G3 Rash Research Articles

Melphalan 180mg/m 2 Can Be Safely Administered as Conditioning Regimen Prior to an Autologous Stem Cell Transplantation in Multiple Myeloma Patients with Creatinine Clearance ≤60ml/min/1.73 m 2 with Use of Palifermin for Cytoprotection: Results of a Phase I Trial

The majority of multiple myeloma (MM) patients (pts) with abnormal renal function (AbRF) receive attenuated dose of therapy. Melphalan (M) is the most effective conditioning for MM pts receiving autologous stem cells transplant (ASCT). M 140 mg/m2 is the standard of care in pts with AbRF, as M 200 mg/m2 resulted in severe oral mucositis (OM). Palifermin (P) as a cytoprotective agent has demonstrated efficacy in reducing the intensity & duration of OM. Due to lack of prospective data on the use of P in MM pts with AbRF, we designed this study to determine the maximum tolerated dose (MTD) of M when used with P, in order to decrease OM. Eligibility criteria: creatinine clearance ≤ 60ml/min/1.73 m2, age ≥18 years, Durie-Salmon stage 2/3, ECOG PS ≤ 2, no dialysis, no active OM & a suitable candidate for ASCT. Level (L) 1 began at M 140 mg/m2 with P 60 mcg/kg/d, given as I.V bolus on Day -5,-4, -3 and Day +1, +2 & +3 (Stem cells infused on Day 0). M was given on D-2 & dose-escalation proceeded at 20 mg/m2 increments, up to a maximum dose of 200 mg/m2 in L4. If no symptomatic G ≥ 3 dose limiting toxicities (DLTs) were noted, an additional cohort of 3 pts was entered at the next dose level. Dose escalations were to stop if ≥ 2 DLTs occurred at a M dose (MTD). Grade (G) 4 OM, G4 diarrhea, ≥ G3 rash, & ≥ G3 cardiac toxicity were considered as DLT; G 3/4 hematological toxicity was acceptable. The G of OM was assessed daily (WHO OM scale-G 0-4). Nineteen pts were enrolled from 06/2007 to 06/2011. Data on 15 evaluable pts is reported as 4 pts were removed. Median age was 59 years (36-67).TablePatient Characteristics (N = 15)Sex – Male- no. (%)8 (53)Median Age- yr (Range)59 (36-67)Race- Caucasian- no. (%)12 (80)Median Creatinine clearance (Range)42.8 (29-60)Disease Status at the time of Transplant– no. (%)CR4 (27)VGPR3 (20)PR3 (20)PD5 (33)Median no. of infused CD34+ cells x 10∧6/Kg (Range)4.2 (2.6 - 8.0)Median number of days to neutrophil engraftment (Range)12 (11-21)Median number of days to platelet engraftment (Range)19 (0 - 86)Median duration of hospitalization- days (Range)16 (12 -74) Open table in a new tab The overall incidence of OM ≥ G3 was 53% (8/15) and a median duration of ≥ G3 OM was 6.5 days (3-42). One patient in L2 (M 160 mg/m2) developed atrial fibrillation. Two pts in L4 (M 200mg/m2) developed G4 OM, hence reaching DLT. Three more pts were then enrolled in L3 (M 180mg/m2). No DLT was observed in 6 pts enrolled in L3. Fourteen pts were evaluable for response at D+100 (4 CRs). One patient died in L4 due to multi-organ failure and infection. The most common adverse events include rash (13 events, no G 3), asymptomatic elevation of amylase (9, 3 pts G 3) and lipase (2, 1 pt G 3) and diarrhea (12, 1 pt G 3 (C.Difficile +ve)). Nine pts required narcotics; 4 pts needed TPN/NG feeding. Median duration of hospitalization for ASCT was 16 days (12-74). P has permitted safe dose escalation of M up to 180 mg/m2 with acceptable toxicity in AbRF pts.

Abstract B243: A phase I dose-escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced solid tumors.

Abstract Background: The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival, and is often aberrantly activated in many cancers. MEK162 (ARRY-438162) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2. The objectives of this completed Phase 1 dose-escalation study were to determine the maximum tolerated dose (MTD) and characterize the safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients (pts) with advanced solid tumors. An expansion phase of the study is ongoing in order to further explore toxicity and PK in pts with biliary cancer and in pts with KRAS- or BRAF-mutant metastatic colorectal cancer. Methods: Pts were enrolled in successive cohorts using a 3 + 3 design and received MEK162 as a single oral dose on Day (D) 1 followed by twice daily (BID) dosing starting on D2. Safety was assessed by adverse events (AEs), clinical laboratory tests, physical exams, ECGs, ECHO/MUGA scans and ophthalmic exams. Plasma samples were used to assess PK. Levels of circulating cytokines and growth factors in serum and expression and/or phosphorylation status changes in relevant growth factor pathway proteins in skin were evaluated to assess PD. Mutation status of RAS, RAF and other relevant genes and expression and/or phosphorylation status of MEK pathway protein were assessed from archival tumor samples. Tumor response was assessed every 6 weeks. Results: Nineteen pts of median age 57 years (range 33–79) were enrolled in 4 dose cohorts (30 [4], 45 [4], 60 [7] and 80 [4] mg BID). All pts had prior chemotherapy and were ECOG 0–1. Tumor types included colorectal (7), pancreatic (3), cholangiocarcinoma (2) and other (7). The most common treatment-related AEs were rash, diarrhea, nausea, vomiting and peripheral edema, and most were Grade (G) 1/2. G3/4 treatment-related AEs included G3 rash (2), G3 palmar-planter syndrome (1), G3 central serous-like retinopathy (1) and G3/4 creatine kinase elevation (1 each). Seventeen pts were evaluable for MTD determination (30 [4], 45 [3], 60 [7] and 80 [3] mg BID). All DLTs occurred at 80 mg BID (G3 rash and central serous-like retinopathy, 1 pt each); thus, the MTD was 60 mg BID. Of the 17 pts evaluable for response, 1 pt with NRAS-mutant cholangiocarcinoma achieved a PR, and SD was achieved in 9 pts. Of the 11 other evaluable pts with known mutational status, 2 were wild type on all loci tested, plus 5 KRAS, 1 NRAS, 1 BRAF, 1 PIK3Ca and 1 dual KRAS/PIK3Ca mutants. Exposure increased in a dose-proportional manner with good inter-pt variability (∼30% CV). Exposure by D15 averaged 36% > corresponding D1 values indicating modest accumulation. The median t1/2 was ∼5 hr. Mean steady-state plasma concentrations were continuously maintained above the in vitro IC50 value for cell proliferation at all dose levels. In 7 paired skin biopsies from the 60 mg cohort, decreases in pERK and Ki67 were observed post-dose by immunohistochemistry. In serum, a decrease in TNFα was also observed across all dose cohorts. Conclusions: MEK162 had an acceptable safety profile at doses up to the MTD of 60 mg BID and showed preliminary signs of clinical activity. MEK162 displayed desirable PK properties with dose-dependent exposures. MEK162-induced changes in PD markers of MEK activity suggest that MEK162 has target-related PD activity at multiple-dose levels at and below the MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B243.

Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436).

CRA8503 Background: In preclinical models, the BRAF/MEK inhibitor (i) combination GSK436/GSK212 has demonstrated enhanced activity against BRAF-mutant cancer cells compared to either drug alone, delayed emergence of GSK436 resistance, and prevented proliferative skin lesions attributable to BRAFi exposure. Methods: Eligible patients (pts) had BRAF V600 mutation positive solid tumors. Part 1: pharmacokinetic (PK) drug-drug interaction (DDI) study. Part 2: Dose escalation of continuous daily dosing of the combination followed by expansion cohorts; Part 3: Randomized phase II trial in untreated stage IV melanoma. Results: 45 pts have received ≥ 1 dose of GSK212 + GSK436, including 43 melanoma (all BRAFi naïve), 1 NSCLC and 1 salivary duct carcinoma. PK results of 7 pts in Part 1 showed no effect of GSK212 on single dose of GSK436. There was no clinically meaningful DDI between GSK436 and GSK212 after repeat dosing of the combination (Part 2). GSK436 was dosed 75-150 mg BID in combination with GSK212 1.0, 1.5, 2.0 mg QD. The recommended dose was 2 mg QD GSK212 in combination with 150 mg BID GSK436. At 1.5 mg GSK212, there was one DLT, a recurrent grade (G) 2 neutrophilic panniculitis. The only G4 adverse event (AE) was a sepsis-like syndrome with fever/hypotension. G3 AEs included generalized rash (n=2, 4%) and neutropenia (n=2, 4%). Skin toxicity ≥ G2 occurred in 9 (20%) pts; of these, G2 rash (n=4, 8%) and G2 macular rash (n=1, 2%). No cutaneous squamous cell carcinoma (SCC) or hyperproliferative skin lesions have occurred at any dose level. Other common G2 toxicities were pyrexia (n=5, 11%), vomiting (n=2, 4%) and fatigue (n=2, 4%). Of 16 evaluable pts in Part 2, 13 pts had PR and 3 SD for an ORR of 81% (95% CI 54.4%-96.0%) and all but 2 pts remain on study. In 10 evaluable pts who received 150 mg BID GSK436 + ≥1 mg QD GSK212, 9 pts had PR and 1 SD. Conclusions: GSK212 at 2 mg QD combines safely with GSK436 150 mg BID, no SCC thus far and decreased frequency of rash compared to previous trials of single agent GSK436 and GSK212, respectively. The preliminary anti-tumor activity warrants further investigation; the randomized phase II trial (Part 3) is accruing.

Phase I study of aflibercept (VEGF Trap) and temozolomide in newly diagnosed, high-grade glioma.

2043 Background: Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGFA, VEGF-B and placental growth factor (PlGF), depleting circulating levels of these growth factors. Methods: The Adult Brain Tumor Consortium (ABTC) conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGG). Three cohorts were examined: Cohort 1: Aflibercept with radiotherapy and concomitant temozolomide; Cohort 2: Aflibercept and adjuvant temozolomide using the 5/28 regimen; and Cohort 3: Aflibercept and adjuvant temozolomide using the 21/28 day regimen. Eligibility criteria included histologically proven newly-diagnosed glioblastoma (GBM) or anaplastic glioma (AG), > 18 yrs old, KPS > 60, adequate bone marrow reserve and organ function. Patients initially received 2 mg/kg of aflibercept every 2 weeks. If no dose-limiting toxicities (DLT's) were observed the dose was increased to the single agent dose of 4mg/kg every 2 weeks in the next cohort of patients. No further dose escalation was permitted. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose where DLT's occurred in fewer than 1/6 patients. At least 6 patients were treated at the MTD. Once this was defined, an additional 9 patients were treated for a total of 15 patients. Results: To date 48 patients have been enrolled, of whom 43 were evaluable. Median age was 56.9 years (23.91-69.19); median KPS 90 (70-100). The MTD of aflibercept for all 3 cohorts was 4mg/kg every 2 weeks. DLTs at the MTD were: Cohort 1: 0/6 patients; Cohort 2: 2/15 patients (G3 DVT, G4 ANC; Cohort 3: 3/15 patients (G4 biopsy-confirmed thrombotic microangiopathy; G3 rash, G4 thrombocytopenia). Conclusions: The combination of aflibercept and TMZ was generally well tolerated. The recommended phase II dose of aflibercept with radiotherapy and concomitant and adjuvant temozolomide is 4mg/kg every 2 weeks.

Final results of a translational phase l study assessing a QOD schedule of the potent AKT inhibitor MK-2206 incorporating predictive, pharmacodynamic (PD), and functional imaging biomarkers.

3001^ Background: MK-2206 is a novel allosteric inhibitor of all 3 isoforms of AKT, which are targets implicated in malignant progression. Methods: The investigational agent MK-2206 was given orally QOD to patients (pt) with advanced solid tumors. PD studies of AKT and downstream protein phosphorylation (p) were carried out in tumor biopsies and platelet-rich plasma with MesoScale Discovery (MSD) ELISA, and hair follicles with immunofluorescence. Tumor biopsies were sequenced with Sequenom Oncocarta panel for putative predictive biomarkers and stained with IHC for PTEN expression. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), MR spectroscopy (MRS) and diffusion weighted imaging (DWI) were conducted. Results: 71 pt (37 M; median age 59y; ECOG PS 0/1: 22/49) received MK-2206 at 30, 60, 75, 90 mg QOD. G3 rash (n=6) was dose limiting at 75-90 mg QOD, establishing MTD at 60mg QOD. Four MTD expansion cohorts were then undertaken: paired tumor biopsies (n=14), functional imaging (n=13), ovarian...

Final toxicity results of a phase I dose-escalation trial of tremelimumab (CP-675206) in combination with gemcitabine in chemotherapy-naive patients (pts) with metastatic pancreatic cancer.

4081 Background: Tremelimumab (CP-675206) is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA4) on T lymphocytes and T regulatory cells. It is thought to stimulate the immune system to attack tumor cells by blocking the CTLA4-negative regulatory signal. The primary objective of this phase I study was to determine the maximum tolerated dose and evaluate the safety of tremelimumab plus gemcitabine in pts with previously untreated metastatic pancreatic cancer. Methods: In Part A of the study, pts received gemcitabine only during a 1-mo lead-in period. Gemcitabine (1,000 mg/m2) was administered on days 1, 8, and 15 of a 4-wk cycle. Escalating doses of tremelimumab (6 mg/kg, 10 mg/kg, and 15 mg/kg) were then administered intravenously on day 1 of each 12-wk cycle. In Part B, tremelimumab at 2 dose levels (10 mg/kg and 15 mg/kg) was administered simultaneously with gemcitabine. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 wk after the first dose of tremelimumab. Results: A total of 34 pts (M/F = 22/12; median age 59; range 29-76) received at least 1 dose of tremelimumab. The median number of cycles was 1 (range, 1-5). No DLTs related to tremelimumab were observed at any dose level. Most frequent grade (G) 3-4 toxicities were neutropenia (n=8), fatigue (n=5), transaminases increase (n=4), nausea (n=3), and diarrhea (n=3). Two cases of G3 diarrhea, 1 case of G3 nausea, and 1 case of G3 transaminases increase were considered related to tremelimumab. Other toxicities related to tremelimumab were G2 diarrhea (n=6), G2 thrombocytopenia (n=1), G2 rash (n=1), and G2 vitiligo (n=1). Two of 25 evaluable pts had confirmed partial responses (PR), and 5 had stable disease (SD) at 7 wk (defined by measurements demonstrating neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease after the start of treatment). One pt with SD as best result remains progression free after 14 mo of therapy. Conclusions: Tremelimumab (up to 15 mg/kg every 12 wk) plus gemcitabine was well tolerated in pts with metastatic pancreatic cancer.

Phase I Trial of the Combination of Lenalidomide, Thalidomide and Dexamethasone In Relapsed/Refractory Multiple Myeloma

AbstractAbstract 1948 Background:The combination of lenalidomide (Len) and dexamethasone(D) have demonstrated overall response rates (ORR) of 60% in relapsed/refractory multiple myeloma (RRMM). The three drug combination of Len/Thalidomide/D has not previously been evaluated in RRMM. The ORR with LenD with prior Thalidomide(Thal) is 40–50%, while the ORR with ThalD after prior Len is < 20%. Preclinical studies have demonstrated Len resistance is mediated via the wnt-β-catenin pathway which is modulated by Thal. The minimal overlapping side effect profile and differing mechanism of action of Len and Thal and preclinical data provided the rationale for the combination of Len/Thal/D in an attempt to improve RR and overcome lenalidomide resistance. The aim of this study was to determine the tolerability, maximum tolerated dose (MTD) and evaluate preliminary activity. Methods:Patients(pts) with relapsed/refractory myeloma with ≥ 1 line of therapy were eligible with adequate hematology, cardiac, pulmonary, and renal function. Patient were eligible regardless of prior Imid exposure or Imid refractory disease, enrolled in 3 dose cohorts(C), C1: Len 15 mg/Thal 100 mg/Dex, C2:Len 25 mg/Thal 100 mg/Dex, and C3: Len 25 mg/Thal 200/Dex. Dexamethasone was dosed in pulse dose fashion cycles 1–2 and reduced to weekly Dex in cycles 3 and beyond. Pts were treated until disease progression or toxicity. All patients received anticoagulation with warfarin or low molecular weight heparin. Results:18 patients with median 3 prior lines of therapy (range: 1–6) were enrolled, age 67 (range: 52–81), male/female: 13/5; 3 in cohort 1, 6 in cohort 2 and 9 in cohort 3. There were no dose limiting toxicity (DLT) in cohort 1 (0/3), 1/6 DLT in cohort 2 and 2/8 DLT in cohort 3 (1 pt was unevaluable for DLT due to disease progression within cycle 1 and removed prior to completing cycle 1). The DLT in cohort 2 was due to steroid induced toxicity, requiring reduction in dex dosing in cycle 1. The DLT in cohort 3 included one patient with G3 rash due to thalidomide and asymptomatic G2 atrial fibrillation (a. fib) and a second patient with G3 hypertensive crisis and volume overload due to dexamethasone. Other toxicity included a patient with new onset symptomatic a fib in Cohort 3 (during cycle 2, therefore not a DLT) with concurrent newly diagnosed cardiac amyloidosis, and non-neutropenic fever and pneumonia in patient in Cohort 2. Among the 8 patients in C3 who received > 1 cycle, 5 required dose reduction of Thal to 100 mg. No DVT/PE were observed with use of anticoagulation. No G3/4 peripheral neuropathy has been observed.13 patients were evaluable for efficacy (6 unevaluable: 1 withdrew consent after cycle 1, 4 patients in cycle 2 currently and responses not repeated/confirmed). Among the 13 evaluable patients the ORR (> PR) was 92%, 2 nCr, 3 VGPR, 7 PR and 1 with PD in cycle1. Among the 13 evaluable, 6/13 patients had prior thal, 10/13 autologous stem cell transplant, 9/13 prior Len and 8 patients were lenalidomide refractory. Among the 8 patients with Len refractory disease (4 had prior thal), the ORR was 88%, with 1 VGPR, 6 PR, and 1 PD in cycle 1. 4 pts, all with Len refractory disease, have discontinued therapy due to progressive disease after cycle 1, 4, 4, 6 (after initial PR to therapy), the other 4 remain on trial on cycle 3, 5, 7 and 9. Conclusions:The maximum recommended dose is lenalidomide 25 mg/thalidomide 100 mg/dex due to the DLT observed and need for dose reductions in thalidomide. The combination is well tolerated with only 1 pt discontinued therapy due to toxicity (a fib) and 4 pts discontinued secondary to PD. The very high ORR of 92% was much higher than seen with two drug regimen of Len/Dex. The preserved superior activity in lenalidomide refractory disease, supports the modulation of lenalidomide resistance with thalidomide, however a phase 2 trial is open and additional pts at cohort 2 will be enrolled to further evaluate the activity of this combination. Disclosures:Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Orlowski:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding.

Phase I study of lapatinib (L) in combination with whole-brain radiation therapy (WBRT) in patients (pts) with brain metastases from HER2-positive breast cancer.

1154 Background: In preclinical models, lapatinib sensitizes breast cancer cell lines to radiation. This study was designed to determine the maximum tolerated dose (MTD) and feasibility of L + WBRT in pts with brain metastases from HER2+ breast cancer. Methods: Eligible pts had HER2+ breast cancer and at least one brain metastasis. Measurable disease (dz) was not required. Pts received L 750 mg BID on day 1, followed by 1,000 mg, 1,250 mg, or 1,500 mg QD, beginning 1-8 days(d) prior to WBRT (37.5 Gy in 15 fractions) and continuing through RT. Following WBRT, pts received trastuzumab 2 mg/kg weekly and L 1,000 mg QD. The primary endpoint was determination of the MTD, defined as the dose at which DLTs occurred in 7 d during WBRT. Planned accrual at the MTD was 27 pts to fully assess feasibility. The regimen would be considered feasible if ≤ 3/27 patients experienced a DLT. Secondary endpoints included objective response, QOL, and survival. Results: 35/35 planned pts have enrolled. 0/3 pts receiving L 1,000 mg and 0/5 pts receiving L 1,250 mg experienced a DLT. At L 1,500 mg, DLTs were observed in 2 pts: G3 diarrhea and G3 rash, each associated with L dose hold of 16 d during cycle 1. An additional 22 pts were enrolled at the MTD (1,250 mg); DLT have been observed in 5/24 pts with >/=8 wks data (21%, 95% CI 7-42%): 2 cases of pulmonary embolus (PE), 1 pt with G3 herpes simplex rash, 1 pt with G3 hypoxia, 1 pt with G3 hyponatremia/hypokalemia. No G3/4 neurological toxicity has been reported. Of 24 pts with measurable dz and who have at least 8 wks follow-up, 20 (83%, 95% CI 63-95%) achieved an objective CNS response by 1 month after completion of WBRT. Conclusions: The study did not meet the predefined criteria for feasibility. However, the relationship between study treatment and some of the DLTs (e.g. PE) seems uncertain. L + WBRT using this dose or a lower dose of L could still be considered in future trials, though careful safety monitoring would be required. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline BrainLAB Genentech, GlaxoSmithKline

First-in-class phase I trial of a selective Akt inhibitor, MK2206 (MK), evaluating alternate day (QOD) and once weekly (QW) doses in advanced cancer patients (pts) with evidence of target modulation and antitumor activity.

3009 Background: Akt mediates cell proliferation, survival, and angiogenesis and is deregulated in cancer. MK is a potent, allosteric Akt1/2/3 inhibitor, with wide preclinical antitumor activity and a predicted long terminal elimination half-life (t1/2). Methods: MK was initially given QOD; due to the observed long t1/2, a QW schedule was also evaluated. Archival tumor and circulating nucleic acid were analyzed for PTEN and PIK3CA aberrations. Pharmacodynamic (PD) analyses of AKT and downstream target phosphorylation (p) were conducted in tumor (mandatory biopsies at MTD), platelet-rich plasma (PRP) and hair follicles (HF). Circulating endothelial cell (CEC) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies were conducted. Results: 70 pts (41 M; median age 60 yr; ECOG PS 0/1: 23/47) received MK. 55 pts received MK at 30, 60, 75 or 90 mg QOD; G3/4 rash (n=6) and G3 mucositis (n=1) were dose-limiting at 75 and 90 mg QOD. 15 pts received MK at 90, 135, 200 or 300 mg QW; G3 rash (n=3) was dose-limiting at 300 mg QW. Common reversible drug-related toxicities included rash (48.6%), nausea (20.0%), fatigue (17.1%) and hyperglycemia (12.9%). Pharmacokinetics were dose proportional; median Tmax was 6-8 hrs; mean t1/2 was 55-78 hrs. 9 pts at 60 mg QOD had serial tumor biopsies demonstrating pAKT inhibition following MK (>90% in 4/9; >70% in 7/9). This correlated with sustained falls in pAKT in PRP (p<0.001) and pPRAS40 in HF (p<0.05). A PTEN-negative (immunohistochemistry) pancreatic cancer pt (60 mg QOD) had 23% RECIST tumor shrinkage and 60% CA19-9 decline, with PD effects in tumor and HF. Minor tumor regressions (melanoma, neuroendocrine cancer), CA125 declines, PSA stabilization, tumor necrosis, and decreased ascites were seen following MK administration. Moreover, 18 of 23 (78.3%) evaluable pts had post-MK CEC declines of up to −100% (median change −69%); DCE-MRI studies (n≥12) are ongoing. Conclusions: MK has a long t1/2 and can be administered either on a QOD or QW schedule that is well tolerated and can induce sustained AKT blockade. MK also has antitumor activity and may be antiangiogenic. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck Chemotherapy Foundation, Merck Merck

Neoadjuvant cisplatin (CDDP) chemotherapy (CT) with docetaxel (D) and cetuximab (Cmab) followed by concurrent radiochemotherapy (RTCT) in locally advanced head and neck cancer (LA-HNC).

e16025 Background: Induction CT with D and CDDP followed by concurrent platinum RTCT has emerged as a therapeutic option for LA-HNC. Cmab also challenged the role of CDPP in RTCT. A schedule based on these advances may be valuable in the treatment of LA-HNC. Methods: Patients (pts) with LA-HNC are included in a pilot phase I-II study, having as primary endpoint tolerance and as secondary local progression-free (LPFS), distant metastasis-free (DMFS) and overall survival (OS). Thirteen pts (median age 68 years, median PS 0) with LA-HNC participated. A short course of neoadjuvant CT (two bi-weekly cycles) with D (40mg/m2), CDDP (60mg/m2) and Cmab (400mg/m2) was applied before RTCT with weekly CDDP (40mg/m2) and Cmab (250 mg/m2). Conformal RT was given in 19-21 daily fractions of 2.7Gy supported with high- dose daily amifostine (500-1000mg, using a previously described algorithm). After completion, the same induction regimen was given for 2-4 cycles, depending upon tumor response. The study has completed accrual. Results: Analysis of a minimum of 7 months (m) of follow-up (FU) is presented. Induction CT was well tolerated with only 1 pt experiencing grade (G) 3 leucopenia, 1 pt with G3 anemia and no pt experiencing any thrombopenia. Fatigue of G2 in 3 pts and G3 in 1 pt was noted. Cetuximab was well tolerated with 5 pts experiencing G2 rash and 1 G3. Concurrent RTCT was also well tolerated: 7 pts presented with G1/2 and 1 with G3 mucositis and 1 pt with G1 fungal infection. Amifostine was well tolerated and no pt had any rash. Cetuximab-related rash did not deteriorate during RT. No other toxicities were noted. Minimal/partial response to CT was noted in 11/13 pts. Complete response to RTCT was noted to 11/13 pts. Median LPFS was 9.07m (range: 7-18), with 4 pts experiencing a local recurrence, DMFS was 9.53 m (7-18) with 2 pts having a distant metastasis and OS was 9.61m with all pts alive at the time of the evaluation. Conclusions: The above regimen appears safe and effective for LA-HNC. Although this interim analysis provided no superior results to a previous published study of ours using the RTCT regimen alone, a phase II study is ongoing to extract mature results. No significant financial relationships to disclose.

Erlotinib and bevacizumab in chemotherapy-naive performance status 2 patients with advanced non-small cell lung cancer

e19082 Background: Poor performance status is a negative prognostic variable for survival and a risk for increased toxicities with standard chemotherapy. A phase 2 study combining erlotinib (E) and bevacizumab (B) demonstrated encouraging efficacy in the treatment of recurrent NSCLC with acceptable toxicity. We, therefore, tested this regimen in untreated PS 2 patients with advanced NSCLC. Methods: Single-arm phase 2 trial in treatment-naïve patients with advanced non-squamous NSCLC and either a PS of 2 or age &gt;75. Only patients eligible for bevacizumab per label were allowed onto study. Patients received E 150 mg orally daily and B 15 mg/kg IV on day 1 every 21 days for up to 6 cycles. The primary end-point was the rate of non progressive disease at 4 months (alternative hypothesis P&gt;60%). Other end-points included overall survival, progression free survival (PFS), toxicity evaluations and patient-reported PS (PRPS) measures. Results: 25 patients were enrolled. Patient characteristics: 56% female, median age 77 years (range: 52–90); 88% stage IV; 92% were PS 2; 20% were never or remote smokers (&gt; 30 years) The PRPS was 1, 2, 3 in 32%, 52%, 8% respectively with data on 2 patients missing. The rate of non-progression at 4 months was 40%; overall best response: 5% PR, 40% SD, 50% PD and 5% unevaluable; median PFS 2.6 months, 95% CI (1.3–5.1); MST 5.8 months, 95% CI (3.8- 8.7). 2 patients had G3 rash. G3 diarrhea, G3 hemorrhage, G3 proteinuria, G3 duodenal ulcer and G3 pneumonitis each developed in one patient. Conclusions: E + B is an active regimen with an acceptable toxicity profile; however, this study did not meet its’ primary endpoint. Further study of this combination will not be pursued in the Hoosier Oncology Group for this patient population. [Table: see text]

Dose-finding study of NKTR-102 in combination with cetuximab

e13503 Background: NKTR-102 is an advanced polymer conjugate of irinotecan with broad single agent activity and a unique pharmacokinetic (pk) profile. The apparent half-life of the active metabolite SN-38 in patients (pts) administered NKTR-102 is approximately 50 days. NKTR-102 in combination with cetuximab was evaluated in pts with refractory solid tumors to define the maximum tolerated dose (MTD). Methods: NKTR-102 was infused over 90 minutes every 3 weeks per cycle. Cetuximab was infused over 2 hours at 400mg/m2 on day 1 followed by a weekly 1 hour infusion at 250mg/m2. Cohorts of 3 -12 pts were treated with escalating doses of NKTR- 102. MTD was established based on the dose limiting toxicities observed in cycle 1 and safety data from subsequent cycles. Serial plasma samples were collected throughout the study for PK analysis. Results: Eighteen pts were enrolled: main tumor types include colon (5), pancreas (4), rectal (2), breast (2), gastric (1), other (4). Pts received 100 mg/m2 (12) or 125 mg/m2 (6) of NKTR-102 for a median of 2.5 cycles (range 1 to 11+). At 125 mg/m2, 3 pts had G3 diarrhea, 1 in cycle 1; 2 in cycle 2. At 100mg/m2, 1 pt had G3 diarrhea in cycle 1 and a further pt had G4 fatigue in cycle 2. Other G3 toxicities for all patients in both dose groups include nausea (3), vomiting (3) and neutropenia (2). No G3 rash was reported. Partial responses (PR) were observed in 3 pts at 100 mg/m2: confirmed (rectal, colorectal) and unconfirmed (gastric). Another pt with pancreatic cancer had a decrease in CA19–9 from 2000 at baseline to 157 U/ml with associated symptomatic benefit. NKTR-102 resulted in sustained exposure to SN-38 with no evidence of PK drug interactions between NKTR-102 and cetuximab. Conclusions: NKTR-102 shows evidence of clinical antitumor activity in combination with cetuximab. Toxicity is manageable; diarrhea and neutropenia are dose limiting. The recommended dose of NKTR-102 with cetuximab is 100mg/m2 every three weeks. Data support further evaluation of this combination in appropriate tumor types. [Table: see text]

Final results of a dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of two schedules of OSI-930 in patients (pts) with advanced solid tumors

3564 Background: OSI-930 is an oral TKI with potent activity against Kit, VEGFR2, and PDGFR. Preclinical studies demonstrate tumor regression with long-term remissions across multiple xenograft models. Methods: Sequential cohorts of pts with advanced solid tumors received continuous daily OSI-930 to determine the maximum tolerated dose (MTD) and to evaluate safety, PK/PD and efficacy of OSI-930 with both QD and BID dosing. An expansion cohort was enrolled for detailed PD analysis including sVEGFR2 plasma levels, PET imaging in GIST pts or DCE-MRI in selected pts. Results: A total of 58 pts were treated (20M/38F; median 60 years (range 19–83)). OSI-930 was dosed up to 1600 mg QD without reaching MTD. 46 pts received BID dosing [mg(# pts treated)]; 400(7), 500 (31) and 600(8). DLT's were seen in 3/8 pts at 600 mg BID; G3 rash (2 pts) and G4 GGT; and 3/31 at 500 mg BID; G3 myalgia, G3 fatigue and G3 lipase. G3 hypertension was noted in 3/46 pts but not dose-limiting. Common G1/2 toxicities were fatigue (37%), diarrhea (27%), nausea (31%), and rash (24%). Objective (CA125) responses were seen in platinum-resistant ovarian cancer (2 PR/8) while in heavily pretreated GIST (median 4 prior therapies including imatinib/sunitinib), 8/18 pts achieved SD ≥12 w. Median therapy duration in the BID arm was 9 w and 18/46 pts with SD ≥12 w. PK indicated that Css were achieved after ∼7d with BID dosing. PET scans showed reduction in glycolytic activity in 4/9 pts and DCE-MRI response was seen in 4/6 pts. A trend in decreased sVEGFR levels was seen at higher doses. Conclusions: At the MTD level of 500 mg BID OSI-930 is an active, well-tolerated compound with clinically relevant antitumor activity and exposure levels consistent with antitumor activity in preclinical models. PD data indicate mechanistic proof of concept for OSI-930. OSI-930/erlotinib combination phase I study is currently enrolling. [Table: see text]

Phase I study of RAD001 (everolimus), cetuximab, and irinotecan as second-line therapy in metastatic colorectal cancer (mCRC)

e15115 Background: The PI3K/AKT/mTOR pathway is frequently dysregulated in colorectal cancer (Cancer Res 2005;65:11227). In a phase I study in patients with advanced solid tumors, everolimus an oral mTOR inhibitor demonstrated clinical benefit including a partial response in pts with colorectal cancer (J Clin Oncol 2008;26:1603–10; J Clin Oncol 2008; 26:1588–95). Methods: This open-label, multicenter phase I study uses a Bayesian logistic model to identify feasible doses of everolimus + irinotecan + cetuximab. Adult pts with mCRC progressing despite prior 5-FU/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (XELOX) plus bevacizumab (if standard practice) were treated using a sequential dose escalation scheme (Table). Dose decisions were driven by the probability of dose-limiting toxicity (DLT) in the first 2 cycles. Dose level decisions were based on maximizing the probability that end-of-cycle-2 DLT rate would be within the targeted toxicity interval (20% to &lt;35%) and minimizing the risk of over-dosing (&lt; 5% risk of unacceptable toxicity and &lt; 25% risk of excessive/unacceptable toxicity). Results: 18 pts were treated from April ‘07 to August ‘08, 5 pts at dose level A1 and 13 pts at dose level B1. Two DLTs (G3 rash on cycle 2 day 1 lasting &gt; 7 days and G3 mucositis on cycle 1 day 14 lasting &gt; 7 days, 1 pt each) were reported in 4 evaluable pts at dose level A1. No DLTs were reported in 7 evaluable patients at dose level B1. Conclusions: At dose level B1 everolimus in combination with irinotecan and cetuximab was generally well tolerated. The study was stopped due to changes in clinical practice based on emerging data indicating that cetuximab has limited efficacy in mCRC patients with KRAS mutations and that efficacy data favors daily RAD001 over weekly dosing. Patients in this study were treated with cetuximab irrespective of KRAS status. [Table: see text] [Table: see text]

Phase II study of a 3-weekly liposome-encapsulated doxorubicin/docetaxel/pegfligrastrim in combination with weekly trastuzumab as primary treatment in HER2 positive early stage breast cancer patients (II-IIIa). GEICAM 2003-03 study.

Abstract Abstract #5117 Objective: To assess the safety and efficacy of Myocet (M), Docetaxel (T), Trastuzumab (H) with prophylactic Pegfilgrastrim (N) as neoadjuvant chemotherapy in operable breast cancer patients (pts). The primary efficacy end point was pathologic complete response in the breast. Methods: Eligible pts had pathologically confirmed stage II or IIIA untreated breast cancer and HER2 overexpression determined by FISH in a central laboratory. M 50 mg/m2 and T 60 mg/m2 were given on day 1 and N on day 2 every 3 weeks for 6 cycles (Cy); H (4mg/Kgr loading dose, then 2 mg/Kgr/week) was given intravenously for 17 weeks, recommended dose in a phase I study (Proc ASCO 2007,25:596s Abstr.# 11.032). After all chemotherapy was completed, clinical responses were assessed. After surgery, pathological responses were evaluated using the Miller Payne scoring scale (MPSS). Results: 59 pts have been evaluated. Median age was 47.6 years (range 24-71) and median clinical tumour size 47.5 mm (range, 10-80). 19 pts (32.2%) presented with stage IIIA disease and 40 pts (67.8%) with stage II, 36 pts (61.0%) were premenopausal; 50 pts (84.8%) had histological grade 2-3 tumours; and 29 (49.2%) were ER-PgR-negative. All the pts received M and T 6 Cy with medium relative doses intense of 98.9% and 99.1% respectively. Objective clinical response rate was 84.7% (CI: 75.5-93.9) with 31 (52.5%) complete responses and 19 (32.2%) partial responses. 42 pts (71.2%) underwent conservative surgery, 17 pts (28.8%) achieved a pathological complete response in breast (Grade 5 in MPSS), of these, 16 pts (27.1%) achieved a pathological complete response in breast and axilar (Grade 5A+Grade 5D). Main grades (G) toxicities during MTHN treatment: leucopenia G3/4 was present in 18 pts (30.5%); neutropenia G3/4 in 17 pts (28.8%); febrile neutropenia G3 in 3 pts (5.1%); diarrhea G3 was present in 3 pts (5.1%); G2 rash in 2 pts (3.4%); G3 asthenia in 5 pts (8.5%) and stomatitis G3 in 1 pt (1.7%). 8 pts (13.6%) experienced asymptomatic and reversible cardiac left ventricular function G2. Conclusions: Concomitant administration of M plus THN is highly effective and active regimen with little toxicity in pts with HER2+ and early stage breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5117.

Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04–02)

2057 Background: Glioblastomas (GBM) frequently have amplification/mutation of EGFR and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have only modest activity, there is a rationale for combinations of these agents. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor CCI-779 in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, &gt; 18 yrs old, KPS &gt; 60, adequate bone marrow reserve and organ function. Patients (pts) must not be receiving enzyme inducing antiepileptic drugs. The dose of erlotinib was fixed at 150 mg/d. Patients initially received CCI-779 50 mg intravenously once weekly and the dose was adjusted based on toxicities. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade (G) 4 hematologic toxicity except for G3 thrombocytopenia, and any G3 or unacceptable G2 non-hematologic toxicities. Escalation was performed in groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 pts. Results: To date 22 eligible pts have been enrolled (15 GBM; 7 AG). Patient characteristics were 12 male, 10 female; median age: 54 (26–74); median KPS 90 (70–100); median prior chemotherapy regimens 1 (0–3). Two of 3 pts receiving 50 mg of CCI-779 developed DLTs (intolerable G2 rash &amp; mucositis, &amp; G3 liver function abnormalities; G3 rash &amp; dehydration). Three of 6 pts receiving 25 mg of CCI-779 weekly experienced DLTs (G3 rash; G3 rash, diarrhea, dehydration; G3 mucositis &amp; infection). Two of 6 patients receiving weekly 15 mg of CCI-779 experienced G3 rash. The protocol was amended to define a DLT only if &gt; G3 toxicities persisted despite maximal therapy. Six additional pts were treated at 15 mg of CCI-779. One of 6 pts developed a G3 rash. Conclusions: The combination of erlotinib and CCI-779 was associated with a higher than expected incidence of rash and mucositis. The MTD for this combination is likely to be 150 mg/d of erlotinib and 15 mg/d of CCI-779. Final pharmacokinetics and response data will be presented. No significant financial relationships to disclose.

Phase I dose escalation pharmacokinetic study of erlotinib after failure of prior chemotherapy in patients with advanced NSCLC who continue to smoke

3597 Background: The survival benefit associated with erlotinib is greater in never smokers than in current smokers. Former/never smokers experience a higher incidence of toxicity (e.g., rash) than current smokers, potentially due to greater erlotinib exposure. A higher dose of erlotinib, if feasible, may improve outcome in current smokers. Methods: A 2-part study was initiated to investigate the feasibility of escalating erlotinib to define the MTD in smokers and evaluate pharmacokinetics in patients (pts) dosed at this MTD versus 150 mg/d. Part I: sequential cohorts of advanced NSCLC pts currently smoking =10 cigarettes/d for = 1yr, ECOG PS 0–1, adequate organ function, and no prior EGFR inhibitor, received escalating doses of erlotinib for 14 days until DLT was seen in 2/6 pts. Part II: Upon identification of the MTD, pts were randomized between MTD and 150 mg/d erlotinib and PK assessed at D14. Pts could receive erlotinib beyond D14 until PD or toxicity. Results: Twenty-two pts were enrolled in Part I at 4 dose levels (#pts (MTD-evaluable pts)/dose level in mg/d): 3(3)/200, 6(3)/250, 8(6)/300 and 5(5)/350). Median/range age was 61 yrs (45–69) with 13 males and 9 females. Histology was Adenocarcinoma (9/22), Squamous (6/22) and other (7/22). Fourteen pts had prior RT and all had prior CT (median/range # prior regimens 1 (1–2)). Median/range # cigarettes smoked and duration of smoking was 18/d (10–40) and 42 yrs (10–54), respectively. DLT was observed in 1/6 MTD- evaluable pts at 300 mg/d (G3 rash) and 2/5 pts at 350 mg/d (G3 acneiform dermatitis and G3 fatigue/decreased ECOG PS). Otherwise treatment was well tolerated with common G1/2 toxicities limited to skin toxicity (59%), diarrhea (55%), and nausea, vomiting and metabolic or eye disorders (each 14%). Conclusions: The MTD of erlotinib in NSCLC pts who continue to smoke was 300 mg/d. Part II continues to compare the steady state PK of erlotinib at 300 versus 150 mg/d. The potential benefits of a higher dose of erlotinib in current smokers may warrant further evaluation. No significant financial relationships to disclose.

A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies

3594 Background: Erlotinib is a potent oral TKI of the epidermal growth factor receptor (EGFR). At the current recommended daily dose of 150 mg/day there is activity in advanced stage NSCLC, but with frequent grade 1/2 rash and diarrhea. We performed a phase I dose escalation study of erlotinib with a once and twice weekly schedule to assess the PKs, PDs, and to determine if toxicities would be less on an intermittent but high dose schedule. Methods: A standard dose escalation schedule starting at 1,400 mg once/week and 600 mg twice/week with increments of 200 mg to 4 dose cohorts/schedule was utilized with three patients per cohort. A cycle consisted of 3 weeks of therapy. PKs were performed on cycle 1 and 2. PDs on normal skin punch biopsies were performed at baseline and after cycle 1. Tumour evaluation was done following every 2nd cycle. Subjects were treated until progression or unacceptable toxicity. Results: 32 patients were enrolled from Oct 2004-April 2006. Median age 58 years (28–74 years); median PS 1 (0–2); and median prior palliative systemic regimens 2 (0–6). In the once weekly schedule the maximum tolerated dose (MTD) was not reached with the top dose of 2,000 mg/week. A median of 2 cycles were delivered (1–14), with 3/13 patients achieving stable disease = 3 months. 4/13 patients had G1 rash and 6/13 patients G1 diarrhea during the first 2 cycles. In the twice weekly schedule the MTD was reached at 1,200 mg twice/week with 2/6 subjects experiencing G3 rash. The recommended dose level is 1,000 mg twice/week. A median of 4 cycles were delivered (1–28) with 2 partial responses, 1 minor response and 6 stable disease = 3 months out of 19 patients in total. G1/2 rash or diarrhea occurred in 13 and 9 patients respectively. No corneal toxicity was seen. The PK data demonstrated a variable but linear pattern. At 1,000 mg twice/week the median Cmax, Tmax and AUC0–24 hr was 6.28 μg/ml, 2 hours and 135 μg.h/ml respectively. PD analysis is ongoing. Conclusions: A once weekly and twice weekly high dose schedule of erlotinib is feasible, with MTD not reached in the once weekly schedule. A recommended dose of 1,000 mg twice/week has clinical activity, is generally well tolerated, and results in significantly higher systemic exposure than the 150 mg once daily dose. No significant financial relationships to disclose.

Patterns of management of rash associated with epidermal growth factor receptor inhibitors (EGFRIs): A national practice survey

14081 Background: Dermatological toxicities are frequent in patients receiving epidermal growth factor inhibitors (EGFRIs), which significantly affect health and quality of life. No current consensus or guidelines exist for the management of these manifestations. In order to gain insight on actual management approaches, a retrospective survey was conducted across oncology practices in the US. Methods: A survey in person was carried out that included 51 questions to 110 practitioners administering EGFRIs in the US, during which time erlotinib, cetuximab and gefitinib were FDA-approved. Open- and closed-ended questions relating to frequency and CTC-graded (G) severity of rash observed, management patterns, and impact on continued EGFRI therapy were evaluated. Statistical testing for correlations was done using Fisher’s exact test. Results: Respondents (resp) included MDs (72%), nurses (23%), NPs (4%), and pharmacists (1%). Majority (&gt;50%) of rash events observed were mild/moderate (G1 in 39% + G2 in 34%). Interventions against rash by resp was based on severity, with G1 treated by 47%, G2 (71%), G3 (87%), G4 (80%). Treatments for G1/2 included only topical agents (TA) by 30% of providers, and combined TA + systemic agents (SA) for G3 (G4) by 48% (30%) of providers. Interestingly, 84% of resp indicated G2 rash improved with TA+SA therapy and only 44% with SA only. Although severe events were reported infrequently (4% and 3% of resp see &gt;50% of G3 and 4 events, respectively), EGFRIs were frequently dose modified (76%) or discontinued (32%) due to rash. Conclusions: Rash is frequent and its management heterogeneous across the US, which increases with rash G. These findings suggest that combined therapy (TA + SA) is more effective than single-agent. Therefore, the high frequency of dose EGFRI modification/discontinuations reported may be minimized by proactive interventions. Trials evaluating proactive and reactive combined TA + SA against rash are currently underway. No significant financial relationships to disclose.

A Phase 1/2 Study of SKI-606, a Dual Inhibitor of Src and Abl Kinases, in Adult Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphocytic Leukemia (ALL) Relapsed, Refractory or Intolerant of Imatinib.

SKI-606 is an orally available, dual Src/Abl kinase inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation in biochemical assays. BaF3 cell lines and primary cells from pts expressing different imatinib-resistant Bcr-Abl mutant proteins are sensitive to SKI-606 in vitro. Unlike imatinib and dasatinib, SKI-606 exhibits no significant inhibition of c-kit or PDGFR. This differential selectivity may result in clinical benefit by altering the safety profile. In the phase 1 portion of this phase 1/2 study, pts in chronic phase with imatinib relapsed or refractory disease were eligible for treatment with SKI-606 once-daily dosing. 18 pts [median age: 62 yrs (range 27 – 72); 14 male; 4 female; median CML duration: 5.8 yrs (range 0.9 – 11.1); and median time on imatinib (n=16): 3.9 yrs (range 0.8 – 6.5)] have been enrolled in the following dose cohorts (mg/day): 400 (3 pts), 500 (3 pts) and 600 (12 pts), and have been on treatment for 30 to 192 days. 17/18 pts remain on study; 1 pt discontinued with disease progression. The following SKI-606-related AEs have been reported (n=15, G1/2): diarrhea (87%), nausea (33%), vomiting (20%), abdominal pain (13%), rash (13%), asthenia (13%), and increased AST/ALT levels (7%). 2 pts treated at 600 mg experienced a G3 toxicity: rash and thrombocytopenia. 5 pts (4 pts at 600 mg and 1 pt at 500 mg) had dose reductions for rash, thrombocytopenia, diarrhea, fever and increased AST/ALT levels. No pleural effusion or pulmonary edema has been reported. Of the 7 pts who entered the study in hematologic relapse and have completed 1 month of treatment, all have achieved complete hematologic response. Of the 7 pts on treatment ≥ 12 weeks (time of first cytogenetic assessment), 3 pts have achieved complete cytogenetic response and 1 pt a minimal cytogenetic response. 6/7 pts who have achieved complete hematologic response had pre-treatment imatinib-resistant Bcr-Abl mutations: M351T; F359V; T315I; F359(V,F); and 2 pts with multiple mutations [L248(L,V) and H396(H,R); H396(H,P) and E286(E,G) and M351(T,M)]. The 3 pts with complete cytogenetic response had mutations: M351T; M244V; and H396(H,P), E286(E,G) and M351(T,M). Based on the emergence of 1 DLT of G3 rash, and additional G2 GI and dermatologic toxicities observed at 600 mg, 500 mg has been selected as the dose for the phase 2 portion of the study. Patients in all phases of CML and Ph+ ALL are now being enrolled. SKI-606 is well tolerated in pts with CML, with a primarily GI and dermatologic safety profile, and with encouraging evidence of clinical activity in imatinib-resistant patients with complete hematologic and cytogenetic responses.