Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Background: Myeloablative conditioning can be given safely to older patients by administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen. (Popat, et al Lancet Haematology 2018). This longer conditioning regimen duration allows the addition of oral targeted agents like sorafenib, which may be synergistic with conditioning chemotherapy and thus further improve disease control. Therefore, we added sorafenib to fludarabine and fractionated busulfan regimen (f-bu) in a phase 1 dose-finding trial studying 4 different doses of sorafenib with f-bu (NCT03247088). Here we report the results of this trial. Methods: Between 3/2018 and 6/2021, 24 patients with AML aged 18 to 70 years with adequate organ function and 8/8-HLA matched related or unrelated donors were enrolled prospectively. The dose of sorafenib was varied among the four values 200, 400, 600, and 800 mg administered from day -24 to -5. Dose-limiting toxicity (DLT) was defined as grade 3 or higher regimen-related non-hematologic, non-infectious, non-GVHD toxicity occurring between day -24 and day 3. The Bayesian Model Averaging Continual Reassessment Method (BMA-CRM) with target DLT probability 0.30 was used to choose doses for successive cohorts of 3 patients. The first cohort was treated at the lowest sorafenib dose 200, with all successive cohorts' doses chosen adaptively by the BMA-CRM. The doses and schedules of busulfan and fludarabine were fixed, with f-Bu dose targeting an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over 3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered on days -20 and -13 on an outpatient basis. The last four Bu doses were calculated to give a total course AUC of 20,000 ± 12% μmol.min and were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Recipients of unrelated donor grafts also received MMF. All patients were eligible to receive post-transplant maintenance sorafenib after engraftment. Results: The median age was 52 years (range, 30-70). Disease status was CR in 16 (66.6%) patients, CRi in 5 (20.8%), and advanced in 3 (12.5%). Adverse risk karyotype was present in 10 (41.7%) patients. MRD was present in 13 (54.2%). 9 (38%) had mutated flt3. The donor was unrelated in 14 (58%), and peripheral blood stem cells were the graft source in 21(87.5%). Due to the absence of DLTs, the BMA-CRM assigned 200mg, 400mg, 600mg, and 800mg of sorafenib, respectively, to the first 4 cohorts, and the next 4 cohorts were given 800mg. Only 2 dose-limiting skin toxicities were seen, one in cohort 3 with 600mg of sorafenib and the second in cohort 6 with 800mg of sorafenib. 800mg was the final recommended phase 2 dose. The median follow-up in 20 surviving patients was 7.6 months and 1-year progression free survival was 89% (95% CI 75-100%). Other outcomes are summarized in Table 1. Conclusion: Sorafenib can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising, with an 89% PFS at 1 year of follow up. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Bayer: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GSK: Other: Scientific Advisory Board ; Virogin: Other: Scientific Advisory Board ; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding; Pharmacyclics: Other: Educational grant, Research Funding; Caribou: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Biolline: Research Funding; Amgen: Research Funding; Oncopeptides: Other: Advisory Board; NexImmune: Research Funding; Angiocrine: Research Funding; Janssen: Research Funding. Daver: Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Novimmune: Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Ravandi: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Shpall: Magenta: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Magenta: Honoraria; Adaptimmune: Consultancy; Novartis: Consultancy; Navan: Consultancy; Novartis: Honoraria; Takeda: Patents & Royalties; Affimed: Patents & Royalties; Axio: Consultancy. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding.

Post-Transplant Cyclophosphamide Versus Tacrolimus and Methotrexate to Prevent Graft-Versus-Host Disease in Recipients of Matched Donor Transplantation: Comparison of Sequential Cohorts in a Prospective Trial

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than our "standard" four-day fludarabine-busulfan (Flu-Bu) regimen. (Popat et al Lancet Haematology 2018). To further improve outcomes of this fractionated (f-Bu) regimen in patients undergoing matched donor hematopoietic cell transplantation (HCT), we added cladribine (Clad) to f-Bu-Flu regimen in a prospective clinical trial (NCT02250937). GVHD prophylaxis was tacrolimus and methotrexate (Tac/MTX). After enrolling the first 29 patients, the study was amended and GVHD prophylaxis was changed to post-transplant cyclophosphamide (PTCy) and tacrolimus for the next 53 patients based on very promising data observed in patients undergoing haploidentical transplantation. We hypothesized that PTCy will reduce GVHD and non-relapse mortality (NRM), thus improving survival in patients undergoing HCT from a matched donor. In this study, we compared these two sequential cohorts with reference to GVHD prophylaxis. Methods: Between 2/2015 and 12/2018, 82 patients with AML or MDS, 18-70 years of age, with adequate organ function and 8/8-HLA matched related (n=38%) or unrelated (62%) donors were enrolled. The conditioning regimen was f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over a period of 2-3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered either consecutively (days -13 and -12) or with further fractionation, one week apart (days -20 and -13) on outpatient basis. Then, inpatient fludarabine 10 mg/m 2, and cladribine 10 mg/m 2 were given followed by Bu on days -6 to -3. GVHD prophylaxis was Tac/Mtx (n=29) or PTCy 50mg/kg on days 3 and 4 followed by tacrolimus from day 5 (n=53). Results: Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 59 (range, 18-70) and 61 (range, 24-70) years (P=0.20); 49% and 59% had primary induction failure at HCT (P=0.58); High or very-high disease risk index was present in 40% and 41%, (P=0.40); Comorbidity index score >3 was present in 42% and 40% (P=0.24); Donor was a sibling in 34% and 45% (P=0.35), and peripheral blood graft was used in 81% and 76% (P=0.58), respectively in PTCy and Tac/Mtx cohorts. Median follow up was 42.7 months. In the PTCy and Tac/Mtx cohorts, at 3-years overall survival was 69% vs 38% (P=0.0004), NRM was 8% vs 28% (P=0.009) [Table 1, Figure 1], incidence of grade 3-4 acute GVHD at day 100 was 4% vs 17% (P=0.04), and chronic GVHD was 21% vs 28% at 3 years (P=0.53). Median time to neutrophil engraftment was prolonged by 3 days with PTCy (15 vs 12 days; P<0.0001). Full donor chimerism at day 30 was noted in 81% vs 28%, in the PTCy and Tac/Mtx cohorts respectively, (P=0.005). The toxicity profile was similar except neutropenic fever (likely cytokine-related) was higher in PTCy group (60% v/s 24%, P=0.002). Likewise, the incidence of hemorrhagic cystitis was higher in the PTCy group (36% vs 14%, p-0.04). Most of the later events were grade 1 or 2. Conclusion: Compared with Tac/Mtx, PTCy reduced severe acute GVHD and NRM, and improved survival in AML/MDS patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning and transplant from a matched donor. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Navan Technologies: Other: Scientific Advisory Board; Caribou: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Pharmacyclics: Other: Educational grant, Research Funding; Bayer: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding; Virogin: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board . Qazilbash: Janssen: Research Funding; Biolline: Research Funding; Oncopeptides: Other: Advisory Board; NexImmune: Research Funding; Angiocrine: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board. Kadia: Liberum: Consultancy; AstraZeneca: Other; Sanofi-Aventis: Consultancy; Genfleet: Other; Pulmotech: Other; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Astellas: Other; Jazz: Consultancy; Aglos: Consultancy; Ascentage: Other; Cellonkos: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau. Kantarjian: BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Precision Biosciences: Honoraria; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; Immunogen: Research Funding; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; NOVA Research: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Shpall: Adaptimmune: Consultancy; Magenta: Consultancy; Novartis: Honoraria; Affimed: Patents & Royalties; Navan: Consultancy; Magenta: Honoraria; Novartis: Consultancy; Takeda: Patents & Royalties; Bayer HealthCare Pharmaceuticals: Honoraria; Axio: Consultancy.

Incidence and Outcomes of Toxoplasma Reactivation in Patients with Hematologic Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Toxoplasmosis is a rare complication of allogeneic hematopoietic stem cell transplantation (AlloHSCT) usually through reactivation in a previously seropositive recipient, and is associated with mortality as high as 60% (Paccoud et al. BMT 2020). Seroprevalence in the population varies ranging from 5% or lower in North America to over 50% in France. Risk factors for reactivation include immune suppression, seronegative donors, cord blood grafts, and lack of adequate antimicrobial prophylaxis (Robin et al. BBMT 2019). We sought to evaluate the outcomes of patients with toxoplasma reactivation after undergoing AlloHSCT in the modern era. Methods: This study was a retrospective single center analysis of all patients who underwent AlloHSCT between January 2012 and June 2021 at our center. Primary objectives were to assess the incidence of toxoplasma reactivation and the effects of reactivation on survival. Patients were identified in the department database and relevant demographic and clinical data were extracted. Results of toxoplasma testing [IgG serology and polymerase chain reaction (PCR)] were collected and verified by manual chart review. Patients with negative toxoplasma serology and/or missing serology or PCR data were excluded from analysis. Reactivation was defined as positive PCR in a seropositive patient. Toxoplasma reactivation associations were assessed by logistic regression models. Overall Survival (OS) was estimated using the Kaplan-Meier method and differences compared using the log-rank test. Cox proportional hazards models were used for survival associations. Cumulative incidence of non-relapse mortality (NRM) was determined using competing risks method. This study was approved by the institutional board review (IRB) committee at our center. Results: A total of 370 patients who received AlloHSCT and had a positive toxoplasma IgG were identified. Fifty-two patients had missing toxoplasma PCR and 4 did not meet eligibility criteria and were excluded. Twenty-two (7%) out of the remaining 314 seropositive patients experienced toxoplasma reactivation as confirmed by positive PCR. Median age in the reactivation group was 55 years, and patients were mostly white males with myeloid neoplasms who underwent AlloHSCT in first complete remission using nonmyeloablative conditioning and a matched unrelated donor (table 1). No significant differences in baseline characteristics were seen between the seropositive only and the reactivation groups, except for antimicrobial prophylaxis use (P <0.001). Fifty-nine percent of patients (13 out of 22) in the reactivation group were on toxoplasma prophylaxis compared to 93% (273 out of 292) in the seropositive patients without reactivation. Sixteen out of the 22 (73%) patients with reactivation developed clinical symptoms while 6 (27%) had asymptomatic reactivation. Antimicrobial prophylaxis only with either pentamidine, atovaquone, trimethoprim/sulfamethoxazole but not dapsone, was associated with lower risk of developing reactivation (table 2). With a median follow up of 15.4 months (0.3-98.9), the median OS was 9.6 months in patients with reactivation versus 58.5 months in seropositive patients without reactivation [HR, 2.06; (95% CI, 1.21 to 3.52); P=0.008] (figure 1). NRM was also higher in the reactivation group [HR, 2.61; (95% CI, 1.34 to 5.11); P=0.005] (figure 2). Specifically, day 100, 1-year and 2-year NRM were higher in the reactivation group versus (vs) seropositive patients (36% vs 10%, 41% vs 18%, and 47% vs 20% respectively). Toxoplasma reactivation was associated with worse OS and increased NRM in univariable analysis however this did not reach statistical significance in multivariable analysis. Conclusion: Toxoplasma reactivation in seropositive AlloSCT patients remains low at our center at around 7%. Toxoplasma reactivation is associated with worse outcomes after AlloHSCT and reactivation could be mitigated by improved compliance with antimicrobial prophylaxis. Figure 1 Figure 1. Disclosures Mehta: Kadmon: Research Funding; Incyte: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding. Shah: Amgen: Consultancy; Bluebird Bio: Research Funding; BMS/Celgene: Research Funding; CareDx: Consultancy; CSL Behring: Consultancy; GSK: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Karyopharm: Consultancy; Kite: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding; Takeda: Other: License agreement and research agreement, Patents & Royalties; GSK: Other: Scientific Advisory Board ; Caribou: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; Virogin: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board . Qazilbash: Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Angiocrine: Research Funding; Amgen: Research Funding; Oncopeptides: Other: Advisory Board; Biolline: Research Funding; NexImmune: Research Funding. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Shpall: Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Magenta: Honoraria; Affimed: Patents & Royalties; Novartis: Consultancy; Magenta: Consultancy; Adaptimmune: Consultancy; Axio: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria. Ahmed: Seagen: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding.

Optimizing Myeloablative Fractionated Busulfan, Fludarabine and Thiotepa Regimen: Results of Two Parallel Cohorts in a Phase 2 Prospective Clinical Trial

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan (Bu) over a longer period (fractionated (f)-Bu) with fludarabine (Flu) than the standard four-day regimen. (Popat et al Lancet Haematology 2018). We added thiotepa (Thio) to this f-Bu/Flu regimen in patients with haploidentical (haplo) donors to promote engraftment and to reduce relapse. With encouraging results, Thio was then added in matched unrelated (MUD) and sibling (MSD) donor recipients also. However, the optimal doses of Thio and Bu were undefined. To further optimize the regimen, we tested two different f-Bu/Flu/Thio regimens in parallel prospective cohorts: (a) higher dose Bu with lower dose Thio, and (b) lower dose Bu with a higher dose Thio. Patients were enrolled on these cohorts based on age and co-morbidity index (HCT-CI). Herein, we report on the safety and preliminary efficacy of these regimens (NCT02861417). Methods: Patients <60 years with HCT-CI <3, or >60 years with HCT-CI <2 received IV f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min with Thio 2.5 mg/kg (Bu20K/Thio2.5; Cohort 1). Patients <60 years with an HCT-CI >3, or >60 years with HCT-CI >2, or >70 years irrespective of HCT-CI received f-BU to target AUC of 16,000 with Thio 5mg/kg (Bu16K/Thio5; Cohort 2). In both cohorts, the first two doses of Bu (80 mg/m2 IV each) were given as outpatient on days -20 and -13. The last four Bu doses were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. Thio was given on day -7. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4, tacrolimus and MMF. Results: 66 patients were enrolled - 25 in cohort 1 and 41 in cohort 2, with a median age 60 years (range, 22-69) vs 62 years (range, 30-74), respectively (P=0.14). Diagnoses were AML/MDS (64% vs 54%), CML/MPD (24% vs 22%), ALL (12% vs 22%) and 1 myeloma; P=0.24. Most had intermediate disease risk index (80% vs 73%, P=0.57); median HCT-CI was 1 (range, 0-6) vs 3 (range, 0-9); P<0.0001. Donor was haplo (60% vs 19%), MUD (24% vs 54%) or MSD (16% vs 27%); P=0.002; BM graft was used in 56% vs 27%; p=0.02, respectively, in cohorts 1 and 2. The median follow-up among survivors was 18.7 months. Primary graft failure occurred in 1 patient in cohort 1 and none in cohort 2. The median time to neutrophil engraftment was 17.5 days (range, 14-26) vs 18 days (range, 12-26); P=0.12, respectively; platelet engraftment > 20K was 30 days in both groups; P=0.75. Median donor chimerism at day 30 was 100% in both groups. The incidence of acute GVHD grade III-IV was 4% vs 5%; P=0.88 at day 100; extensive chronic GVHD at 1 year was 13% vs 10%; P=0.83. At 1-year overall survival was 72% vs 78%; P=0.95; relapse was 12% each; non-relapse mortality was 20% vs 17%; P=0.97 [Table 1, Fig 1]. Common grade >3 toxicities were neutropenic fever (64% vs 42%; P=0.13), bacterial infection (44% vs 34%; P=0.45), nausea (12% vs 2%; P=0.15), mucositis (8% vs 5%; P=0.63), pneumonitis (12% vs 7%; P=0.67), hemorrhagic cystitis (8% vs 5%) and sinusoidal obstructive syndrome (8% vs 2.4%). Conclusion: In this population of older patients and/or high co-morbidities, both myeloablative regimens with f-Bu/Flu with thiotepa and PTCy were well tolerated and led to low NRM, low risk of relapse and encouraging survival. Although both regimens led to similar outcomes, the f-Bu/Flu/Thio regimen with Bu16K and thiotepa 5 mg/kg dose may be preferred as this was used in patients who were older and/or had high co-morbidities. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Caribou: Other: Scientific Advisory Board; Virogin: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Bayer: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties; Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding; Biolline: Research Funding. Shpall: Affimed: Patents & Royalties; Adaptimmune: Consultancy; Novartis: Consultancy; Magenta: Consultancy; Magenta: Honoraria; Axio: Consultancy; Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria.

RAHASIA DAGANG SEBAGAI SALAH SATU PERLINDUNGAN HAK KEKAYAAN INTELEKTUAL DARI HASIL PENELITIAN HIBAH SEKOLAH VOKASI IPB TAHUN 2020

ABSTRACTThe Research results as the result of thoughts from researchers or lecturers need to be protected from harmful fraudulent actions. Protection of the research results also provides motivation for researchers or lecturers to continue working. One form of protection provided is the protection of Intellectual Property Rights (IPR). Various forms of IPR can be utilized as long as it meets the criteria of the IPR field. The purpose of this study was to determine the form of protection of trade secrets for the Research Results. In addition, to find out the efforts that need to be made to fulfill trade secret requirements. This research is normative legal research with a qualitative approach. The Research results of The College of Vocational Studies IPB University’s lecturer who research grants in 2020 that can be given protection as trade secrets. The Research results can be protected as trade secrets if they meet the criteria that the research results are confidential information in the field of technology and/or business, have economic value and are kept confidential by researchers or lecturers. To maintain the confidentiality of the research results, efforts were made such as providing a password, writing the word "Secret", storing documents in a safe place, making a confidentiality agreement and inserting a confidentiality clause in the license agreement.

Legal Protection Effort towards Mark Owner from the Share-in Jar Cosmetic Trade

This study aims to analyze and understand the legal protection towards the mark owner from the share-in jar cosmetic trade and the legal consequences for business actors who do share-in jar cosmetic trade. The type of legal research used in this study is a normative juridical legal research method. The data collection in this study was conducted through a literature study from the laws and regulations, journals, research results, and books. The data analysis used in this research is the descriptive analysis method. The results of the study show that the legal protection towards the mark owner from the share-in jar cosmetic trade can be carried out through preventive and repressive legal protection efforts. Legal protection efforts are preventively carried out by registering the mark to get legal protection as a legal mark owner. Repressive legal protection efforts for trademarks can be done by litigation dispute resolution and non-litigation dispute resolution. The legal consequences for business actors who do share-in jar cosmetic trade are compensate for damages and/or ceasing all acts related to mark use. Therefore, it is recommended to the mark owner to provide cosmetics with trial or sample sizes. In this case, so that consumers try first about their compatibility with these cosmetics. On the other hand, business actors doing share-in cosmetic jar trade must make a license agreement with the mark owner. Furthermore, the government needs to include criteria for violations of right on mark in laws and regulations. This is purpose to increase legal protection towards the mark owner from the share-in jar cosmetic trade in the future.

NECESSITY FOR COMMERCIALIZATION OF INTELLECTUAL PROPERTY AND ITS CONTRACTUAL LEGAL FORMS

The article analyzes the methods and forms of commercialization of the results of intellectual activity. Possibilities of solvingthe problem of commercialization of intellectual property as an independent direction of entrepreneurial activity in relation to industrial and scientific organizations are proposed. Describes the main contractual relationship in the commercialization of intellectual property, as well as the conditions for concluding a license agreement and successful sale through it. Other legal forms are also considered. The development of this sector in our country is also analyzed. The article analyzes the methods and forms of commercialization of the results of intellectual activity````

Inventor-Entrepreneurs: Patents and Patent Licensing in the Early Republic

Independent inventors have limited routes to secure financial returns on the time and capital they invest to develop and realize a new idea. Research into two centuries of inventors has identified their options as licensing patents once they are issued, selling inventions (and patents) to existing companies, forging consulting arrangements with operating firms, or raising funds and starting a business. This article explores patent licensing as an entrepreneurial approach using a case study of the largely unknown licensing program undertaken by Samuel Hopkins after receiving the first U. S. patent. A license agreement signed between Hopkins and Eli Cogswell, a potash manufacturer in Vermont, offers a case study of how an inventor-entrepreneur worked in the early American republic. It also provides insights into the links between intellectual property and entrepreneurship, the mindset of inventor-entrepreneurs, and the challenges of bringing a new technology to market at a foundational moment in U. S. history.

Exercise of economic intellectual property rights to wellknown trademarks.

The exercise of intellectual property rights is the realization bythe subject of intellectual property rights of moral and / or economic intellectual propertyrights, the content of which in relation to certain objects of intellectual propertyrights is determined by the Civil Code of Ukraine and other laws. The exercise of intellectualproperty rights is also the realization of economic intellectual propertyrights by other persons on the basis of the permission of the person who has the rightto allow the use of such object of intellectual property rights.The Law «On Amendments to Certain Legislative Acts of Ukraine ConcerningStrengthening the Protection and Protection of Rights to Trademarks and IndustrialDesigns and Counteraction to Patent Trolling» (which entered into force on August16, 2020) has аmended the Law of Ukraine «On Protection of Rights to Marks forGoods and Services» (hereinafter — the Law). The amendments have removed theprovision that a well-known trademark receives the same legal protection as thetrademark for which the certificate is issued. Such changes have created a gap in thelegislation in part of defining what does the exercising of intellectual property rightsto well-known trademarks include.In this connection the following questions arise: (1) can the right to use a wellknownmark (as well as the mark for which the certificate is issued) be the subject ofa license agreement, a commercial concession agreement; (2) whether it is possible tocontribute economic intellectual property rights to a well-known trademark to the authorizedcapital of a legal entity; (3) whether it is possible to transfer such rights onthe basis of an agreement on the transfer of economic intellectual property rights or to provide as collateral. We believe that these issues should be addressed through theadoption of appropriate amendments to Art. 25 of the Law.In our opinion, the right to use a well-known trademark may be the subject of licenseagreements and commercial concession agreements. According to the currentlegislation of Ukraine, it is impossible to transfer economic intellectual propertyrights to a well-known mark to another person.It is expedient to make changes to Art. 25 of the Law, which would provide necessityof creation and functioning of the State register of Ukraine of well-knowntrade marks.The introduction of the proposed amendments to the legislation of Ukraine in thefield of economic intellectual property will help to improve the relevant legal relationsrelated to the exercise of property rights to well-known trademarks.Key words: trademark, well-known trademark, economic intellectual propertyrights, exercise of economic intellectual property rights, assignment (transfer) of economicrights of intellectual property

Economic and legal prospects of activation of science parks activity on the way to neoeconomics

Butnik-Siverskiy О. Economic and legal prospects of activation of science parks activity on the way to neoeconomics. The author researches and substantiates by generalizing the scientific points of view improving the legal regulation of the created science parks on the initiative of higher education institutionsand / or research institutions, taking into account the economic and legal prospect of intensifying their activities. National and foreign experience of science parks activity is considered. The content of using the founding agreement on creation of a science park and the agreement on partnership of business entities witha science park is provided. Problems that have not yet been resolved in the process of creating science parks and using innovative developments are noted. The classical content of entrepreneurship in innovation is provided and considered from the standpoint of clarifying the content of the innovation structure, which is based on the commercialization of intellectual property rights by their types, which is a part of the intellectual capital cycle with a corresponding effective result. There is substantiated the procedure of formation of the statutory capital of the science park, to which higher educational institutions and / or scientific institutions cannot use intellectual property rights to the objects, created at the expense of budgetary funds, but can only under the conclusion of a license agreement with business entity, having non-state and state form of ownership as transferred assets, which does not require the alienation of the object of intellectual property rights as part of intangible assets. It is proposed to use the target budget funds as the initial start-upcapital, which is provided on reverse terms to the state budget in case of closure (liquidation) of the science park by the decision of the founders or on the basis of a court decision. Alternatively, in the absence of target budget funds, it is proposed as a source of money to contribute to the statutory capital of the science park as a start-up capital to send part of the special fund of the state budget. It is justified the creation of a technology transfer office, which will be a structural unit of higher education institutions and / or research institutions, which will deal with the process of filing and reviewing a patent application and subsequent licensing. It isnoted that the science park can be the founder (co-founder) of small innovative enterprises and enter into partnership agreements with them for the implementation of certain innovative projects.Keywords: intellectual and innovation environment, science park, founding agreement, statutory capital, intellectual property rights, license agreement, legal status