SarCNU, a Nitrosourea Analog on a Day 1, 5, and 9 Oral Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Tumors

2003 ◽  
Vol 21 (2) ◽  
pp. 232-240 ◽  
Author(s):  
L. Panasci ◽  
S.F. Stinson ◽  
D. Melnychuk ◽  
V. Sandor ◽  
W.H. Miller ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Time Profile ◽  
Terminal Phase ◽  
Advanced Solid Tumors ◽  
Human Glioma ◽  
Phase Ii Trials ◽  
Selective Cytotoxicity

Purpose: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma. SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter. The purpose of this phase I study was to determine the maximum-tolerated dose (MTD), the toxicity profile, the pharmacokinetics profile, and recommended phase II dose. Patients and Methods: Forty-three eligible patients with advanced solid tumors were enrolled. SarCNU was administered orally on days 1,5, and 9 every 28 days. The dose ranged from 30 to 1,075 mg/m2. Pharmacokinetic evaluation was done on the first cycle (one dose was given intravenously on day 1 or 5 of the first cycle to determine bioavailability). Results: Delayed myelosuppression (thrombocytopenia and neutropenia occurring 4 to 6 weeks after administration) was the dose-limiting toxicity (DLT). Anemia occurred but was mild. Nonhematologic toxicity was generally mild, but one patient died with pulmonary toxicity that was probably secondary to SarCNU. There were no partial or complete responses, but eight patients had stable disease for 19 to 46 weeks. The oral bioavailability of SarCNU was 80% ± 37%. The terminal phase half-life was similar after intravenous (58.4 ± 23.5 minutes) or oral (64.0 ± 34.8 minutes) administration. The total plasma clearance was 20.4 ± 8.8 L/h/m2, and the apparent volume of distribution was 29.9 ± 17.6 L/m2. The area under the plasma concentration–time profile increased proportionally with the dose, and the pharmacokinetics seemed to be independent of the route of administration and the number of doses. Conclusion: SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial

2005 ◽  
Vol 23 (7) ◽  
pp. 1555-1563 ◽  
Author(s):  
Susan M. Blaney ◽  
Frank M. Balis ◽  
Stacey Berg ◽  
Carola A.S. Arndt ◽  
Richard Heideman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Neoplastic Meningitis ◽  
In Vitro Cytotoxicity ◽  
Pharmacokinetic Studies ◽  
Preclinical Studies ◽  
Phase Ii Trials ◽  
Cytotoxicity Studies

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2544-2544
Author(s):  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Advanced Solid Tumors ◽  
Grade 3

2544 Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

Safety of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3063-3063
Author(s):  
Melissa Lynne Johnson ◽  
Manish R. Patel ◽  
Mohamad Cherry ◽  
Yoon-Koo Kang ◽  
Kensei Yamaguchi ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
T Cell Response ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Median Treatment

3063 Background: LAG-3, an immune checkpoint receptor involved in T-cell regulation, is frequently co-expressed with PD-1. LAG-3 and PD-1 signaling contributes to immune cell exhaustion and reduces the immune response to tumor cells. Dual inhibition of PD-1 and LAG-3 may reactivate the T-cell response better than blockade of either individual pathway. Here, we report combined safety data from 4 trials investigating BI 754111, an anti-LAG-3 mAb, in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: Data from 2 phase I dose-escalation/expansion trials, 1 phase I imaging trial, and 1 phase II trial were included. Eligible patients had advanced and/or metastatic solid tumors with measurable disease and an Eastern Cooperative Oncology Group performance status ≤1. Patients received BI 754111 (intravenously [iv], 4–800 mg) in combination with BI 754091 (iv, 240 mg fixed dose) every 3 weeks (q3w). Patients remained on treatment until progressive disease or unacceptable toxicity. In each trial, safety was assessed by incidence and severity of adverse events (AEs), and graded according to Common Terminology Criteria for AEs, version 5. Results: Overall, 321 patients were treated with BI 754111 in combination with BI 754091 (200 [62%] male; median age, 63 years [range 18–88]). Median treatment exposure was 85 days (range 9–625). Of these patients, 282 (87.9%) had any AE (G≥3 in 99 [30.8%]). 285 patients received the 600 mg recommended phase II dose of BI 754111 plus BI 754091 240 mg q3w. Median treatment exposure in these patients was 74 days (range, 8–590). The table shows the 3 most common AEs and 4 most common immune-related AEs, and their frequency. 21 (7.4%) patients had AEs leading to study drug discontinuation, most commonly infusion-related reactions (IRRs) in 6 (2.1%) patients. Serious AEs (all-cause) occurred in 77 patients (27.0%), most commonly pleural effusion in 6 (2.1%) and deep vein thrombosis in 4 (1.4%) patients. 2 patients (0.7%) experienced an AE resulting in death (cardiac tamponade and acute kidney injury, both related to underlying diseases). Conclusions: The combination of BI 754111 and BI 754091 had a manageable safety profile, similar to other checkpoint inhibitors. Clinical trial information: NCT03156114, NCT03433898, NCT03697304, NCT03780725 . [Table: see text]

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
R. Sangha ◽  
C. Ho ◽  
L. Beckett ◽  
D. H. Lau ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Gene Copy ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Egfr Inhibition ◽  
Biomarker Analysis

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

Phase I dose-escalating study of PM02734 in a 24-hour infusion schedule every 21 days in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2511-2511
Author(s):  
T. R. Evans ◽  
A. Oaknin ◽  
R. J. Jones ◽  
A. Vandermeeren ◽  
C. Coronado ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ii Studies ◽  
Flat Dose ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Escalating

2511 Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m2. Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m2), the MTD was 6.8 mg/m2 and the RD was 5.4 mg/m2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m2. Preliminary PK data is characterized by long half life (>100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD > 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg. [Table: see text]

Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2530-2530 ◽  
Author(s):  
Rebecca Suk Heist ◽  
Leena Gandhi ◽  
Geoffrey Shapiro ◽  
Naiyer A. Rizvi ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Skin Rash ◽  
Phase Ii ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
Mapk Signaling ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Phase Ib

2530 Background: PI3K/mTOR and MAPK signaling pathways are often deregulated in tumors. Simultaneous inhibition of these pathways with the MEK1/2 inhibitor, pimasertib, plus the dual PI3K/mTOR inhibitor, SAR245409, (ClinicalTrials.gov NCT01390818) was investigated. Methods: This was a phase Ib, modified 3+3, dose-escalation trial in patients (pts) with advanced solid tumors. Pts received pimasertib and SAR245409 at the following dose levels (DLs): DL1, 15/30; DL2a, 30/30; DL2b, 15/50; DL3, 30/50; DL4a, 60/50; DL4b, 30/70; DL5, 60/70; DL6a, 90/70; DL6b 60/90 and DL7, 90/90 mg (once-daily, qd). After the qd maximum tolerated dose (MTD) was established, twice-daily (bid) dosing was tested: DL1a, 60/30; DL1b, 45/50 and DL2 60/50 mg bid. A recommended phase II dose (RP2D) was determined. Enrollment continued at the RP2D in four expansion cohorts (18 pts each): dual KRAS/PIK3CA mutated (mt) colorectal cancer (CRC), triple-negative breast cancer, KRAS mt non-small cell lung cancer (NSCLC) and BRAFmt melanoma. Results: 53 pts were treated qd and 7 pts bid. The most common tumors were CRC (n=16), NSCLC (n=8), ovarian and pancreatic (n=7, each). At DL6b 2/3 pts had dose-limiting toxicities (DLTs; both grade [Gr] 3 nausea/vomiting). DL6a was confirmed as the MTD for the qd schedule. At bid DL1a 2/4 pts (both Gr 3 skin rash) and at DL1b 2/3 pts (Gr 3 skin rash and Gr 3 asthenia) had DLTs. DL5 was the RP2D based on tolerability after prolonged exposure. The most common adverse events in qd schedule were: rash (62%, 13% Gr 3), diarrhea (56%, 4% Gr 3), fatigue (51%, 2% Gr 3), nausea (49%, 2% Gr 3), vomiting (45%, 2% Gr 3), peripheral edema and pyrexia (34%, each) and visual impairment with underlying serous retinal detachment (21%). Preliminary pharmacokinetic results suggest no drug-drug interaction. There were 4 partial responses: KRAS mt CRC (n=1) and low-grade ovarian cancer (n=3, 1 KRAS mt/PIK3CA mt and 2 wild-type). Enrollment in expansion cohorts at DL5 is ongoing. Conclusions: Continuousqd dosing of pimasertib and SAR245409 is tolerated and has shown signs of activity. Phase II trials are being planned. Clinical trial information: NCT01390818.

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