuation rates and the rates of successful PBSC collection. The trial was registered at ClinicalTrials.gov with ID NCT01453504.Results: From 7/2014 to 3/2018 we recruited a total of 59 patients in the phase II part. Because of poor recruitment the placebo group was closed in 9/2015 after 9 patients were randomized. These patients are analyzed in a descriptive way only. Of 50 patients in the everolimus group two were not evaluable because of retracting consent and not starting therapy; three additional patients discontinued Ever-DHAP because of toxicity. PBSC collection was successful in 37/39 documented patients receiving Ever-DHAP (95%). After two cycles of therapy we observed a CT-based CR in 12/45 patients of the everolimus group (27%) and in 2/9 patients of the placebo group (22%). A PET-based CR was achieved by 19/38 patients of the everolimus group (50%) and by 4/5 patients of the placebo group. In the everolimus group two patients had refractory disease (4%) and two died (4%), 3 and 4 months after starting but not related to Ever-DHAP. Final results and additional analyses will be presented.Conclusions: Adding everolimus to time-intensified DHAP is feasible, however, the Ever-DHAP regimen failed to show an improved efficacy. Disclosuresvon Tresckow:Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD: Honoraria, Other: Travel support, Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Viardot:Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

Continuous low-dose everolimus shrinkage tuberous sclerosis complex-associated renal angiomyolipoma: a 48-month follow-up study

Tuberous sclerosis complex (TSC) is a rare disease that causes multisystem benign neoplasm, induced by dysregulation of the mammalian target of the rapamycin pathway (mTOR). This study aimed to examine...

Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies.

Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer). The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. clinicaltrials.gov Identifier: NCT01698918.

Cost-effectiveness of nivolumab in patients with advanced renal cell carcinoma treated in the United States

BackgroundWe evaluated the cost-effectiveness of nivolumab versus everolimus in patients with advanced renal cell carcinoma (RCC) from a US payer perspective.MethodsA partitioned survival model consisting of three health states, progression-free survival (PFS), progressive disease, and death, was developed to evaluate the cost-effectiveness of intravenous nivolumab versus oral everolimus over a lifetime. The proportion of patients in each state was calculated based on parametric distributions fitted to PFS and overall survival (OS) data from CheckMate 025 (N = 821), a large randomized phase 3 trial of nivolumab versus everolimus for advanced RCC. Health state utility data were derived from CheckMate 025 EQ-5D data. Scenario analyses and deterministic and probabilistic sensitivity analyses assessed the impact of uncertainty in model inputs on outcomes.ResultsOver a 25-year lifetime horizon, treatment with nivolumab resulted in a gain of 0.64 quality-adjusted life-years (QALYs) versus everolimus. Nivolumab had greater total costs versus everolimus ($US197,089 vs. $US163,902), mainly due to higher acquisition costs. The incremental cost-utility ratio (ICUR), a measure of incremental costs divided by incremental QALYs, was $US51,714 per QALY gained for nivolumab versus everolimus, and an incremental cost-effectiveness ratio was $US44,576 per life-year gained for nivolumab versus everolimus. In sensitivity analyses, average body weight had the greatest impact on the ICUR for nivolumab versus everolimus (base case $US51,714; range $US8863–$US94,566). At a $US150,000 willingness-to-pay (WTP) threshold, nivolumab had a 91.7% probability of being cost-effective versus everolimus.ConclusionsIn the United States, at a WTP threshold of $US150,000 per QALY, nivolumab was found to be cost-effective. Key drivers of cost-effectiveness were survival inputs for OS and the average weight of patients; the latter directly affects nivolumab drug acquisition cost.

Prophylactic Oral Management of a Patient with Tuberous Sclerosis Taking Oral Everolimus

Prophylactic Oral Management of a Patient with Tuberous Sclerosis Taking Oral Everolimus

Evaluation of the Effect of Everolimus on Retinal Pigment Epithelial Cells and Experimental Proliferative Vitreoretinopathy

ABSTRACTPurpose: Failure of retinal detachment surgery is most commonly due to the development of proliferative vitreoretinopathy (PVR). Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), and is available as oral tablets. In this study, we investigated the effect of everolimus on retinal pigment epithelial cells and modification of the severity of experimental PVR.Methods: In our in vitro studies, primary culture of retinal pigment epithelium (RPE) cells was obtained from pigmented Rex rabbits. Cell proliferation was assayed with the tetrazolium dye cytotoxicity test, and cell migration assay was performed in 24-well transwell units with 8-μm filters. In the in vivo study, pigmented Rex rabbits weighing between 2 and 2.5 kg were used. Each rabbit eye underwent gas compression; one week later, 5 × 104 RPE cells were injected into the vitreous cavity to induce PVR, and each eye was graded with indirect ophthalmoscopy on days 1, 3, 7, 14, 21, and 28. The rabbits were administered everolimus (0.5 mg/day orally) from the day of PVR induction. Total proteins extracted from RPE cells and dissected retinal samples were processed for Western blotting analysis of mTOR and ribosomal protein S6 (RPS6).Results: The in vitro studies showed that everolimus significantly inhibited the proliferation of RPE cells at 0.1 μg/ml; additionally, at 10 μg/ml, it suppressed the migration of RPE cells and significantly suppressed the expression of mTOR and RPS6 in RPE cells. The in vivo study did not show any benefit of oral everolimus (0.5 mg/day) in suppressing experimental PVR. Thus, everolimus significantly suppressed the expression of mTOR and RPS6 in PVR.Conclusions: Everolimus suppressed the proliferation and migration of RPE cells in vitro. Oral everolimus (0.5 mg/day) suppressed the expression of mTOR and RPS6 in the retina, but showed no effect in suppressing experimental PVR.