G3 Anorexia Research Articles

First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer.

3010 Background: PF-07104091 is a novel CDK2-selective inhibitor under investigation in pts with selected advanced or metastatic solid tumors. We present the first disclosure of data from the first-in-human, multicenter, phase 1 study of PF-07104091 monotherapy (NCT04553133). Methods: Pts with HR+/HER2- advanced/metastatic breast cancer (mBC) who received ≥ 2 lines of treatment for mBC including prior endocrine therapy (ET) + CDK4/6 inhibitors (CDK4/6i), and pts with other solid tumors, were included. Prior therapy with fulvestrant and chemotherapy was allowed for pts with mBC. PF-07104091 (75-500 mg) was given twice daily (BID) orally in 28-day cycles, following Bayesian design with overdose control, to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics and preliminary anti-tumor activity. Results: At data cut off (Aug 23, 2022), 35 pts with advanced solid tumors (n = 29 mBC) with median age 62y (range 32-80y), median 4 lines of prior systemic therapy (range 1–12) and ECOG PS 0 (20% pts) or 1 were enrolled. Of 29 pts with mBC, all had prior CDK4/6i, 25 (86.2%) prior fulvestrant, and 21 (72.4%) prior chemotherapy. Treatment-emergent adverse events (TEAEs) were observed in 34 pts (97.1%; 20 [57.1%] grade [G] ≥ 3). The most frequent TEAEs (all G≤3) were nausea (77.1%; 14.3% G3), diarrhea (48.6%; 8.6% G3), vomiting (48.6%; 2.9% G3), fatigue (45.7%; 20.0% G3) and anemia (45.7%; 8.6% G3). Dose-limiting toxicity occurred in 5 pts: 1 pt (G3 fatigue) at 300 mg BID; 2 pts (1 G3 nausea and G3 anorexia, 1 G3 nausea) at 375 mg BID, and 2 pts (1 G3 fatigue and 1 G3 diarrhea) at 500 mg BID. Steady-state PF-07104091 plasma exposures increased proportionally with dose. A trend of early decrease in ctDNA was observed. Further pharmacodynamic studies are ongoing. PF-07104091 300 mg BID was identified as the MTD and selected as the monotherapy RDE. Among 16 response evaluable mBC pts (all prior CDK4/6i+ET) with measurable disease at baseline, confirmed RECIST v1.1 partial responses were observed in 3 (18.8 %) pts (2 pts with duration of response > 6 months and 1 ongoing at data cut off), and stable disease in 6 (37.5%) pts. Disease control rate was 61.5% in mBC pts (response evaluable set, 95% CI: 40.6, 79.8). Conclusions: Treatment with PF-07104091 monotherapy was generally well tolerated and showed antitumor activity in heavily pretreated HR+ HER2- mBC pts who progressed on prior CDK4/6i. Dose expansions of PF-07104091 are ongoing as monotherapy in pts with ovarian cancer and in combination with fulvestrant in pts with breast cancer. Clinical trial information: NCT04553133 .

Safety and efficacy of PIPAC in patients with ovarian cancer with peritoneal metastases: A first-in-US phase I study.

5554 Background: Epithelial ovarian cancer (EOC) is characterized by chemoresistant recurrences primarily confined to the intraperitoneal cavity, frequently leading to malignant small bowel obstructions. Intraperitoneal (IP) chemotherapy has been incorporated in EOC, but only in the first-line setting. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel IP drug delivery method that optimizes tissue penetration depth and drug distribution, to treat recurrent peritoneal malignancies. Recent trials outside the U.S. demonstrated partial to stable response following PIPAC in recurrent EOC. To date, no clinical trials have been completed investigating the role of PIPAC in EOC in the United States. Methods: We performed a multicenter prospective phase I trial using IP cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 via PIPAC at 6-week intervals. Patients were eligible if they had recurrent disease with peritoneal metastasis; extraperitoneal metastasis was allowed. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included progression free survival, PCI scoring, RECIST measurements, and quality of life (QoL). The patients with gastric and uterine cancers’ toxicity data were used but given inherent prognostic differences the treatment efficacy for these patients were not used in this analysis. Adverse event (AE) monitoring was graded using CTCAE spanning 18 weeks. Following completion of treatment (³2 PIPACs) patients were followed up every 12 weeks. QoL was measured using patient-reported assessments at 0, 6, 12, and 18 weeks. Baseline demographics were summarized. Mean change in PCI was calculated between cycle (C) 1 and 2, and cycle 2 and 3. Toxicities attributed to the surgery or PIPAC were reported with highest grade for each patient. Results: Nine heavily pretreated, recurrent patients were enrolled in the trial: 7 with platinum-resistant recurrent EOC, 1 with uterine cancer, and 1 with gastric cancer. PIPAC completion rate was 71.4%. Median age of participants was 65 years. Median prior lines of chemotherapy were 4 (range 2 - 10). No surgical complications occurred in the cohort. Two patients came off study: one for G3 abdominal pain and the other for G3 anorexia. For the EOC cohort, the median PCI reduction was -1.4% (C1 to C2) and -2.8% (C1 to C3). One low-grade serous EOC patient demonstrated a partial response based on RECIST criteria and received 6 cycles. Two EOC patients showed an initial response based on PCI reduction, but progressed following Cycle 2. Overall, QoL was stable. Conclusions: PIPAC with cisplatin/doxorubicin in platinum-resistant ovarian cancer is well tolerated. Intraperitoneal responses were seen in a subset of low-grade serous ovarian cancer patients, which may warrant further study. Heavily pretreated, platinum-resistant high-grade EOC patients derived limited intraperitoneal control from PIPAC monotherapy. Clinical trial information: NCT04329494 .

A Multi-Center Phase Ib Trial of the Histone Deactylase Inhibitor (HDACi) Entinostat in Combination with Anti-PD1 Antibody Pembrolizumab in Patients with Refractory/Relapsed Myelodysplastic Syndromes (RR-MDS) or Oligoblastic Acute Myeloid Leukemia (RR-AML) after Hypomethylating Agent (HMA) Failure

Introduction: Pts with MDS and HMA failure have a poor prognosis and need novel therapies. Success with anti-PD1 therapy in myeloid malignancies has been limited and resistance mechanisms are poorly understood. Preclinical data suggest that myeloid-derived suppressor cells (MDSCs) contribute to MDS progression (Chen et al. JCI 2013). and may mediate resistance to anti-PD1 therapy (Kim et al. PNAS 2014). As HDACi decrease MDSCs, synergistic anti-tumor efficacy with anti-PD-1 has been hypothesized leading to this phase Ib study (NCT02936752) of the HDACi entinostat and anti-PD1 antibody pembrolizumab in pts with MDS or oligoblastic AML and HMA failure. Methods: We conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program (NCI-CTEP)-sponsored, multicenter, dose escalation and expansion phase Ib trial. Adult (≥18 years) pts with MDS or oligoblastic AML (bone marrow [BM] blasts 20-30%) and HMA failure were enrolled. Pts had to have adequate end organ function and ECOG performance status ≤2. The dose-escalation part used 2 dose levels (DL1: entinostat 8mg PO on days 1 and 8 of each 21-day cycle; DL2: entinostat 8mg PO on days 1, 8, and 15 of each 21-day cycle) with pembrolizumab 200mg IV on day 1 of each 21-day cycle starting with cycle 2. In cycle 1, pts received only entinostat to determine its impact on MDSCs separately from pembrolizumab. Toxicities were tabulated and graded according to CTCAE-5. Dose-limiting toxicities (DLT) were defined as any of the following if deemed possibly related to trial therapy: Grade (G) 3/4 non-hematologic toxicity, any ≥G3 immune related adverse events (IrAEs) or any IrAE resulting in pembrolizumab interruption or discontinuation during the first 2 cycles of combined therapy. Hematologic AEs were considered a DLT only if they were unrelated to MDS and lasted for >42 days. The primary endpoint was safety and determination of the maximum tolerated dose. The secondary endpoint was the overall response rate defined as a composite of complete remission, partial remission, and hematologic improvement (HI) per the 2006 IWG response criteria in MDS and change in MDSCs and PD1/PDL-1 in BM. Results: Between 06/26/2017 and 02/03/2021, we enrolled 28 pts (25 MDS and 3 AML). Median age was 74 years (range [R], 57-86), all pts had received prior HMA with 5 pts (18%) having had ≥3 prior lines of therapy. Median IPSS-R at screening for MDS pts was 5.5 (R: 2-10). Baseline demographic and clinical characteristics are shown in Table 1. During dose escalation, 7 pts were enrolled in DL1 (1 pt not evaluable due to early disease progression during DLT period), and 6 pts were treated on DL2. There was 1 DLT on DL1 (G5 pneumonia/bronchoalveolar hemorrhage (BAH), while 2 pts experienced DLTs at DL2 (G3 pharyngeal mucositis and G3 anorexia). There were no hematologic DLTs during dose escalation. Thus, DL1 was expanded, and another 15 pts were enrolled at DL1. Across the entire study, pts received a median of 3 cycles of therapy (R: 1-12 cycles). The most frequent cause of treatment discontinuation was disease progression in 9 pts. Four pts died during the study, 2 due to therapy-related complications (1 from pneumonia/BAH, 1 from multi-organ failure which occurred after the DLT period in DL2). A summary of the AEs is presented in Table 2. Hematologic AEs were common. The most common non-hematologic ≥G3 AEs independent of treatment attribution were infection (32.1%), hypoxia/respiratory failure (10.7%) and dyspnea (10.7%). Potential IrAEs of any grade were reported in 5 pts including G3 pneumonitis in 2 pts. Serious AEs were reported in 14 pts; 8 of which were potentially attributed to treatment. Among the 19 pts with the first BM efficacy assessment after 3 months, no pt achieved a protocol-defined response. However, 2 pts had mCR (BM blasts decreased from a baseline of 7% and 10% to 2% and 4%, respectively) without HI. Twelve pts had stable disease, while 5 had progressive disease. With a median follow-up of 5.9 months (R: 0.5 - 59.1 months), median OS was 6.9 months (95% CI: 4.8 - 13.6 months). Correlative studies are being conducted. Conclusion: In this multi-center phase 1b investigator-initiated trial in MDS and oligoblastic AML pts after HMA failure, entinostat + pembrolizumab at DL1 was reasonably tolerated but had limited therapeutic efficacy. Ongoing correlative work will explore the disconnect between the preclinical and clinical data regarding potential synergy of entinostat + pembrolizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim analysis of a phase II study of simultaneously integrated boost intensity modulated radiation therapy (SIB-IMRT) in combination with 5-FU and mitomycin-C among patients with locally advanced anal canal cancer.

e15501 Background: Concomitant radiochemotherapy is the standard treatment of locally advanced epidermoid anal canal carcinoma (EACC) but conventional radiotherapy (RT) frequently induces significant non-hematological toxicities, resulting in long treatment breaks. Given the numerous anatomic pelvic structures, EACC has become of interest for Intensity-Modulated Radiation Therapy (IMRT) despite the induced cutaneous toxicities responsible for RT breaks. Given the deleterious effect of treatment duration on local control and survival in other epidermoid cancers, continuous IMRT is challenging to control EACC. Several SIB-IMRT schedules provided similar results with moderate doses and schedules delivering higher doses with short breaks. Yet, standard SIB-IMRT schedule in EACC still not exists. We propose to concomitantly assess the safety and efficacy of continuous SIB-IMRT without planned breaks and concurrent chemotherapy (CT) to improve the treatment of locally advanced EACC by reducing the proportion of patients (pts) requiring RT breaks for toxicities. Methods: The CANAL-IMRT-01 phase 2 trial (NCT02701088) targets pts with histologically proven EACC candidate for concomitant RT of pelvic and inguinal nodes plus CT. Applying a two-step Bryant & Day design, the main criterion is based on both efficacy and safety. Efficacy is defined as the proportion of pts alive with no local disease progression 3 months after the end of IMRT; safety is defined as the proportion of pts with no RT breaks required by grade ≥3 toxicities. Assuming the unacceptable and acceptable proportions of pts without toxicity requiring IMRT break are 60 and 80% respectively, the unacceptable and acceptable 3-month-progression-free-survival are 80 and 90%, 14 assessable pts at first step and 46 in the second are required (alpha risk 5%, 90% power). To anticipate a 10% drop out rate, 16 pts were needed in first step, with ≥11 objective local responses and ≤6 toxicity-induced IMRT breaks to pursue. Treatment consists in 50 days of concomitant CT (2 cycles of 5FU and Mitomycin-C) and SIB-IMRT delivered by helical tomotherapy: 61.2Gy/1.7Gy to the primary tumor, 57.6Gy/1.6Gy to involved nodes, and 54/1.5Gy to elective pelvic lymph nodes. Results: From December 2015 to June 2017, 16 pts were enrolled: 11 female (73%), median age 62 [55-66]. 15 pts were assessable for efficacy and safety. All 15 pts had a 3-month locoregional response (12 complete responses, 3 partial responses). SIB-IMRT breaks were required by toxicities for 4 out of 15 pts: G1 radiodermitis, G2 inguinal and epithelitis, G1 fever, G3 anorexia and vertigo. Conclusions: The planned interim analysis of continuous SIB-IMRT plus CT allowed pursuing this phase 2 trial to assess the relevance of such schedule for locally advanced ASCC. Enrolment is still ongoing. Clinical trial information: NCT02701088.

Phase 1 study of OKI-179, an oral class 1-selective depsipeptide HDAC inhibitor, in patients with advanced solid tumors: Final results.

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with Cmax > 2,000 ng/ml and AUC > 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. Tmax was 2 hours and T1/2 was 6-8 hours. OKI-179 treatment resulted in > 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.

S1206: A dose-finding study followed by a phase II randomized placebo-controlled trial of chemoradiotherapy (CRT) with or without veliparib in stage III non-small cell lung cancer (NSCLC).

8523 Background: Veliparib (V), a PARP inhibitor, may potentiate the antitumor effect of CRT in NSCLC. Methods: Eligibility included newly diagnosed unresectable stage III NSCLC. Patients were randomized to receive concurrent CRT with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) with V at 120 mg or placebo (P) twice daily during CRT followed by 2 cycles (every 21 days) of consolidation carboplatin (AUC 6), paclitaxel (200 mg/m2) with V at 80 mg or P (per randomized arm) orally on days 1-7 of each cycle. Progression-free survival (PFS) was the primary endpoint. The accrual goal was 132 patients. Results: The dose-finding study results were previously presented (ASCO 2016;A8537). V 120 mg twice daily was the recommended phase II dose. A total of 31 eligible and evaluable patients were enrolled in the phase II randomized trial: 17 on V and 13 on P (1 patient in the V arm withdrew prior to starting any treatment, thus was not evaluable). The study was closed to accrual early due to the positive results from the PACIFIC trial that changed standard practice. Median follow-up among alive patients was 16 months. During CRT, the following grade (G) 3-4 adverse events (AE) were seen with V vs P: any G3 AE (6 vs 6), any G4 AE (2 vs 3), G3 pneumonitis (0 vs 1), G3 esophagitis (1 vs 1), G3 oral mucositis (1 vs 0), G3 anorexia (1 vs 1), G3 hyponatremia (0 vs 3), G3 anemia (1 vs 0), G3 neutropenia (3 vs 1), G3 thrombocytopenia (1 vs 0), G4 hypoglycemia (0 vs 1). Also, 2 patients per arm had G4 lymphopenia. During consolidation (11 evaluable patients with V; 10 with P), G3 anemia (1 vs 0), G3 anorexia (1 vs 0), G3 weight loss (0 vs 1), G3 dehydration (1 vs 0), G3 dysphagia (2 vs 0), G3 fatigue (1 vs 0), G3 hypomagnesemia (0 vs 1), G3 nausea (1 vs 0), G4 hyperglycemia (0 vs 1), G3-4 neutropenia (3 vs 0), G3 thrombocytopenia (1 vs 0), G3-4 lymphopenia (2 vs 1); a G5 pneumonitis occurred in the P arm. Response rates were 56% (95% CI, 31-78%) and 69% (95% CI, 38-91%) on the V and P arms, respectively. PFS at 1 year was 47% (95% CI, 23% - 68%) with V and 46% (95% CI, 19% - 70%) with P. Overall survival (OS) at 1 year was 89% (95% CI, 61%-97%) with V and 54% (95% CI, 25%-76%) with P. Adding the 6 patients treated at 120 mg in the phase I part, 1-year with V was 91% (95% CI, 69%-98%). Conclusions: V in combination with CRT was tolerable with expected toxicities that relate to the backbone regimen. In the small number of randomized patients there was a suggestion of promising survival with V that may provide rationale for future trials of PARP inhibitors with CRT. Clinical trial information: NCT01386385.

Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): Phase I results.

600 Background: PD-L1- and VEGF-targeted therapies have improved survival for mRCC pts and mechanisms of synergy have been reported. We conducted a phase I/II study to evaluate the safety and efficacy of pembro and cabo in mRCC pts. Phase I data are presented here. Methods: mRCC pts received pembro and cabo in a standard 3+3 dose escalation to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and objective response rate (ORR). Cabo was dosed at 40mg QD and 60mg QD in the first and second cohorts, respectively. Pembro was dosed at 200mg IV Q3W in all cohorts. The DLT window was 21 days. Scans were obtained every 9 weeks. Treatment beyond progression was allowed. Results: Eight pts (6M, 2F) were enrolled in the dose escalation cohort with cabo 40mg (5 pts) or 60mg (3 pts) and pembro 200mg. Two pts were not evaluable for DLT due to missing ≥25% of the planned cabo doses in C1, not related to DLT. Median age was 52.5 yrs (range 40-68). Seven pts had clear cell RCC and 1 pt had non-clear cell RCC. Seven pts had MSKCC intermediate risk and 1 pt had MSKCC poor risk. All pts had prior nephrectomy. Median number of prior therapies was one (range 1-3). No DLTs were observed. Drug-related G1 and G2 adverse effects included fatigue (87.5%), weight loss (75%), anorexia (50%), diarrhea (50%), dysgeusia (50%), and abnormal LFTs (50%). One pt had SAE of G3 reversible posterior leukoencephalopathy syndrome during C4, attributed to cabo. One pt each developed G3 hypertension, G3 anorexia, and G3 confusion, all occurring outside the DLT window. No dose reductions were needed at the 40mg cohort. One pt in the 60mg cohort required dose reduction to 40mg after C5. All patients were evaluable for response: 2 PR (at 60 mg cohort), 5 SD [median duration SD 18 wks (range 9-36+)], 1 PD; ORR 25%; clinical benefit rate 87.5%. No correlation was seen between PD-L1 status (archival tissue) and response. Conclusions: The MTD was determined to be pembro 200 mg Q3W and cabo 60 QD. Enrollment in the phase II dose expansion is ongoing and the MTD may be adjusted based on additional pt experience and long-term tolerability. There was encouraging early efficacy. This is an investigator-initiated study sponsored by Merck. Clinical trial information: NCT03149822.

Volumetric modulated arc therapy (VMAT) in the treatment of esophageal cancer patients.

The aim of the study is to evaluate feasibility, safety, toxicity profile, and dosimetric results of volumetric modulated arc therapy (VMAT) to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients. A total of 68 patients were treated with VMAT between March 2014 and March 2018 (44% vs 56% for definitive and neoadjuvant settings, respectively). Dose prescription differed depending on the clinical scenario (54-60Gy in 30 fractions for definitive treatments; 41.4/45Gy in 23-25 fractions in the pre-operative setting). Most of the patients were given concurrent chemotherapy. Two coplanar and one non-coplanar arcs were employed for VMAT delivery. Treatment was generally well tolerated. Acute toxicity was generally mild. In patients treated with definitive intent, ≥ G3 toxicities were observed for esophagitis (30%), anorexia (26.7%), fatigue (26.7%), nausea (6.7%), and vomiting (3.3%). In patients treated within a neoadjuvant approach, ≥ G3 anorexia (21%), esophagitis (15.8%), fatigue (13.3%), nausea (5.3%), and vomiting (2.6%) were observed. Dosimetric results were consistent in term of both target coverage and normal tissue sparing. In conclusion, VMAT proved to be a feasible, safe, and effective strategy to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients.

Abstract B176: Results of a phase I study of PLX8394, a next-generation BRAF inhibitor, in refractory solid tumors

Abstract Background: First-generation BRAF inhibitors (BRAFi) such as vemurafenib and dabrafenib demonstrated high response rates and prolonged survival in some BRAFV600-mutated cancers; however, most patients ultimately develop resistance. Furthermore, treatment-emergent skin and other epithelial malignancies present safety concerns. PLX8394 is a next-generation, orally available, small-molecule BRAFi. Unlike first-generation BRAFi, PLX8394 [a] does not induce paradoxical activation of the RAF/MEK/ERK pathway in cells with stimulated RAS signaling, and [b] blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 mutations. Thus, we hypothesize that PLX8394 may yield improved safety and broader, more durable efficacy than first-generation BRAFi. Methods: Trial protocol PLX120-03 (NCT02428712) incorporates an open-label, multicenter, phase I study using a 3+3 design to determine the recommended phase II dose (RP2D) in patients with refractory or relapsed solid tumors with or without BRAF mutation. Other endpoints are safety, including dermatologic and ophthalmic adverse events (AEs), pharmacokinetics (PK), and response per RECIST1.1. Dose escalation includes cohorts with either PLX8394 monotherapy or PLX8394 coadministered with an oral CYP3A4 inhibitor, cobicistat 150mg, to enhance systemic PK. Enrollment at the RP2D continues in the subsequent phase II study. Results: Of 26 patients who received at least 1 dose of PLX8394, 15 patients (10 with BRAF mutation) were enrolled to cohorts with PLX8394 monotherapy: 450mg BID (n=8), 900mg BID (n=3), 450mg TID (n=4). PK studies demonstrated lower than expected drug exposures; the protocol was amended and 11 additional patients (8 with BRAF mutation) were enrolled in cohorts with PLX8394 coadministered with cobicistat: 450mg BID (n=5) and 900mg BID (n=6). As of 31 May 2017 cutoff, 15 subjects terminated the study: 14 for disease progression, 1 subject withdrawal. Duration of study drug exposure was a median of 56 (22 - 727) days. Reversible Grade (G) 3 transaminitis in a patient treated with PLX8394 900mg BID + cobicistat was the only dose-limiting toxicity (DLT); rechallenge with PLX8394 alone was tolerated without recurrence of transaminitis. PLX8394 900mg BID + cobicistat was declared as RP2D. Treatment-related G>3 AEs other than DLT included G3 diarrhea (n=1), G3 anorexia (n=1), both in PLX8394 monotherapy cohorts and both manageable with supportive care. There were no cutaneous or ocular AEs. Cobicistat coadministration resulted in a 2-3 fold increase in PLX8394 systemic exposure, with RP2D achieving the projected efficacious exposure range based on preclinical models. There were no objective responses in PLX8394 monotherapy cohorts; however, to date 2 (28%) of 7 evaluable BRAF mutant patients treated with PLX8394 + cobicistat achieved partial responses (BRAFV600E-mutated colorectal cancer, 42% and BRAFV600E-mutated glioma, 65%; both BRAFi naive), which were confirmed by 8-wk serial scans. Tumors without BRAF mutation showed no response. Conclusion: PLX8394 with cobicistat was very well tolerated and showed promising activity in refractory solid tumors with BRAF mutation. A phase II study in BRAF-mutated cancers is ongoing. Citation Format: Filip Janku, Ulka Vaishampayan, Vivek Khemka, Minny Bhatty, Chao Zhang, Henry H. Hsu, Paul S. Lin, Sandra Tong, Sunil Sharma. Results of a phase I study of PLX8394, a next-generation BRAF inhibitor, in refractory solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B176.

A Dose-Escalation (DE) Study with Expansion Evaluating Safety, Pharmacokinetics and Efficacy of the Novel, Balanced PI3K/mTOR Inhibitor PQR309 in Patients with Relapsed or Refractory Lymphoma

Background:PQR309 is an oral balanced, pan-PI3K, mTORC1 and mTORC2 inhibitor. It is in clinical development for the treatment of solid tumors and hematologic malignancies. 1st generation mTOR inhibitors inhibit the activity of mTOR within the TORC1 complex only with activation of TORC2 proposed as a putative resistance mechanism. PI3 kinase inhibition may reduce subsequent AKT activation which can bypass some effects of mTOR inhibition. Potent antiproliferative activity of PQR309 was previously demonstrated in lymphoma cell lines in vitro and in vivo. Maximum tolerated dose (MTD) of PQR309 in solid tumours was established at 80 mg using a continuous once daily dosing schedule (OD).Methods:We performeda modified 3+3 DE of PQR309, open label phase 1 trial with expansion, to evaluate safety, pharmacokinetics (PK) and efficacy. Patients with relapsed or refractory lymphoma (any sub-type, ECOG PS of 0-1) were treated in two sequential cohorts with escalating doses of PQR309 administered on an OD dosing schedule to assess the MTD of PQR309. The starting dose of PQR309 was 60mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). PK samples were obtained at predefined time points. Clinical efficacy was evaluated according to revised Cheson criteria. In the expansion phase, patients will be treated at the MTD as defined in the DE phase of the study.Results: 15 patients were enrolled between August 2015 and March 2016 and treated with 60mg (n=8) or 80mg (n=7) of PQR309. Demographics: 5F:10M; median age 60 (range: 34-75), median number of prior systemic treatments 5 (range: 1-8). Lymphoma indications are shown in Table 1. Mean duration on therapy was 39 days (range: 3-160). One patient with follicular lymphoma remains on treatment. Grade (G)3/4 drug-related AE were seen in 3 patients treated with 60mg: 1 G4 rhabdomyolysis, 1 G4 neutropenia, 1 G3 hyperglycemia and one patient who developed G3 anorexia and G4 sepsis. Four patients treated with 80mg developed G3/4 drug-related AEs: two patients developed G3 hyperglycemia, one patient developed G3 fatigue and G3 pneumonitis. No DLT was observed. Preliminary PK showed rapid absorption (Tmax 1-2h), dose proportionality for Cmax and AUC and an estimated T1/2 of around 50 hours, consistent with PQR309 studies in solid tumours that evaluated dose levels from 10 to 150 mg PQR309.Responses observed in each patient are shown in the table below. 4 patients were non-evaluable, 3 due to disease progression requiring cessation of study drug and one requiring steroid doses exceeding protocol defined criteria, all within the 21 day DLT assessment period.Conclusion:The MTD and recommended PQR309 dose for the expansion of the study was 80mg OD, in agreement with earlier dose-finding studies in solid tumours. Adverse event patterns were consistent with those seen in studies involing solid tumours. Hyperglycemia, a predicted on-target effect of PI3K/mTOR inhibition, was observed in the majority of patients, providing evidence of pharmacodynamic effects of PQR309. PK was dose-proportional. Encouraging clinical activity including a CR was observed. The study expansion is ongoing. [Display omitted] DisclosuresCollins:Takeda: Consultancy, Honoraria, Speakers Bureau. Eyre:GSK: Honoraria; Celgene: Other: Travel, Accomodation; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Takeda: Honoraria, Other: Travel, Speakers Bureau. Ivanova:PIQUR: Employment. Schmitz:PIQUR: Employment. Dimitrijevic:PIQUR: Employment. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

C21 - First Italian Multicentre Experience in using Ra-223 in patients with metastatic castration resistant prostate cancer (mCRPC)

Aim: Radium-223 is a novel bone-targeted &agr;-emitter associated with a survival benefit. We present first Italian multicentre experience in using Ra-223 in mCRPC patients. Material and methods: Data from mCRPC pts submitted to Ra-223 treatment over 3 years (August 2013-February 2016) were retrospectively collected. Information included Gleason score, age, prior treatments, bone symptoms, analgesic requirements, imaging and blood results. Ra-223 (50 kBq/kg) was administered every 4 weeks, up to the recommended 6 therapy cycles. Endpoints assessed included Overall Survival, pain score using Visual Analog scale (VAS), side effects, skeletal related events (SREs), disease biomarkers (PSA & ALP levels) and haematological parameters. Results: 90 pts received Ra-223 in three Italian Oncology/Radiotherapy/Nuclear Medicine Departments. Up to April 2016 only Pisa Departments data are available. Median age was 69 yr (range 52-85 yr). Median follow-up was 8,6 months (range 1-18 months). Mean Gleason score was 7. All patients received 3 previous lines of treatment on average. All bone scans showed foci of abnormal uptake. CT scans was used to exclude visceral involvement and the presence of pathologic lymph nodes with a diameter = 3 cm. 16/32 pts completed the recommended 6 cycles, of whom: 5 had bone pain reduction, 3 had worsening, 8 had absence of bone pain, remaining stable and not requiring analgesia. 16 pts stopped treatment : 3 cases of delay due to lack in radiopharmaceutical supplies, 9 developed extra skeletal disease/skeletal progression, 3 deteriorated clinically, 1 experienced SRE during treatment. About non-haematological toxicity we observed 3 cases of G3 anorexia, 3 cases of G1 diarrhoea, 2 cases of G2 asthenia. No patients developed SREs during follow-up. Concerning haematological toxicity, bone marrow failure resulted in 8 cases of G2 anaemia, 6 cases of G3 anaemia, 2 cases of G2 leucopoenia, 1 case of G2 thrombocytopenia. Regarding biomarkers, median ALP decline was 50%, median LDH decline was -5%, 32% of pts showed a reduction in PSA level. OS mean is at the present date about 8 months, and median OS has not been achieved yet. Conclusion: Ra-223 has a major impact on serum ALP levels, with negligible effect on PSA levels. Therefore, ALP appears to be a useful biomarker of therapy response. Haematological and non-haematological side effects were acceptable. Stability in pain or palliative effects occurred in the majority of patients.

725P - A Phase I Study of Gemcitabine (Gem), Cisplatin (Cddp), and S-1 Combination in Untreated Patients (Pts) with Advanced Biliary Tract Cancer (Abtc)

ABSTRACT Aim: GEM plus CDDP has been established as standard first-line chemotherapy based on the results of the phase III study (ABC-02) in ABTC. An oral FU derivative, S-1 showed a similar activity to GEM in a phase II study and is mainly used in GEM-refractory pts in Japan. To develop a triplet regimen, GEM + CDDP + S-1 (GPS), we assessed its safety in this phase I study. Methods: The main eligibility criteria were; histologically or cytologically confirmed ABTC, ECOG Performance Status (PS) 0-2, no prior chemotherapy, and written informed consent. Dose limiting toxicities (DLT) were evaluated in following 2 dose levels; GEM (1000 mg/m2 at level 1 and 1200 mg/m2 at level 2 on day 1) + CDDP (fixed dose of 30 mg/m2 on day 1) + S-1 (fixed dose of 40—60 mg/day bid for 7 days), repeated every 2 weeks until progression. The relative dose intensity of GEM and CDDP at level 2 corresponded to 90% of standard GEM plus CDDP regimen. In each level, 6-10 pts were enrolled and assessed. DLTs were evaluated during the first 2 cycles. Results: Between Oct 2011 and Oct 2013, 18 pts were enrolled and 16 pts were evaluated (median age: 71 years, ECOG PS 0/1: 10/6, intrahepatic/extrahepatic/gallbladder: 7/3/6). DLTs (grade 3 nausea to stop S-1 in cycle 1 and treatment delay due to grade 3 neutropenia in cycle 2) at level 1 were observed in 2 of the first 6 pts. Additional 4 pts enrolled at this dose level experienced no DLTs. A DLT (G3 anorexia) at level 2 was observed in 1 of 6 pts. Grade 3 or 4 treatment-related adverse events within the first 2 cycles were leukocytopenia (38%), neutropenia (50%), thrombocytopenia (0.6%), nausea (0.6%), and anorexia (0.6%). Of 14 pts with measurable lesions, 7 (50%) pts had partial response and 6 (43%) patients had stable disease. Median progression free survival was 9.2 months (95%CI 6.8-11.6, event in 63%) and overall survival did not reach the median value (event in 38%). Conclusions: GPS of dose level 2 (GEM 1200 mg/m2 and 30 mg/m2 on day 1 plus S-1 for 1-7 days, given bi-weekly) was well tolerated, and showed preliminary anti-tumor activity. Further study is warranted. Clinical trial information: UMI06123. Disclosure: T. Moriwaki: Research funding for other study and honoraria from Taiho Pharmaceutical; I. Hyodo: Research funding for other study from Taiho Pharmaceutical and Lilly. Honoraria from Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

CPT-11 as a second-line treatment for patients with advanced/metastatic gastric cancer who failed S-1 (CCOG0702)

In Japan, CPT-11 is often used to treat unresectable gastric cancer in the second-line setting. However, evidence regarding benefit of second-line chemotherapy remains sparse, especially after failing S-1. A phase II study to evaluate the efficacy and safety of weekly administration of CPT-11 at a dose of 100mg/m(2) after failing a S-1-containing first-line treatment was planned with response rate as a primary end point. UGT1A1*6, *27, and *28 genotyping were performed in all cases, and those found to have either homozygous for *28, homozygous for *6, heterozygous for both *6 and *28, and heterozygous for *27 were rendered ineligible for the phase II trial. Two patients of homozygous for *28, two patients of homozygous for *6, and one patient of heterozygous for *27 were found among 39 recruited patients. The median number of courses delivered was 3 courses. The overall response rate was 15.4% and disease control rate was 65.4%. The median time to treatment failure was 87.5days and median overall survival was 268days. Twenty-two (73%) of 30 valuable patients experienced protocol-specified skip of treatment and 8 (30%) of patients could continue treatment with dose reduction. ≥G3 neutropenia was found in 30% and ≥G3 anorexia and diarrhea were found in 23 and 17%, respectively. Weekly CPT-11 at 100mg/m(2) showed moderate response among gastric cancer patients who were refractory to S-1, but the disease control rate seemed meaningful. Even after selection of patients by UGT1A1 polymorphism of *6, *27, and *28, severe toxic events could not be prevented completely.

Phase I study to evaluate the safety and to assess the food effect of HM781-36B, a novel pan-HER inhibitor continuously given in patients with advanced solid tumors.

2565 Background: HM781-36B, a novel pan-HER tyrosine kinase inhibitor, showed potent in vitro and in vivo antitumor activities for EGFR mutant models including T790M mutation. In the previous 2-weeks on, 1-week off phase I study, the maximum tolerated dose (MTD) was determined as 24 mg/day. Phase I study with a continuous daily dosing schedule was conducted to determine the recommended dose (RD), and to assess the effect of food on pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation study, and additional 8 patients were enrolled to test food effects. Results: 20 pts (median age: 55 years [range32-77], M:F=13:7, ECOG PS 0/1/2/3 8/12/0/0) were enrolled (5 NSCLC, 4 colon cancer, 3 stomach cancer, 2 breast cancer, 2 rectal cancer, 2 common bile duct cancer, 1 pancreatic cancer and 1 esophageal cancer); 12 in the dose escalation and 8 in the food effect study cohort. Twelve pts were heavily pretreated(≥4 regimens). Dose limiting toxicities (DLTs) were G3 anorexia in 1 pt at 18mg/day, G3 diarrhea and anorexia in 1 pt, and drug compliance <80% due to G2 adverse events in 1 pt at 24mg/day. The MTD was determined as 18 mg/day, and RD was determined as 16 mg/day. The most common drug-related adverse events were diarrhea, stomatitis, skin rash, paronychia, pruritus and anorexia. Among 16 evaluable pts, 4 achieved partial responses (PR)[1 NSCLC, 2 breast cancer, 1 common bile duct cancer], and the duration of response were 32, 40+, 21, and 8 weeks, respectively. Five pts had stable disease (SD). The median duration of treatment in pts with PR or SD was 33.5 weeks (range, 15-82). Under both fasted and fed condition, there were no significant differences of AUClast values, whereas Cmax values were lower in fed condition than in fasted condition. Conclusions: Continuous daily dosing schedule of HM781-36B is safe and well tolerated in advanced solid tumors. It exerts anticancer activity, without being influenced by food. Updated data will be presented at the meeting. Clinical trial information: NCT01455584.

Safety Verification Trials of mFOLFIRI and Sequential IRIS + Bevacizumab as First- or Second-Line Therapies for Metastatic Colorectal Cancer in Japanese Patients

Objective: S-1 is effective in sequential combination with irinotecan (IRIS) in treating metastatic colorectal cancer. We conducted a randomized phase II trial of modified leucovorin, fluorouracil and irinotecan (mFOLFIRI) + bevacizumab and sequential IRIS + bevacizumab as first- or second-line therapies. Methods: Sixty metastatic colorectal cancer patients were randomly assigned to receive mFOLFIRI + bevacizumab or sequential IRIS + bevacizumab (7.5 mg/kg of bevacizumab and 150 mg/m² of irinitecan, and 80 mg/m²/day of S-1 orally from day 3 until day 16 as a 3-week course). The primary endpoint was the safety of each method until week 12, with the secondary endpoint being the comparison of the safety and efficacy of the two methods. Results: The safety of the two treatments was comparable, except that G3 anorexia and diarrhoea were less frequent with sequential IRIS + bevacizumab. The overall response rate was 62% [95% confidence interval (CI) 40.1–79.8] versus 72% (95% CI 50.6–86.2), and progression-free survival was 324 days (95% CI 247–475) versus 345 days (95% CI 312–594) with mFOLFIRI + bevacizumab versus IRIS + bevacizumab, respectively. Conclusion: Sequential IRIS + bevacizumab is a safe and effective method of systemic chemotherapy against metastatic colorectal cancer and is compatible with mFOLFIRI + bevacizumab.

A phase I dose-escalation and pharmacokinetic study of sunitinib in combination with pemetrexed in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer

PurposeThe primary objective of this phase I dose-escalation study was to identify the maximum tolerated dose (MTD) of sunitinib plus pemetrexed in patients with advanced cancer.MethodsUsing a 3 + 3 dose-escalation design, patients received oral sunitinib qd by continuous daily dosing (CDD schedule; 37.5 or 50 mg) or 2 weeks on/1 week off treatment schedule (Schedule 2/1; 50 mg). Pemetrexed (300–500 mg/m2 IV) was administered q3w. At the proposed recommended phase 2 dose (RP2D), additional patients with non-small cell lung cancer (NSCLC) were enrolled.ResultsThirty-five patients were enrolled on the CDD schedule and seven on Schedule 2/1. MTDs were sunitinib 37.5 mg/day (CDD/RP2D) or 50 mg/day (Schedule 2/1) with pemetrexed 500 mg/m2. Dose-limiting toxicities included grade (G) 5 cerebral hemorrhage, G3 febrile neutropenia, and G3 anorexia. Common G3/4 drug-related non-hematologic adverse events (AEs) at the CDD MTD included fatigue, anorexia, and hand–foot syndrome. G3/4 hematologic AEs included lymphopenia, neutropenia, and thrombocytopenia. No significant drug–drug interactions were identified. Five (24%) NSCLC patients had partial responses.ConclusionsIn patients with advanced solid malignancies, the MTD of sunitinib plus 500 mg/m2 pemetrexed was 37.5 mg/day (CDD schedule) or 50 mg/day (Schedule 2/1). The CDD schedule MTD was tolerable and demonstrated promising clinical benefit in NSCLC.

Phase I Trial of Panobinostat (LBH589) in Combination with Trastuzumab in Pretreated HER2-Positive Metastatic Breast Cancer (mBC): Preliminary Safety, Efficacy and Pharmacokinetic Results.

Abstract Background: Panobinostat (LBH589), a potent inhibitor of histone deacetylases (HDACs), has demonstrated single-agent activity and synergistic effects when administered in combination with trastuzumab or docetaxel in HER2-positive breast cancer xenografts.Methods: This multicenter study is enrolling patients with metastatic breast cancer (mBC) who have progressed on or within 6 months of trastuzumab-based therapy. Patients receive panobinostat either intravenously (i.v.) (Day 1+8 every 3 weeks) or orally (three times per week, continuously) in combination with trastuzumab 2 mg/kg weekly. Phase Ib of the study evaluates the maximum tolerated dose (MTD) for each formulation, three i.v. dose cohorts (10, 15 and 20 mg/m2) and four oral dose cohorts (15, 20, 30 and 40 mg) are planned. Once the MTDs are established, Phase IIa of the study will assess the efficacy of these doses. The pharmacokinetic (PK) profile is also being determined.Results: In this ongoing trial, 33 patients have received treatment. At baseline these patients had a median age of 52 y (33–65). All breast cancers were HER2-positive and 16 (48%) were ER and PR negative. Lung (45%), liver (33%) and the central nervous system (21%) were the most common sites of metastatic disease. Most patients had received prior taxanes and/or anthracyclines. For the i.v. arm, the 10 mg/m2 (n=7) and 15 mg/m2 (n=7) cohorts completed with no dose-limiting toxicity (DLT), while two out of six patients experienced DLTs in the 20 mg/m2 cohort. One patient experienced Grade (G) 4 thrombocytopenia, and one patient had G4 nausea, vomiting and diarrhea. The 20 mg/m2 cohort is currently being expanded to a total of 12 patients to confirm the MTD. For the oral arm, one of six patients experienced a DLT in the 15 mg cohort (uncomplicated G4 thrombocytopenia) and two of eight patients experienced DLTs in the 20 mg cohort. One patient had G3 unstable angina and G3 thrombocytopenia, and the second patient experienced G3 thrombocytopenia and G3 anorexia. The 20 mg cohort has been expanded to 12 patients. Overall the most frequent adverse events reported included gastrointestinal events of nausea, vomiting and diarrhea, and hematologic events of thrombocytopenia and neutropenia. To date, no clinically significant ECG changes have been observed from the 820 ECGs performed. Two patients experienced tumor reduction of 29% (one patient each in the i.v. 10 mg/m2 and oral 20 mg cohorts); both patients had liver metastasis. Eight of the 25 patients (32%) with tumor measurements had a best response of stable disease, across all cohorts. Five of these patients received over 18 weeks of treatment with the combination.Conclusions: These preliminary results demonstrate that the combination of panobinostat and trastuzumab is well tolerated and shows promising activity. Additional patient safety, efficacy and PK data will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6101.

Phase I radiation dose-escalation trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer

4602 Background: Current treatments of non-metastatic, unresectable pancreatic cancer result in poor survival and nearly uniform local persistence of disease. We hypothesized that intensification of local therapy would result in better local control and improve survival. The primary objective of this trial was to determine maximum tolerated radiation dose delivered with IMRT and concurrent FDR-G. Methods: Eligibility included tissue diagnosis of adenocarcinoma, unresectable by radiological criteria, Zubrod performance of 0–2, ANC of ≥ 1500/mm3, platelets ≥ 100,000/mm3, creatinine < 2 mg/dl, bilirubin < 3 mg/dl, ALT and AST ≤ 2.5 x ULN, and informed consent. Patients (pts) received FDR-G (1000 mg/m2, 100-minute infusion) on days -22 and -15. IMRT started day 1 (radiation dose levels [L2-L6] 50, 52.5, 55, 57.5 and 60 Gy, all in 25 fractions) with concurrent FDR-G on days 1, 8, 22, and 29. GTV was defined on pancreas protocol CT in the treatment position. PTV was GTV plus 1 cm expansion. Active Breathing Control was used to reduce breathing motion, except in 3 pts, in whom 4D CT was used to generate an ITV. Post IMRT, up to 4 cycles of FDR-G were given. DLT was defined as GI toxicity ≥ G3, neutropenic fever, or deterioration in Zubrod to ≥3 between day 1 and 126. IMRT dose level was assigned using the Time-to-Event Continual Reassessment Method. With a sample size of 50, the design allows concurrent assessment of efficacy. Results: From 8/06, 27 pts have been accrued. DLTs have been observed in 6 (G3 anorexia, nausea vomiting, and/or dehydration [5 pts]; duodenal bleed [1 pt]). The posterior estimates of probability of DLT are 0.17, 0.21, 0.24, 0.27, and 0.28 for L2 to L6, respectively. The response rate is 52.4% (95% CI 29.8% to 74.3%). The median overall survival and progression-free survival are 23.1 months (95% CI 9–23.1) and 7.2 months (95% CI 5.0–8.0), respectively. Only 1 patient (4%) progressed locally. Two patients have undergone resection (R0), and demonstrated near- and complete pathological responses. Conclusions: High dose radiotherapy and concurrent FDR-G, utilizing the techniques above, is well tolerated and results in highly encouraging response rates, local control rates and overall survival. No significant financial relationships to disclose.

Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma

e16107 Background: Sorafenib (SOR) is a multi-kinase inhibitor, targeting Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. Interferon-α (IFN) is most commonly used for metastatic renal cell carcinoma (RCC) in Japan. In this phase I study, we investigated the safety profile, pharmacokinetics (PK), and tumor response of SOR/(recombinant)IFN combination in Japanese patients (pts) with RCC. Methods: After 2 weeks of IFN-alone treatment, a total of 18 pts (6 in each cohort) with unresectable/metastatic RCC received 28-day cycles of continuous SOR 200 (Cohort 1 [C1]) or (Cohorts 2 and 3 [C2 and C3]) 400 mg bid combined with intramuscular IFN 6 (C1 and C2) or 9 (C3) MIU three times a week (tiw). Objectives were safety/tolerability and recommended dose of SOR/IFN as primary, and tumor response and PK as secondary. Results: Pt characteristics were: median 64.5 y.o.; ECOG-PS 0:1, 14:4; prior anticancer therapy in 13 pts. All pts completed Cycle 1 and entered Cycle 2 or later cycles. At data cut-off (September 30, 2008), dose-limiting toxicities were reported in all cohorts, including G3 fatigue, G3 anorexia, and G3 skin disorders. Common drug-related grade 3/4 adverse events (AEs) included fatigue (50%), lipase increased (44%) and neutropenia (39%), all of which were reversible and manageable. AEs resulting in treatment discontinuation in Cycle 2 or later cycles were seen in 5 pts in Cohort 3. One death was reported in C1 at Cycle 18 due to gastrointestinal and intraabdominal hemorrhage. It seemed attributable to DIC accompanied by RCC. Five PR (1 in C1 and 4 in C3) and 11 SD (4 in C1, 5 in C2, and 2 in C3) were achieved as the best response. IFN had no relevant impact on PK of SOR. Conclusions: SOR/IFN combination has promise for clinical benefit in RCC, and its recommended dose was continuous SOR 400 mg bid and IFN 6 MIU tiw. [Table: see text]

Cisplatin-Based Three Drugs Combination (NIP) as Induction and Adjuvant Treatment in Locally Advanced Non-small Cell Lung Cancer: Final Results

This phase III trial was conducted in non-small cell lung cancer patients with locally advanced stage II B (only T3N0) III A and III B (only T4 N0). Primary endpoint was 2-year survival; secondary were toxicity, disease-free survival, and overall survival. After three cycles of vinorelbine (N) 25 mg/m2 on days 1 and 5, ifosfamide/mesna (I) 3 g/m2 on day 1, cisplatin (P) (NIP), patients were treated by surgery and within 45 days were randomized to two additional cycles of NIP versus observation. Median tumor diameter was 5.5 cm (1.2-10.6). Overall, 155 of 156 patients received chemotherapy: 133 (85%) men, median age: 59 years (35-75). Sixty-five percentage of patients were stage III A, 28% II B, and 7% III B. The study has been closed prematurely because of the low inclusion rate. After three cycles of induction in 143 assessable patients, 82 reported an objective response (57.3%) (95% CI: 48.8-65.6), with 3.5% complete response and 53.8% partial response. Relative dose intensity during neoadjuvant NIP (%) was 97, 98, and 98.5 for vinorelbine, ifosfamide/mesna, and cisplatin, respectively. Tolerance: G3 to 4 neutropenia in 3% of patients and G3 to 4 anemia in 4%; nonhematological toxicities included G3 nausea/vomiting in 11%, G3 anorexia and G3 to 4 infection in 6.5%, G3 asthenia in 10% and G3 to 4 alopecia in 25.5%. After a median of 32 days after NIP, 107 patients (69%) underwent operation with complete resection (R0) in 74% (79 of 107 patients). Downstaging (N2 to N0) after surgery was 29%. Operative mortality rate was 2.8%. Twenty-one days (median) after surgery, 79 patients were randomized to adjuvant NIP (47%) or control (53%). Tolerance of adjuvant NIP: 12.5% G3 to 4 nausea/vomiting, 19% G3 alopecia, 6% G3 infection, and G3 asthenia. Overall median survival 32.3 versus 31.8 months in the observation and NIP arms, respectively. NIP allows 74% of R0 with no surgery delay. The few number of randomized patients did not allow to conclude on the efficacy of adjuvant chemotherapy.