Ottmann, Oliver G.

Abstract Abstract 677 Background: Activating mutations of NRAS and KRAS (‘RAS’) are found in 10–30% of myeloid malignancies. Evidence of constitutive activation of the RAS-RAF-MEK-ERK pathway, however, is more ubiquitous. Trametinib is a potent, selective, allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A Phase I/II study of single, daily, oral dosing of trametinib in myeloid malignancies is ongoing. Here we report the results from Phase I/II patients receiving the recommended Phase II dose (RP2D) of 2 mg. Methods: Patient eligibility was limited to patients with relapsed/refractory myeloid malignancies and adequate hepatic, renal and cardiac function. There were no hematologic eligibility criteria. Patients were prospectively screened for KRAS mutations at amino acids 12, 13 and for NRAS mutations at amino acids 12, 13 and 61. Clinical response was assessed using International Working Group (2003 and 2006) criteria for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), respectively. Pharmacodynamic marker (pERK) analysis was conducted in phase II patients with patient paired (pre/during treatment) blood and bone marrow samples. Results: Eighty-seven (9 in Phase I and 78 in Phase II) patients received 2 mg of trametinib daily: AML (n=66), MDS (n=11), chronic myelomonocytic leukemia (CMML) (n=7) or other (n=3) (RAS mutations, n=57; RAS wild type, n=15 and RAS unknown, n=15). Median age was 68 years (range 21–87) and for close to half of the patients, trametinib was 3 3rd line of therapy. Trametinib exhibited a long effective half-life with small peak/trough ratios, and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Results of the pharmacodynamic analysis indicated an on-target effect of trametinib. Responses by RAS mutation status for Phase I/II subjects are summarized in Table 1. Responding patients have continued therapy for median of 16.9 weeks (range, 10.9 – 36.7). Drug-related grade 3/4 adverse events (AEs) were encountered in 31/87 (36%) of the Phase I/II patients and there was one grade 5 drug-related AE,cerebrovascular accident. Hepatic toxicities (9%), gastrointestinal disorders (7%) and rash (5%) were the most frequent grade 3/4 AEs. AEs possibly related to inhibition of MEK signaling were blurred vision (total,13%; grade 3, 1%) and decreased cardiac ejection fraction (total, 9%; grade 3, 6%); events were generally reversible. Conclusion: At the RP2D of trametinib (2 mg orally daily), trametinib has shown promising clinical activity and responses (CR/CRp/Marrow CR/MLFS/PR) were almost exclusively seen in patients with refractory myeloid malignancies characterized by somatic RAS mutations. Expansion of the CMML cohort for RAS positive subjects is ongoing. Disclosures: Borthakur: GlaxoSmithKline, Sigma-Tau, Eisai, XBiotech: Research Funding. Off Label Use: Trametinib, to report outcome of clinicla trial to audience at ASH meeting. Foran:GlaxoSmithKline: Research Funding. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding. Giagounidis:GlaxoSmithKline: Honoraria. Ottmann:GlaxoSmithKline: Clinical trial participation Other. Kadia:GlaxoSmithKline: Research Funding. Bauman:GlaxoSmithKline: Employment, Equity Ownership. Wu:GlaxoSmithKline: Employment. Liu:GlaxoSmithKline: Employment. Schramek:GlaxoSmithKline: Employment. Zhu:GlaxoSmithKline: Employment. Wissel:GlaxoSmithKline: Employment, Equity Ownership.

7056 Background: No therapies are approved for MDS after HMA failure. 04-24 was a single-arm study to evaluate best BMBL response as a potential surrogate for OS in higher-risk (HR) MDS pts who progressed on or after an HMA. Rigo is a Ras-mimetic that inhibits the RAS-RAF-MEK pathway, which is frequently activated in HR MDS (Athuluri-Divakar Cell 2016; Gil-Bazo Cancer Biol Ther 2016). Methods: Eligible MDS pts had 5-30% BMBL confirmed within 6 wks pre-study and progression per International Working Group (IWG) 2006 criteria on or after HMAs within 2 yrs. Rigo 1800 mg/24 hrs was continuously infused over 72 hrs q 2 wks × 8 cycles, then q 4 wks until progression or unacceptable toxicity. Primary endpoint was relationship of best BMBL IWG response to OS by Kaplan Meier method. Results: 64 pts were treated (median 5 cycles, range 1-32+), with 61% male, median age 73 (range 47-87), median prior HMA duration 10.8 mos (range 1.2-70.2). Revised International Prognostic Scoring System scores were low 2%, intermediate 11%, high 27%, very high 53%, and unknown 8%. ≥Grade 3 adverse events in ≥10% of pts were anemia 19%, thrombocytopenia 19%, and febrile neutropenia 16%. At the analysis time 40 pts (63%) had died. Best BMBL IWG response was marrow complete response (mCR) 14 pts (22%), stable disease (SD) 30 (47%), progressive disease (PD) 15 (23%), and failure (early death/withdrawal) 5 (8%); 2 mCR pts had transplant. Median OS was 7.0 mos (95% confidence interval 4.8-10.8). Landmark median OS (from day of best BMBL response) was mCR not reached; SD 6.3 mos; PD 3.3 mos. Median OS of mCR+SD was 8.5 mos, with log-rank p = 0.011 (mCR+SD OS to PD OS). Conclusions: BMBL response is a predictor of survival for MDS pts receiving Rigo after HMA failure, confirming findings in earlier Phase 1/2 studies (Silverman ASCO 2015 Abstr 7017). Based on earlier results identifying an MDS subset benefitting from Rigo (Garcia-Manero Lancet Oncol 2016; ASCO 2016 Abstr 165681), a randomized Phase 3 trial of Rigo vs physician’s choice (INSPIRE) is ongoing to determine if Rigo improves survival after HMA failure within 9 cycles. Clinical trial information: NCTO 1928537.

BACKGROUNDNVP‐AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed NVP‐AUY922 alone and with bortezomib in patients with relapsed or refractory MM.METHODSDose escalation was guided by an adaptive Bayesian logistic regression model. In phase 1, patients who progressed after 2 to 4 prior therapies received NVP‐AUY922 intravenously once weekly. In phase 1B, patients who progressed after 2 or fewer prior therapies received NVP‐AUY922 plus bortezomib. The primary objective was to determine the maximum tolerated dose (MTD) of NVP‐AUY922.RESULTSTwenty‐four patients received NVP‐AUY922 monotherapy at doses of 8 to 70 mg/m2. One dose‐limiting toxicity (DLT) was observed (grade 3 blurred vision at 70 mg/m2); no MTD was reached. The recommended phase 2 dose was 70 mg/m2. The most frequent drug‐related adverse events (AEs) were diarrhea, nausea, and ocular toxicities. Grade 3/4 AEs were uncommon (<10%). Eight patients discontinued treatment because of AEs; 5 had ocular toxicities (≥45 mg/m2). The best response was stable disease in 66.7% of the patients. There were no partial or complete responses. Five patients received NVP‐AUY922 (which was started at 50 mg/m2) plus bortezomib (1.3 mg/m2). Three of these patients experienced DLT. No further dose escalation was performed; the MTD for NVP‐AUY922 plus bortezomib was not established.CONCLUSIONSThis study showed disease stabilization with NVP‐AUY922 in patients with relapsed or refractory MM. The MTD for NVP‐AUY922 was not reached, but reversible ocular toxicity has been reported at high dose levels. Bortezomib at the standard recommended dose plus NVP‐AUY922 was not tolerated. Cancer 2015;121:2185–2192. © 2015 American Cancer Society.