Dose-finding Cohort Research Articles

Pilot trial of ibrutinib plus nivolumab in patients with metastatic renal cell cancer (mRCC): results from a dose-finding cohort.

4580Background: Immune checkpoint inhibitor therapy (CIT) has transformed the management of patients (pts) with mRCC, with a fraction experiencing durable tumor responses. However, most eventually ...

Single-agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of LEN + etoposide (ETP) + ifosfamide (IFM) in patients (pts) aged 2 to ≤25 years with relapsed/refractory osteosarcoma (OS).

11527Background: LEN is a multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET. In human pediatric OS xenograft models, LEN enhanced the antitumor activity of IFM + ETP. In a phase (Ph)...

Pilot trial of ibrutinib plus nivolumab in patients (pts) with metastatic renal cell cancer (mRCC): Results from a dose-finding cohort.

600 Background: Immune checkpoint inhibitor therapy (CPI) has transformed the management of pts with mRCC, with a fraction experiencing durable tumor responses. However, most eventually develop disease progression after either an initial response to CPI or while on CPI. Newer agents that modulate immune response can possibly potentiate CPI therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate CPI. We conducted an investigator-initiated pilot trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC pts, particularly in those previously exposed to CPI. Here we report initial safety and efficacy results from the dose-finding cohort. Methods: Pts with mRCC of any histologic subtype and who have completed at least one line of prior systemic therapy including prior CPI were eligible. Pts must have acceptable end-organ function and Zubrod PS of 0-2. Treatment consisted of nivolumab 240 mg IV q2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade(Gr) 3+ adverse event (AE) attributable to therapy. Results: As of 9/18/17, 12 pts have been enrolled, six to each dose level. Patient characteristics: Mean age = 62 years (range 44-78); Male sex = 7 (58%); White race = 9 (75%); Prior CPI = 11 (92%). Three pts experienced one DLT each in dose level 0 (all Gr3): elevated lipase, hypoalbuminemia, & nausea. Only 1 DLT has been seen thus far in dose level -1 (Gr3 infection). The most common Gr3+ AEs include anemia (n = 5), ALT elevation (4), AST elevation (3), nausea (3), hypoalbuminemia (2), esophagitis, infection, lipase increase, and vomiting (1 each). Two pts with prior CPI had partial tumor response (1 confirmed, 1 unconfirmed). Conclusions: Ibrutinib at a dose of 420mg orally once daily in combination with nivolumab 240mg IV q 2 weeks appears feasible and tolerable in mRCC patients. No unique immune-related AEs have been seen thus far. Anti-tumor activity was seen in 2 pts previously exposed to PD1-targeted therapy. Further evaluation of this combination is warranted. (Supported by Pharmacyclics and UCDCCC). Clinical trial information: NCT02899078.

Trace element repletion following severe burn injury: A dose-finding cohort study

Major burn patients are characterized by large exudative losses of Cu, Se and Zn. Trace element (TE) repletion has been shown to improve clinical outcome. Having increased the TE doses over time, the study aimed at analysing if our repletion protocol corrected TE plasma concentrations and if the necessity for continuous renal replacement therapy (CRRT) might increase the TE needs. Retrospective analysis of prospectively collected data in burn patients requiring intensive care (ICU) between 1999 and 2015. Admission on day 1, full treatment, burned surface area (TBSA) ≥20% and ≥1 TE plasma determination during the stay. Four groups were constituted according to protocol changes. Period 1 (P1): 1999-2000, P2: 2001-2005, P3: 2006-2010, P4: 2011-2015. Changes consisted in increasing TE repletion doses and duration. Demographic data, daily TE intakes and weekly plasma concentrations were retrieved for the first 21 ICU-days. Data as median (IQR). 139 patients completed the criteria, aged 37 (28) years, burned on 35 (25) % TBSA. As a result of prescription, Cu, Se and Zn intakes increased significantly between P1 and P4, resulting in normalization of plasma Cu (16μmol/l) since P3 and Zn (13.5μmol/l) since P2. Median plasma Se were above reference range (1400nmol/l) during P3 and P4. CRRT patients required higher doses of Cu for maintenance within normal ranges. This dose finding study shows that the latest repletion protocol is safe and normalizes Cu and Zn concentrations. Se doses result in supra-normal Se concentrations, suggesting prescription reduction. CRRT patients are at high risk of Cu depletion and require specific monitoring.

Abstract OT3-06-02: A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy)

Abstract Background: Resistance to endocrine therapy remains an important clinical problem in hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC), necessitating alternative treatment options. The insulin-like growth factor (IGF) axis and cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway have been implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including BC. Binding of IGF-I and -II to the IGF receptor results in upregulation of cyclin D1, and subsequent progression through the cell cycle, thus providing rationale for the simultaneous inhibition of IGF-I and -II and CDK4/6. This Phase Ib trial assesses the maximum-tolerated dose (MTD)/recommended phase II dose (RP2D), safety and preliminary efficacy of the IGF-ligand-neutralizing antibody, xentuzumab, in combination with abemaciclib, a selective, small-molecule inhibitor of both CDK4 and 6, in patients (pts) with solid tumors. The trial includes four dose finding cohorts followed by two expansion cohorts. Only those cohorts that will include pts with postmenopausal HR+, HER2- BC will be presented here. Trial design: In this phase Ib multicenter, non-randomized, open-label, dose escalation trial (BI 1280.18 [NCT03099174]), the key aims in the BC cohorts (Cohorts B–D, F) are to define the MTD or recommended phase 2 dose (RP2D), and to evaluate the preliminary efficacy, safety and tolerability of xentuzumab plus abemaciclib in combination with endocrine therapies. Eligible pts include adults ≥18 yrs (≥20 for Japan), with measurable or evaluable disease, adequate organ function, ECOG PS ≤1, and postmenopausal locally advanced or metastatic HR+, HER2- BC (Cohorts B–D, F). CDK4/6 inhibitor-naïve pts (Cohorts B–D) and pts who have received prior CDK4/6 inhibitors (palbociclib or ribociclib) plus aromatase inhibitors (Cohort F) are included. The MTD/RP2D of xentuzumab plus abemaciclib to be used in Cohorts B–D will be established in pts with solid tumors (Cohort A) who will receive xentuzumab (starting dose 1000mg weekly iv) plus abemaciclib (starting dose 150mg every 12 hours). CDK4/6 inhibitor-naïve pts with BC will receive xentuzumab plus abemaciclib at the RP2D determined in Cohort A in combination with letrozole (2.5mg/day; Cohort B), anastrozole (1mg/day; Cohort C), or fulvestrant (500mg/month; Cohort D). CDK4/6 inhibitor pre-treated pts with BC (Cohort F) will receive xentuzumab plus abemaciclib and fulvestrant at the RP2D determined in Cohort D. Primary endpoints in the BC cohorts are the MTD and/or RP2D of xentuzumab plus abemaciclib in combination with endocrine therapies, and the objective response (OR) in CDK4/6 inhibitor pre-treated pts with advanced BC (Cohort F); disease control (DC), duration of DC, time to OR, duration of OR, and progression-free survival (PFS) in Cohort F are secondary endpoints. Additionally, PK outcomes, safety and tolerability will be assessed in all cohorts. This study will be conducted in the US, Europe and Japan. Pt screening started in May 2017. Target enrolment is ˜88 pts, including ˜56 pts with advanced HR+, HER2- BC, of whom ˜20 had previously been treated with CDK 4/6 inhibitors. Citation Format: Yee D, Sablin MP, Iwata H, Johnston EL, Bogenrieder T, Serra J, Hua H, Lo Russo P, Prat A. A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-02.

A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139).

208 Background: PEGPH20 degrades hyaluronan (HA), a major component of the stroma, increases delivery of gemcitabine and prolongs survival in preclinical models. We evaluated the activity of PEGPH20 in combination with mFFOX in mPC , unselected for tumor HA. Methods: Pertinent eligibility: untreated mPC, PS of 0-1 and adequate organ function. Standard FFOX was modified to add prophylactic growth factor support and omit bolus 5FU. Due to increased thromboembolic (TE) events with PEGPH20, an amendment instituted LMWH prophylaxis in the PEGPH20 arm only. Following a dose finding cohort of mFFOX + PEGPH20, the Phase II study randomized patients (1:1) to the combination arm or mFFOX alone (n = 138). The primary endpoint was overall survival (OS), with a null median OS of 10 mo and an alternative of 15 mo (1-sided type 1 error 0.1, 80% power). Results: PEGPH20 at 3 mcg/kg, q2 weeks was more tolerable than twice weekly dosing. The randomized phase II study began May 2015. The planned interim futility analysis when 35 deaths occurred gave a HR of 0.44 favoring the standard arm, thus the study was closed to accrual (March 2017). As of August 22, 2017 (n = 111), the estimated median OS in the mFFOX arm was 15.1 mo (95% CI 10.1-15.7) vs 7.6 mo (95% CI 4.6-9.2) in the PEGPH20 arm. Conclusions: OS in the mFFOX control arm (15.1 mo) is longest yet reported. Addition of PEGPH20 to mFFOX is not recommended for further study and appears to be detrimental (HR = 0.48). The impact of PEGPH20 on OS was unexpected and in contrast to favorable results reported for the combination of gemcitabine/nab-paclitaxel + PEGPH20 especially in the HA high cohort (Hingorani S et al. A 4008, ASCO 2017). PEGPH20 with mFFOX caused increased toxicity (mostly GI and TE events) and decreased treatment duration compared to mFFOX alone. Tumor HA content will be analyzed. Funding: NIH/NCI grants CA180888, CA180819; and in part by Halozyme Inc. Clinical trial information: 01959139. [Table: see text]

90TiP - A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC; +/- endocrine therapy), or non-small-cell lung cancer (NSCLC)

Background: The insulin-like growth factor (IGF) and the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathways have been implicated in the pathogenesis and resistance mechanisms of various cancers, including HR+, HER2- BC and NSCLC. IGF ligand-dependent signaling via the IGF receptor results in upregulation of cyclin D1, and subsequent progression through the cell cycle, thus providing a rationale for simultaneous inhibition of IGF and CDK4/6. This trial assesses the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, and preliminary efficacy of the IGF ligand-neutralizing antibody, xentuzumab, in combination with abemaciclib, a selective inhibitor of CDK4 and 6, +/- endocrine therapy, in pts with solid tumors. Trial design: Study BI 1280.18 is a phase Ib multicenter, non-randomized, open-label, dose-escalation trial with four dose-finding cohorts (Cohorts A–D) and two expansion cohorts (Cohorts E, F). Pts must be aged ≥18 yrs (≥20 for Japan), with measurable or evaluable disease, adequate organ function, ECOG PS ≤ 1, and unresectable advanced/metastatic solid tumors after failure on standard therapy (Cohort A), postmenopausal locally advanced/metastatic HR+, HER2- BC (Cohorts B–D, F), or stage IV NSCLC after 1–2 lines of therapy and failure after platinum-based chemotherapy and immunotherapy (Cohort E). CDK4/6 inhibitor-naïve pts (Cohorts A–E) and pts who have received prior CDK4/6 inhibitors (palbociclib or ribociclib) plus aromatase inhibitors (Cohort F) are included. Pts will receive either xentuzumab plus abemaciclib alone (Cohorts A, E) or in combination (at MTD defined in Cohort A) with letrozole (Cohort B), anastrozole (Cohort C), or fulvestrant (Cohorts D, F [at MTD for cohort D]). Primary endpoints are MTD and/or RP2D (Cohorts A–D) and objective response (Cohorts E, F). Further efficacy outcomes, pharmacokinetics, safety, and tolerability will also be assessed in all cohorts. This study will be conducted in the USA, Europe, and Japan. Pt screening started in May 2017. Target enrollment is ∼88 pts. Clinical trial indentification: NCT03099174; 1280.18. Legal entity responsible for the study: Boehringer Ingelheim Funding: Boehringer Ingelheim Disclosure: A. Prat: Advisory board for Nanostring Technologies. E.L. Johnston: Owns stocks in and is an employee of Eli Lilly and Company. T. Bogenrieder: Employee of Boehringer Ingelheim and has stocks in Roche, Seattle Genetics and Immunogen. P. LoRusso: Served on advisory boards for Alexion, Ariad, CytomX, GenMab, Glenmark, Halozyme, Ignyta, Menarini, Novartis, Omniox. She served on a data safety monitoring board for Agios. She also was a member of imCORE Alliance with Roche-Genetech. All other authors have declared no conflicts of interest.

Single-agent dose-finding cohort of a phase 1/2 study of lenvatinib (LEN) in children and adolescents with refractory or relapsed solid tumors.

10544 Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced renal cell carcinoma. We show results from the single-agent LEN dose-finding part of a phase 1/2 study in children and adolescents with solid tumors. Methods: Pts had any relapsed or refractory solid tumor, evaluable or measurable disease, were aged 2 to ≤18 years, had < 2 prior VEGF-targeted therapies, and adequate organ function. A starting dose of LEN 11 mg/m2was escalated with a time-to-event continual reassessment method. The primary endpoint was to determine the LEN recommended dose (RD). Secondary objectives included best overall response (BOR), objective response rate, safety, and pharmacokinetics (PK). Results: 23 pts enrolled (11 mg/m2: n = 5, 14 mg/m2: n = 11, 17 mg/m2: n = 7). The most common tumors were rhabdomyosarcoma (n = 5), Ewing sarcoma (n = 4), and neuroblastoma (n = 3). 3 Dose-limiting toxicities occurred in cycle 1 at 14 mg/m2 (increased alanine aminotransferase: 1; hypertension: 2). All pts had any-grade treatment-emergent adverse events (TEAEs; grade 3/4: 65%). Most common any-grade TEAEs were vomiting (52%), abdominal pain (48%), decreased appetite (48%), diarrhea (44%), and hypothyroidism (44%). 1 Pt discontinued LEN due to a LEN-related TEAE (hypertension). BOR was stable disease (n = 10). Effect of age on oral clearance and central volume of distribution was not significant. Exposure was similar to that in adults. LEN 14 mg/m2/day was therefore identified as the RD. Updated cohort 1 data will be shown. Conclusions: The LEN RD in children and adolescents was similar to the adult dose and showed a reasonable safety profile. PK in these pts did not differ significantly from that in adults. The phase 1b dose-finding study of LEN in combination with chemotherapy in osteosarcoma (OS) and phase 2 LEN monotherapy (RD 14 mg/m2) parts in DTC and OS are ongoing. Clinical trial information: NCT02432274.

Commentary: Phase I Trial of Carboplatin and Gemcitabine Chemotherapy and Stereotactic Ablative Radiosurgery for the Palliative Treatment of Persistent or Recurrent Gynecologic Cancer.

Background: We conducted a phase I trial to determine the safety of systemic chemotherapy prior to abdominopelvic robotic stereotactic ablative radiotherapy (SABR) in women with persistent or recurrent gynecologic cancers. Methods: Patients were assigned to dose-finding cohorts of day-1 carboplatin (AUC 2 or 4) and gemcitabine (600 or 800 mg/m2) followed by day-2 to day-4 Cyberknife SABR (8Gy X 3 consecutive daily doses). Toxicities were graded prospectively by common terminology criteria for adverse events, version 4.0. SABR target and best overall treatment responses were recorded according to response evaluation criteria in solid tumors, version 1.1. Findings: The maximum tolerated dose of chemotherapy preceding SABR was carboplatin AUC 4 and gemcitabine 600 mg/m2. One patient experienced manageable, dose-limiting grade 4 neutropenia, grade 4 hypokalemia, and grade 3 nausea attributed to study treatment. One patient had a late grade 3 rectovaginal fistula 16 months after trial therapy. Among 28 SABR targets, 22 (79%) showed a partial response and six (21%) remained stable. Interpretation: Systemic chemotherapy may be given safely prior to abdominopelvic robotic SABR with further investigation warranted. Funding: National Institutes of Health grant P30 CA43703

Phase Ib Study (GO28440) of Venetoclax with Bendamustine/Rituximab or Bendamustine/Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Phase Ib Study (GO28440) of Venetoclax with Bendamustine/Rituximab or Bendamustine/Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Updated Safety and Preliminary Efficacy Data from a Phase 1b Study Combining Venetoclax (GDC-0199, ABT-199) with Bendamustine/Rituximab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Updated Safety and Preliminary Efficacy Data from a Phase 1b Study Combining Venetoclax (GDC-0199, ABT-199) with Bendamustine/Rituximab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Phase I Trial of Carboplatin and Gemcitabine Chemotherapy and Stereotactic Ablative Radiosurgery for the Palliative Treatment of Persistent or Recurrent Gynecologic Cancer.

We conducted a phase I trial to determine the safety of systemic chemotherapy prior to abdominopelvic robotic stereotactic ablative radiotherapy (SABR) in women with persistent or recurrent gynecologic cancers. Patients were assigned to dose-finding cohorts of day 1 carboplatin (AUC 2 or 4) and gemcitabine (600 or 800 mg/m(2)) followed by day 2 to day 4 Cyberknife SABR (8 Gy × three consecutive daily doses). Toxicities were graded prospectively by common terminology criteria for adverse events, version 4.0. SABR target and best overall treatment responses were recorded according to response evaluation criteria in solid tumors, version 1.1. The maximum tolerated dose of chemotherapy preceding SABR was carboplatin AUC 4 and gemcitabine 600 mg/m(2). One patient experienced manageable, dose-limiting grade 4 neutropenia, grade 4 hypokalemia, and grade 3 nausea attributed to study treatment. One patient had a late grade 3 rectovaginal fistula 16 months after trial therapy. Among 28 SABR targets, 22 (79%) showed a partial response and 6 (21%) remained stable. Systemic chemotherapy may be given safely prior to abdominopelvic robotic SABR with further investigation warranted.

Preliminary Results of a Phase 1b Study (GO28440) Combining GDC-0199 (ABT-199) with Bendamustine/Rituximab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

IntroductionNew therapies are needed for patients (pts) with chronic lymphocytic leukemia (CLL). BCL2 is an anti-apoptotic protein that is overexpressed in CLL and may be associated with resistance to available therapies; GDC-0199 is an orally available, selective BCL2 inhibitor. The combination of bendamustine (B) and rituximab (R) has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated pts with CLL and is often used in these pts. Preclinical data suggest that GDC-0199 combined with BR may show synergistic activity in CLL. Moreover, clinical data from single-agent studies of GDC-0199, and in combination with rituximab in pts with CLL, support combining GDC-0199 with BR in this population. Data presented here are from an ongoing phase 1b study that is evaluating the maximum tolerated dose of GDC-0199 when given in combination with BR, as well as the safety, tolerability, and order of administration of this combination in R/R or previously untreated pts with CLL.MethodsPts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts ranging from 100 to 600 mg/day of GDC-0199 using a 3+3 dose escalation design. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or BR (Schedule B) introduced first, both incorporating a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS). Prophylaxis measures to mitigate TLS include IV hydration, treatment to prevent hyperuricemia and hospitalization. After completing combination therapy, R/R pts will continue single-agent GDC-0199 until disease progression. Previously untreated pts will continue single-agent GDC-0199 for up to 18 months. Dose-limiting toxicity (DLT) data are identified after all pts in a cohort have completed ³21 days of combination treatment at the target dose of GDC-0199 and focus on treatment emergent TLS and cytopenias. [Display omitted] ResultsAs of May 2014, 6 pts with R/R CLL have been enrolled in the dose finding stage of the study with a median time on study of 67 (range 43-113) days. All 6 pts were enrolled on Schedule A; 3 pts were enrolled in the 100 mg GDC-0199 cohort and 3 pts were enrolled in the 200 mg cohort. Baseline characteristics of the 6 pts are as follows: median age 67 (range 52-71) years, 3 male pts, median of 2 prior CLL therapies (range 1-3, including 4 pts with previous exposure to fludarabine, cyclophosphamide and rituximab [FCR] and 1 with previous exposure to FCR and B), beta-2 microglobulin ≥3.5 mg/L in 2 pts, and unmutated IGHV in 5 pts. Prior to starting therapy, the median lymphocyte count was 40.85 x 109 cells/L (range 2.11-169 x 109 cells/L), hemoglobin level was 101.5 g/L (range 99-134 g/L), neutrophil count was 2.54 cells/μL (range 1.81-3.8 cells/μL), and platelet count was 83.5 x 109/L (range 49-250 x 109/L). Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 1 pt, medium risk 4 pts, and high risk 1 pt. Cytogenetic data are available for 3 pts: 1 pt had del17p, 2 pts had del 11q, and 3 pts had del 13q.No DLTs were observed. All 6 pts have experienced adverse events (AEs, Figure 2). The most common AE was anemia with most Grade ³3 AEs being hematological toxicities (Figure 2). One serious AE of bronchitis was observed in a pt enrolled in the 100 mg GDC-0199 cohort and resolved after treatment. Two pts in the 100 mg GDC-0199 cohort discontinued BR after the 21-day DLT window secondary to treatment emergent cytopenia: 1 with neutropenia after completing 1 cycle of BR (previous treatment FCR without baseline cytopenia) and the second with thrombocytopenia after completing 3 cycles of BR (previous treatment FCR and chlorambucil with thrombocytopenia at screening). Both pts remain on single-agent GDC-0199. No TLS events (laboratory or clinical) were observed and no deaths reported. [Display omitted] ConclusionThis is the first study to evaluate the combination of GDC-0199 and BR in pts with CLL. Despite 5 pts being identified as medium or high risk for TLS, no pts developed TLS as a result of the ramp-up dosing of GDC-199 and prophylactic measures. The most frequent AEs were hematological toxicities and generally manageable; however, 2 pts had to discontinue BR (after 1 and 3 cycles) but were able to remain on GDC-0199. Dose escalation in R/R pts is continuing in order to evaluate the optimal dose/schedule with a plan to enroll previously untreated pts in the near future. DisclosuresBoyd:Genentech: Research Funding; US Oncology/McKesson: Research Funding; Celgene: Consultancy. Morschhauser:Genentech: Travel grant Other; Gilead, Mundipharma, Bayer, Spectrum, Celgene: Honoraria. Wendtner:AbbVie, Genentech, Hoffman-La Roche, Mundipharma: Consultancy, Research Funding. Lymp:Genentech: Employment. Hilger:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Stilgenbauer:Genentech, Hoffman La Roche: Honoraria, Research Funding.

A Phase I Study of the Mek1/2 Inhibitor Selumetinib in Combination with First-Line Chemotherapy Regimens for Nsclc

ABSTRACT Aim: Selumetinib (AZD6244, ARRY-142886) is an orally available MEK1/2 inhibitor with activity in combination with docetaxel in the second-line setting for KRAS mutation-positive advanced NSCLC. This Phase I study assessed the safety, tolerability, recommended Phase II combination dose (RP2D), pharmacokinetics (PK) and preliminary efficacy of selumetinib in combination with first-line chemotherapy regimens in unselected patients (pts) with advanced/metastatic NSCLC. Methods: This open-label, multicentre study (NCT01809210) enrolled pts into dose-finding cohorts of orally administered selumetinib (50 mg bid [sel50] to 75 mg bid [sel75]) in combination with standard doses of gemcitabine (gem) or pemetrexed (pem) plus cisplatin (cis) or carboplatin (carb). Each dose cohort consisted of at least 3 and up to 6 evaluable pts. On completion of chemotherapy, pts had the option of maintenance selumetinib. Results: As of 20 April 2014, 17 pts were evaluable (8 female; median age 63; 8 adenocarcinoma, 8 squamous, 1 non-squamous histology) to the following treatment cohorts: gem + cis + sel50, n = 3; gem + cis + sel75, n = 1; gem + carb + sel50, n = 7; pem + carb + sel50, n = 2; pem + carb + sel75, n = 4. Median total selumetinib exposure was 78 days (range 16–224). The majority of adverse events (AEs) were CTCAE Grade 1 or 2. Selumetinib-related AEs of Grade ≥3 were seen in 7 pts: gem + cis + sel50, 0/3; gem + cis + sel75, 0/1; gem + carb + sel50, 6/7; pem + carb + sel50, 1/2; pem + carb + sel75, 0/4. One DLT of thrombocytopenia was observed in the gem + carb + sel50 cohort. Combination therapy did not appear to show any marked effect on the PK profile of selumetinib. Across all cohorts, partial responses were seen in 6/17 (35%) pts evaluable for response, and 4/17 (24%) had stable disease. Conclusions: The AE profile of selumetinib in combination with these chemotherapy regimens for NSCLC was consistent with the known profiles. Two tolerated dose regimens have been confirmed: gem + cis + sel50 and pem + carb + sel50. The activity of platinum-based regimens seems to be preserved in this unselected population. Dose escalation and expansion is ongoing; updated data including the RP2D and PK will be presented. Disclosure: F. Blackhall: Research funding: AstraZeneca; R. Califano: Consultancy/honoraria: Roche, Lilly, Boehringer Ingelheim, Pfizer; D. Ghiorghiu: Employment and stock ownership: AstraZeneca; A. Dymond: Employment and stock ownership: AstraZeneca; I. Smith: Employment and stock ownership: AstraZeneca R. Plummer: Consultancy agreement (no remuneration to date): AstraZeneca. Institutional trial costs. All other authors have declared no conflicts of interest.

Abstract B74: A Phase I trial of vertical inhibition of IGF signaling using IMC-A12, an IGF1-R inhibitor, and AZD6244, a MEK 1/2 inhibitor, in patients with advanced solid tumors.

Abstract Background: The IGF1 receptor activates key pro-survival signaling pathways critical in cancer including the RAS/RAF/MEK/ERK and PI3K/mTOR/AKT pathways. Despite this, clinical trials of single-agent IGF1-R antibodies have shown modest clinical benefit. In vitro data suggests that dual inhibition of IGF1-R and MEK synergistically decreases downstream pathway activation and increases apoptosis. Therefore, we performed a phase I clinical trial to test the safety and toxicity of combined IMC-A12 (anti-IGF1-R antibody) and AZD6244 (MEK 1/2 inhibitor). Methods: Patients were required to have advanced solid tumors refractory to standard therapy with adequate performance status and end-organ function. Treatment consisted of AZD6244 hydrogen sulfate capsules orally twice daily, and IMC-A12 intravenously on days 1 and 15 of each 28-day cycle. The study was a 3+3 design, with a dose-finding cohort and an expansion cohort treated at the maximally tolerated dose. Pharmacokinetic studies were performed on all patients, while pre- and post-treatment biopsies for pharmacodynamic assessment of pathway activity were obtained from patients on the expansion cohort. Results: 30 patients were enrolled on the study, 16 in the dose-finding cohort and 14 patients in the expansion cohort. The regimen was well-tolerated in most patients, and the most common study-drug related adverse events included rash, nausea/vomiting, diarrhea, and poor appetite/weight loss. Grade 3 or greater toxicities included nausea and vomiting, anemia, CVA, hypertension, hyperglycemia, and ophthalmologic symptoms (blurry vision, floaters, flashing lights, black dots/lines in field of vision, retinopathy). Three patients treated at dose level 2 (AZD6244 75 mg / IMC-A12 12 mg) developed dose-limiting toxicity of ophthalmologic symptoms; therefore the maximally tolerated combination dose was AZD6244 50 mg / IMC-A12 12 mg. 19 patients remained on study for at least 8 weeks and were evaluable for radiographic response. Two patients achieved a partial response (one unconfirmed), and 6 patients achieved progression-free survival of greater than 6 months. Two of the three patients with BRAF mutations showed prolonged progression-free survival on therapy. Pharmacokinetic analysis is ongoing. Paired pre- and on-treatment biopsies obtained in 5 patients showed significant suppression of phospho-ERK activity with treatment. Conclusions: Vertical inhibition of IGF1-R mediated signaling aims to avoid compensatory escape mechanisms by inhibiting additional downstream targets within the RAS/RAF/MEK/ERK and/or PI3K/mTOR/AKT pathways. Our study of IMC-A12 and AZD6244 showed that the drug combination is safe and well-tolerated, with decreased phosphorylation of ERK indicating effective target inhibition. Further study is necessary to identify biomarkers for patients likely to benefit from this treatment approach, particularly with regards to patients possessing BRAF mutations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B74. Citation Format: Breelyn A. Wilky, Michelle Rudek, Daniel Laheru, David Cosgrove, Ross Donehower, Barry Nelkin, Douglas Ball, L. Austin Doyle, Helen Chen, Xiaobu Ye, Nilofer Azad. A Phase I trial of vertical inhibition of IGF signaling using IMC-A12, an IGF1-R inhibitor, and AZD6244, a MEK 1/2 inhibitor, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B74.

Phase I Trial of Pelvic Radiation, Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC #663249) for Locally Advanced Cervical Cancer

This study assessed the safety/tolerability, pharmacokinetics, and clinical activity of three times weekly i.v. 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in combination with once-weekly i.v. cisplatin and daily pelvic radiation in patients with gynecologic malignancies. 3-AP is a novel small-molecule inhibitor of ribonucleotide reductase (RNR) and is being tested as a potential radiosensitizer and chemosensitizer. Patients with stage IB2 to IVB cervical cancer (n = 10) or recurrent uterine sarcoma (n = 1) were assigned to dose-finding cohorts of 2-hour 3-AP infusions during 5 weeks of cisplatin chemoradiation. Pharmacokinetic and methemoglobin samples and tumor biopsy for RNR activity were obtained on day 1 and day 10. Clinical response was assessed. The maximum tolerated 3-AP dose was 25 mg/m(2) given three times weekly during cisplatin and pelvic radiation. Two patients experienced manageable 3-AP-related grade 3 or 4 electrolyte abnormalities. 3-AP pharmacokinetics showed a 2-hour half-life, with median peak plasma concentrations of 277 ng/mL (25 mg/m(2)) and 467 ng/mL (50 mg/m(2)). Median methemoglobin levels peaked at 1% (25 mg/m(2)) and 6% (50 mg/m(2)) at 4 hours after initiating 3-AP infusions. No change in RNR activity was found on day 1 versus day 10 in six early complete responders, whereas elevated RNR activity was seen on day 10 as compared with day 1 in four late complete responders (P = 0.02). Ten (100%) patients with stage IB2 to IVB cervical cancer achieved complete clinical response and remained without disease relapse with a median 18 months of follow-up (6-32 months). 3-AP was well tolerated at a three times weekly i.v. 25 mg/m(2) dose during cisplatin and pelvic radiation. Clin Cancer Res; 16(4); 1298-306.

Treatment of Children with Relapsed Acute Myeloid Leukemia with Gemtuzumab in Combination with Mitoxantrone and Cytarabine.

Despite improvements in the treatment of children with de novo acute myeloid leukemia (AML), a substantial fraction of patients experience relapse. The Children's Oncology Group Phase I trial, AAML00P2, sought to test the safety and feasibility of combining Gemtuzumab (GMTZ) with a standard AML reinduction regimen of mitoxantrone and cytarabine in a dose de-escalation design. Patients received cytarabine 1000 mg/m2/dose every 12 hours on days 1–4 with mitoxantrone 12 mg/m2/dose daily on days 3–6. The starting dose of GMTZ for dose finding was 3 mg/m2 once on day 7. Doses for patients under 3 years of age were as follows: cytarabine 33 mg/kg/dose, mitoxantrone 0.4 mg/kg/dose, and GMTZ 0.1 mg/kg/dose. Three patients were enrolled in the dose finding strata and an additional 18 patients were subsequently enrolled to acquire further toxicity data. Of these, 15 were male and 6 female. The median patient age was 11.3 years, range 1.2 to 19.2 years. No patients in the initial dose finding cohort experienced a dose limiting toxicity. Toxicities observed in the entire cohort of 21 patients included hematologic and infectious complications typical of AML therapy. One patient had grade III bilirubin elevation. No patients had grade III or IV hepatic toxicity or grade III or IV veno-occlusive disease (VOD). Data on toxicity in stem cell transplant post GMTZ exposure is limited. However, no episodes of VOD have been reported. In summary, GMTZ combined with cytarabine and mitoxantrone is reasonably well tolerated in pediatric AML patients.