Pitou, Celine

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

Abstract Abstract 2814 Background: The majority of primary and secondary MF, PV, and ET neoplasms are characterized by gain-of-function activation of JAK2 V617F/STAT5 signaling. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2 V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. In murine MPN models and in vitro cell based assays, a novel JAK2 inhibitor, LY2784544, demonstrates selective inhibition of JAK2 V617F/STAT5 signaling and mutant cell proliferation (Ma et al. Abstract 4087 ASH 2010). These results provided the basis for the LY2784544 Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). Methods: The primary objectives are to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives include determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria, European Leukemia Net response criteria for PV and ET (EULN), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). The study has a standard 3+3 dose-escalation design to define the maximum tolerated dose (MTD). The study was recently amended to allow cohort expansions at lower than MTD doses demonstrating potential clinical merit. Results: To date, 19 patients have been treated: 1 PV, 1 post-ET MF, and 17 MF patients. Four patients discontinued therapy, 1 for each of the following: Adverse Event, progressive disease, investigator decision, and subject's decision. Reported drug-related serious adverse events were seen in 4 patients, and include: creatinine increase (n=4 grade 2), hyperuricemia (2 grade 4), and hyperkalemia (1 grade 1). All resolved within 14 days with temporary treatment interruption. Analysis of collected laboratory studies using the definitions of Cairo and Bishop (BJH 2004, 2010) demonstrated that 1 instance of laboratory tumor lysis syndrome (LTLS) and 3 instances of Grade 2 clinical tumor lysis syndrome (CTLS) occurred. Hyperuricemia and creatinine increases in cases of TLS were reported as dose-limiting toxicities at 240 and 200 mg with 1 and 3 instances at each respective dose. The most frequently reported drug-related AEs across all grades were diarrhea (3 grade 2, 5 grade 1), nausea (3 grade 2, 4 grade 1), transient increased creatinine (4 grade 2), anemia (3 grade 2, 1 grade 1), and hyperuricemia (2 grade 4). A palpable spleen length reduction of at least 35% was seen in 13 of 17 evaluable patients (76% including 16 MF and 1PV). A partial response by EULN for PV involving 100% reduction in spleen size was observed for >10 months. In MF, 7 patients had a ≥50% reduction, including 4 with sufficient stability or duration of follow-up to qualify as a clinical improvement by IWG-MRT. After 5 cycles of therapy, a reduction in bone marrow fibrosis grade was observed in 3 of the 5 MF patients for whom follow-up biopsy results are available. Using the MPN-SAF questionnaire, patients reported improvements in symptom burden within the first 2 cycles of therapy. Fifty-nine percent (59%) reported a ≥50% improvement in the Key MPN Related Symptoms, and 47% reported a ≥50% improvement in the categories of Fatigue-Enjoyment of Life, Fatigue-Walking Ability, itching, and early satiety. A similar level of improvement was reported by 65% of patients for inactivity, while 35% had improvements in bone pain and night sweats. At tested doses, a reduction in mutant allele burden has not been observed. Conclusions: An MTD for daily dosing of LY2784544 was identified as 120 mg. Based on PK analysis, exposure from doses associated with TLS appear to overlap the lower boundary of the predicted biologically efficacious dose (BED) range established in murine JAK2 V617F models. To allow testing of doses within the BED, the dosing regimen has been amended to include a lower dose lead-in period, intended to reduce tumor burden, prior to further testing of dose escalation. This trial amendment will also further evaluate the bone marrow fibrosis response. Disclosures: Verstovsek: Eli Lilly: Research Funding. Off Label Use: Study of LY2784544 - Purpose is to present results of a study. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding. Kloeker Rhoades:Eli Lilly: Employment, Equity Ownership. Giles:Eli Lilly: Employment, Equity Ownership. Pitou:Eli Lilly: Employment, Equity Ownership. Jones:Eli Lilly: Employment, Equity Ownership. Walgren:Eli Lilly: Employment, Equity Ownership.

Abstract Background MF, PV, and ET are neoplasms characterized by activation of JAK2 signaling, and the majority of cases are associated with the gain of function JAK2 V617F mutation. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. LY2784544 is a selective inhibitor of JAK2 which demonstrates dose dependent selectivity for JAK2 V617F/STAT5 signaling. LY2784544 entered clinical testing in a Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). We have previously reported early interim analysis from this study and provide here an update following completion of study enrollment. Methods The study’s primary objectives were to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives included determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria (2006), European Leukemia Net response criteria for PV and ET (EULN 2009), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). Study design included a standard 3+3 dose-escalation to define the maximum tolerated dose (MTD) and was amended to allow cohort expansions at multiple doses demonstrating potential clinical merit. Results Patients Prior to closing to enrollment, 47 patients were consented; 9 did not meet eligibility screening. The 38 treated patients included 31 MF (22 pMF, 6 post-PV MF and 3 post-ET MF), 6 PVs, and 1 ET patient(s), and 86% had received prior systemic therapy for their MPN. Dosing and tolerability of LY2784544: Systemic exposures were approximately dose proportional across the tested range from 30 to 300 mg. Daily doses of 200 mg or greater were associated with CTCAE Grade 3 increases in serum creatinine. In general, increases in serum creatinine occurred within the first 2 weeks of either starting treatment or after an increase in study drug dose. With the available data, the elevations in serum creatinine appear to be fully reversible after dose reduction or drug holiday in the majority of patients. The maximum tolerated daily dose of LY2784544 when given on a continuous daily basis was determined to be 120 mg per day. Serious AEs, across all grades and doses, included increased creatinine/acute renal insufficiency (4 grade 3, 5 grade 2, 1 grade 1), hyperuricemia (2 grade 4, 1 grade 1), hyperkalemia (1 grade 1), and anemia (1 grade 3). This study allowed intrapatient dose escalation, and 34 patients received 120 mg during their study participation. There were 4 patients dosed at 120 mg with SAEs but all were unrelated to study drug treatment (anemia, influenza, enterococcal bacteremia, hematuria and pneumonia). At 120 mg, the most frequently reported drug-related AEs across all grades were diarrhea (44%), nausea (29%), increased creatinine (21%), and anemia, vomiting, fatigue (9% each). Of these related AEs at 120 mg, there was 1 Grade 3 anemia, 3 Grade 3 increased creatinine, and 2 Grade 3 fatigue. There were no Grade 4 AEs. Efficacy Among a cohort of 10 MF patients who only received 120 mg, 3 achieved a clinical improvement. Analyzing across dose levels, a palpable spleen length reduction of ≥50% was seen in 15 of 27 evaluable patients (56%) at any time. The median duration of these responses was 18.3 weeks (range from 0.7 to 148.1 weeks). At 12 weeks, 56% of patients (15/27) reported a ≥50% improvement in Total Symptom Score on the MPN-SAF. Of the 6 PV patients, 3 achieved a clinicohematologic PR. Findings from a central pathology review of serial bone marrow samples will be presented at the meeting. Conclusions A recommended phase II dose for daily dosing of LY2784544 was identified as 120 mg. This dose has been well tolerated and associated with clinical improvements, supporting ongoing Phase II testing of LY2784544 in MPNs. Disclosures: Verstovsek: Eli Lilly and Co: Research Funding. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding. Salama:Eli Lilly and Co: Research Funding. Giles:Eli Lilly and Co: Employment. Pitou:Eli Lilly and Co: Employment. Hayden Zimmermann:Eli Lilly and Co: Employment. Price:Eli Lilly and Co: Employment. Walgreen:Eli Lilly and Co: Employment. Prchal:Eli Lilly and Co: Research Funding.

Abstract Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.