Teaching adolescents about changing bodies: Randomized controlled trial of an Internet puberty education and body dissatisfaction prevention program

This study tested the efficacy of an Internet-based prevention program, Trouble on the Tightrope: In Search of Skateboard Sam, on pubertal knowledge, body esteem, and self-esteem. One hundred ninety participants (mean age 11.6 years) were randomized to either an intervention or attention placebo control condition and were assessed at baseline, after 3 Internet-based sessions, and at 3-month follow-up. Although the primary hypotheses were not supported, exploratory moderator analyses indicated that the intervention was beneficial for select students. Specifically, pubertal status moderated the effects on weight-related body esteem and several domains of self-esteem, resulting in positive effects for participants in the intervention group who had begun puberty. Gender differences were found on self-esteem subscales, indicating more robust effects for girls than boys. Tailored Internet programs based on personal characteristics such as gender and pubertal status may be a fruitful area for future research with adolescents

ACTR-52. PHASE 1 STUDY OF FT-2102, AN INHIBITOR OF MUTANT IDH1, IN PATIENTS WITH RELAPSED/REFRACTORY IDH1 MUTANT GLIOMAS: PRELIMINARY SAFETY AND CLINICAL ACTIVITY

Abstract BACKGROUND Isocitrate dehydrogenase mutations (mIDH1) are present in > 70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. FT-2102 is a potent, brain penetrant (Kpuu=0.4 in intact rodent) and selective inhibitor of mIDH1. METHODS Patients with advanced relapsed/refractory mIDH1 gliomas received FT-2102 150mg BID, orally. Following a dose confirmation 3 + 3 Phase 1b, 20 pts enrolled in a Simon 2 stage Phase 2 study (NCT: 03684811). RESULTS As of 01-May-2019, 23 with glioma (Grade at enrollment: II/III/IV; n=4, n=12 & n=7 respectively) were treated with FT-2102 monotherapy. The patient’s median age was 46 years (range: 23–64) & 61% were male. Median number of prior treatments was 2 (range 1–5) and 78% had received prior temozolomide. mIDH1 status was locally determined (IHC, NGS or PCR): R132H, R132L, R132C & unspecified (n=15, n=2, n=1 & n=5). Median duration of FT-2102 treatment to date was 40 days (range: 26–177), with 1 patient discontinuing (disease progression). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in >10% of were: fatigue (22%), nausea (17%), diarrhea (17%), ALT increase (13%), headache (13%) and AST increase (13%), none leading to treatment discontinuation. None experienced an adverse event of QTcF prolongation or skin hyperpigmentation. There were no protocol-defined DLT’s. To date, six had at least 1 evaluable post-baseline response assessment, with best response of 1 PR (unconfirmed as of data cutoff), 3 SD and 2 PD. Responses of patients remaining on FT-2102 will be updated as available. Evaluations of serum/CSF pharmacokinetics and selected pharmacodynamics will be provided. CONCLUSION FT-2102 at 150 mg BID demonstrates acceptable safety and tolerability with potential clinical activity in with gliomas. The Phase 2 study is ongoing, evaluating both single agent, FT-2102 and in combination with azacitidine

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: a multicenter, open-label, phase 1b/2 trial

Olutasidenib (FT2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1  R132X mutation.This was an open-label, multicenter, non-randomized, phase 1b/2 clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1  R132Xmutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase 1 and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase 2.Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase 2 dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each).Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1  R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: a multicenter, open-label, phase 1b/2 trial

BACKGROUND: Olutasidenib (FT2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation. METHODS: This was an open-label, multicenter, non-randomized, phase 1b/2 clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1 R132Xmutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase 1 and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase 2. RESULTS: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase 2 dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). CONCLUSIONS: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial

Background Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1(R132X) mutation. Methods This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (>= 18 years) had histologically confirmed IDH1(R132X)-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. Results Twenty-six patients were enrolled and followed for a median 15.1 months (7.3-19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3-4 adverse events (>= 10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). Conclusions Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1(R132X) mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment

Olutasidenib (FT-2102) Induces Rapid Remissions in Patients with IDH1-Mutant Myelodysplastic Syndrome: Results of Phase 1/2 Single Agent Treatment and Combination with Azacitidine

Background: Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematopoietic stem cell disorders with risk of progression to AML. Isocitrate dehydrogenase 1 mutations (IDH1m) occur in approximately 3-4% of MDS patients (pts). Olutasidenib is a highly potent, selective small molecule inhibitor of IDH1m that has shown clinical activity in AML (De Botton, 2019). Methods: The ongoing Phase 1/2 study (NCT02719574) has evaluated the safety, PK/PD, and clinical activity of olutasidenib alone or in combination with azacitidine (AZA) or cytarabine in IDH1m AML/MDS pts. Safety for all pts and efficacy for evaluable pts with MDS in Phase 1 and 2 are reported here. IDH1m variant allele frequency (VAF) was measured at baseline and on treatment by central droplet digital PCR (ddPCR) assay (peripheral blood). Duration of FT-2102 exposure was calculated using Kaplan-Meier methodology; patients on ongoing treatment were censored at the data cutoff date. Results: As of the 19-Jun-2019 data cutoff date, 20 pts with IDH1m MDS had received olutasidenib continuously either as a single agent (SA; n=6) or in combination (COMBO; n=14) with AZA (75 mg/m2 × 7 days q 4 weeks). The study population (3 intermediate risk, 12 high risk, 4 very high risk MDS and 1 missing at data cutoff) included 7 newly diagnosed pts and 13 relapsed/refractory pts who had received a median of 1 prior regimen (maximum 4). Eleven pts received prior hypomethylating agents for a median 7.8 months and 2 pts were missing prior treatment records. The median time on treatment for all MDS pts treated with olutasidenib +/- AZA was 8 months (range: <1, 21 months); 6 months (range: 2, 21 months) for SA and not reached for COMBO. Ten (50%) pts remain on treatment (SA, n=2; COMBO, n=8); 10 (50%) pts (SA, n=4; COMBO, n=6) discontinued treatment due to disease progression (n=3), transplant (n=3), other reasons (n=2 [alternative treatment]), adverse event (n=1), or death (n=1). Olutasidenib has been well tolerated both as SA and in combination with AZA. Overall in SA and COMBO, regardless of causality, most treatment-emergent AEs (TEAEs) were grade (Gr) 1/2, with most common (≥20%) TEAEs: nausea (60%); fatigue (50%); arthralgia, constipation, thrombocytopenia (40% each); neutropenia or dyspnea (35% each); vomiting (30%), extremity pain, headache, hematuria, cough or diarrhea (25% each); and myalgia, decreased appetite, hypokalemia, fever, contusion, dizziness, hypoesthesia, pruritis, angina bullosa hemorrhagica or insomnia (20% each). The most common (≥15%) Gr 3/4 TEAEs for the overall population (Table 1) were neutropenia (30%); thrombocytopenia (25%); febrile neutropenia, fatigue and leukocytosis (15% each). One COMBO pt had Gr 3 differentiation syndrome and one COMBO pt experienced Gr 1 QTc prolongation that resolved without treatment interruption. Clinical responses occurred in 33% SA and 73% COMBO (CR 17% and 55%, respectively; Table 2). Updated mutation analyses and other response endpoints will be presented. Conclusions: Olutasidenib has shown favorable safety profile and clinical activity in IDH1m MDS, with an overall response rate (ORR) rate of 59% (95% CI: 33-82%) and durable disease control. Phase 2 is ongoing at 150 mg BID single agent and in combination with AZA. Disclosures Cortes: Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria. Wang:Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role. Watts:Takeda: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Lee:Ai Therapeutics: Research Funding; Karyopharm Therapeutics: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Roche Molecular Systems: Consultancy; Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy. Baer:Abbvie: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Kite: Research Funding; Al Therapeutics: Research Funding; Forma: Research Funding; Takeda: Research Funding. Dao:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kelly:FORMA Therapeutics: Employment. Sweeney:FORMA Therapeutics: Employment. Brevard:FORMA Therapeutics: Employment. Henrick:FORMA Therapeutics: Employment. Forsyth:FORMA Therapeutics: Employment. Guichard:FORMA Therapeutics: Employment. Mohamed:FORMA Therapeutics: Employment. Wei:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria