Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040.

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA101-LBA101 ◽  
Author(s):  
Anthony B. El-Khoueiry ◽  
Ignacio Melero ◽  
Todd S. Crocenzi ◽  
Theodore Hobart Welling ◽  
Thomas Cheung Yau ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Hepatitis Virus ◽  
Response Duration ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Dose Levels

LBA101 Background: Overexpression of PD-L1 in HCC has a poor prognosis. Safety and preliminary antitumor efficacy of nivolumab, a fully human IgG4 monoclonal antibody PD-1 inhibitor, was evaluated in a multiple ascending-dose, phase I/II study in patients (pts) with HCC. Methods: Pts with histologically confirmed advanced HCC with Child-Pugh (CP) score ≤ B7 and progressive disease (PD) on, intolerant of, or refusing sorafenib were enrolled. Dose escalation occurred in parallel cohorts based on etiology: no active hepatitis virus infection or virus-infected HCC pts. Pts received nivolumab 0.1 – 10 mg/kg intravenously for up to two years. The primary endpoint was safety. Secondary endpoints included antitumor activity using mRECIST criteria, pharmacokinetics, and immunogenicity. Results: The study has enrolled 41 pts with a CP score of 5 (n = 35) or 6 (n = 6), ECOG score of 0 (n = 26) or 1 (n = 15), 73% with extrahepatic metastasis and/or portal vein invasion, and 77% with prior sorafenib use. Eighteen pts remain on study, and 23 discontinued treatment due to PD (n = 17), complete response (CR; n = 2), drug-related adverse events (AEs; n = 2) and non-drug–related AEs (n = 2). Drug-related AEs of any grade occurred in 29 pts (71%; 17% grade 3/4), with ≥ 10% of pts experiencing aspartate aminotransferase (AST) increase and rash (each 17%), alanine aminotransferase(ALT) and lipase increase (each 15%), and amylase increase (12%). Grade 3 and 4 AEs ≥ 5% were AST increase (12%), ALT increase (10%) and lipase increase (5%). A dose-limiting toxicity occurred in an uninfected pt at 10 mg/kg; no maximum tolerated dose was defined in any cohort. Response was evaluable in 39 pts: 2 CR (5%) and 7 partial responses (PR; 18%). Response duration was 14–17+ months for CR, < 1–8+ months for PR, and 1.5–17+ months for stable disease (SD). Overall survival (OS) rate at 6 months is 72%. Conclusions: Nivolumab has a manageable AE profile and produced durable responses across all dose levels and HCC cohorts, with a favorable 6-month OS rate. Updated safety, antitumor activity, and biomarker data will be presented. Clinical trial information: NCT01658878. [Table: see text]

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (9) ◽  
pp. 3037-3043 ◽  
Author(s):  
H S Nicholson ◽  
M Krailo ◽  
M M Ames ◽  
N L Seibel ◽  
J M Reid ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cancer Group ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

Phase I trial of sorafenib with concurrent radiotherapy (RT) in patients with invasive bladder cancer treated with bladder-sparing intent: A Spanish Oncology Genitourinary Group study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 270-270 ◽  
Author(s):  
Juan Martin Liberal ◽  
José Pablo Maroto ◽  
Begoña Mellado ◽  
Ferran Ferrer ◽  
Gemma Sancho ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Stage ◽  
Complete Response ◽  
Hepatic Function ◽  
High Energy ◽  
Maximum Tolerated Dose ◽  
Bladder Preservation ◽  
Radiation Cystitis ◽  
Grade 3 ◽  
Dose Levels

270 Background: Preclinical studies suggest enhanced radiation-induced cell death when VEGFR inhibitor therapies are combined with RT. Methods: Patients with localized muscle invasive urothelial carcinoma of the bladder in clinical stage T2-3 N0 M0, who were not eligible or rejected radical cystectomy, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety and identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of sorafenib and RT. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Treatment consisted of TUR, followed by normofractionated (2 Gy/day) external-beam RT with high-energy photons, 46 Gy to minor pelvis and 66 Gy to bladder, combined with sorafenib given po continuously. Sorafenib was started two weeks before RT and was administered for 12 weeks, finishing 4 weeks after RT. Dose levels 1, 2 and 3 corresponded to sorafenib 200 mg qd, 200 mg bid and 800 mg bid. Pathological response was assessed by post-treatment TUR. Results: Ten patients were included: median age 71 years (44-84); gender 7M: 3F. Patients were treated at 3 dose levels, the MTD was reached at level 3 and the RD was: sorafenib 200 mg bid with RT. Two DLTs occurred, both at the third dose level: diarrhea grade 3 and digestive bleeding grade 3 with secondary anemia and hemodynamic angor in a patient with previous small bowel angiodysplasia. The most frequent toxicity was diarrhea. Other grade 1-2 toxicities included rash, fatigue, hand-foot syndrome, hypertension, dysuria and urinary frequency. One patient developed late radiation cystitis. Pathological complete response was achieved in 8 of 9 patients evaluated. Salvage cystectomy has been performed in one patient due to recurrent superficial bladder tumor. After a median follow up of 30 months, 6 patients remain disease-free with intact bladder. Conclusions: The combination of sorafenib and RT appears to be feasible and safe allowing long-term bladder preservation in selected patients. A phase II study to assess the activity of this promising combination is warranted.

Preliminary Results from a Phase I Study of Revlimid® (Lenalidomide) in Combination with Vidaza® (Azacitidine) in Patients with Advanced Myelodysplastic Syndromes (MDS).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1458-1458 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Alan List ◽  
David Cuthbertson ◽  
Ronald Paquette ◽  
Thomas Loughran ◽  
...  
Keyword(s):  
Phase I ◽  
Injection Site Reaction ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Toxicity Data ◽  
Erythroid Response ◽  
Early Results ◽  
Grade 3 ◽  
Dose Levels

Abstract Background: Early MDS becomes more advanced as immature myeloid cells proliferate, angiogenesis increases, genetic lesions accumulate, and tumor suppressor genes become inactivated through hypermethylation. Progression to acute myeloid leukemia (AML) may be prevented by targeting these defects through combination therapy, using an immunomodulatory, anti-angiogenic agent, lenalidomide (LEN), and a hypomethylating drug, azacitidine (AZA). Methods: We conducted a multicenter, Phase I trial in patients (pts) with advanced MDS (IPSS score ≥1.5, or FAB or WHO classification with ≥5% myeloblasts) starting in 6/06, with results reported through 7/07. Pts were enrolled using a “3+3” design (See Table), and could not receive LEN or AZA previously. Cycles lasted 28 days, to a maximum of 7 cycles of therapy. The primary endpoint was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs, defined as Grade 3/4 non-hematologic toxicity or &gt;50% neutrophil (ANC) or platelet (plt) drop without recovery by Day 56) of the combination. A secondary endpoint was response as defined by the Modified International Working Group. Dose Level AZA Schedule LEN Schedule 1 75 mg/m2 SC days 1–5 5 mg PO days 1–14 2 75 mg/m2 SC days 1–5 5 mg PO days 1–21 3 75 mg/m2 SC days 1–5 10 mg PO days 1–21 4 50 mg/m2 SC days 1–5, 8–12 5 mg PO days 1–14 5 50 mg/m2 SC days 1–5, 8–12 5 mg PO days 1–21 6 50 mg/m2 SC days 1–5, 8–12 10 mg PO days 1–21 Results: Seven patients have been enrolled, 6 are evaluable for toxicity data. Median age was 64 years (range 52–70), 1 pt was female, and median follow-up is 5.5 months (range 1.5–13). All pts had RAEB-2; IPSS scores were 1.5 (4), 2.0 (2), and 3.0 (1), with IPSS cytogenetic risk categories of poor (1), intermediate (1), and good (5). No pt had a del (5q) lesion. Median time from MDS diagnosis was 3.5 wks (range 2–106). No DLTs occurred in Dose Levels 1 or 2, and MTD has not yet been reached. Grade 1/2 non-hematologic toxicities (n=6) included fatigue (4), injection site reaction (6), rash (3), pruritis (3), constipation or diarrhea (6), dizziness (1), and mucositis (1). Grade 3/4 non-hematologic toxicities included febrile neutropenia (1). Median ANC drop was 16.4% and plt drop was 10.4%. Although one patient was delayed 1 week in starting cycle 2 for neutropenia, there were no dose-reductions for toxicities. Four pts are evaluable for response: 2 had a complete response, 1 an erythroid response, and 1 progressive disease. Conclusions: The combination of LEN and AZA is well-tolerated and early results suggest efficacy in advanced MDS. Responses and toxicity data from higher Dose Levels will be presented.

Phase I and Pharmacokinetic Study of Irinotecan and Docetaxel in Patients With Advanced Solid Tumors: Preliminary Evidence of Clinical Activity

2000 ◽  
Vol 18 (5) ◽  
pp. 1116-1116 ◽  
Author(s):  
Alex A. Adjei ◽  
Cheri E. Klein ◽  
Helen Kastrissios ◽  
Richard M. Goldberg ◽  
Steven R. Alberts ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Intravenous Infusion ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Clinically Significant ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Tumor Types ◽  
Dose Levels

PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m2, 160/65 mg/m2, 200/65 mg/m2, and 200/75 mg/m2) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non–small-cell lung cancer, achieved partial remissions. CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m2 and docetaxel 65 mg/m2.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
P. M. Lorusso ◽  
E. Heath ◽  
M. Valdivieso ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Selective Inhibitor ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Grade 3

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6055-6055 ◽  
Author(s):  
P. H. Morrow ◽  
B. S. Glisson ◽  
L. E. Ginsberg ◽  
S. M. Lippman ◽  
M. S. Kies ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Vitamin Supplementation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

A first-in-human phase I study of ER-α36 modifier icaritin in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2614-2614
Author(s):  
Ying Fan ◽  
Binghe Xu ◽  
Xiaoyan Ding ◽  
Fei Ma ◽  
Jiayu Wang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase I Study ◽  
Chinese Herb ◽  
Hepatocellular Cancer ◽  
Fold Increase ◽  
Maximum Tolerated Dose ◽  
Multiple Cancer ◽  
Phase Ib ◽  
Dose Levels

2614 Background: ER-α36 was recently identified to be expressed in varieties of cancers and may play important roles in carcinogenesis and tumor progression. Icaritin, a natural prenylflavonoid derived from the Chinese herb Epimedium, is a first of its kind ER-α36 modifier, which demonstrated potent anti-tumor effect in multiple cancer cell lines and their xenograft models. This study aims to determine its safety, tolerability, pharmacokinetics (PK), and potential antitumor activity. Methods: This phase I study comprises phase Ia and Ib. In phase Ia part, patients with advanced breast cancer (ABC) were treated with escalating doses of Icaritin orally once daily on a continuous 28-day dosing schedule. In phase Ib part, dosing was fixed to 600 or 800mg twice daily and expansion was made to other selected malignancies including hepatocellular cancer (HCC), colorectal cancer (CRC) and intrahepatic cholangiocarcinoma (ICC) to further explore PK parameters and efficacy. Results: 24 patients were enrolled to receive Icaritin at six dose levels ranging from 50mg to 1600mg per day in phase Ia. No dose limited toxicity (DLT) was found even in the highest dose defined in the protocol, thus the maximum tolerated dose (MTD) was not reached. Only grade 1 drug-related adverse events were observed including neutropenia, ALT elevation, hypercholesteremia, fatigue, anorexia, hypertriglyceridemia, proteinuria, myalgia, hot flash and rash. PK data from the fed dosing showed 3-fold increase of Cmax and AUC compared with the fast dosing. Half life was around 2-7 hours. Among 22 evaluable subjects, no complete or partial response (CR or PR) was detected, 5 patients had stable disease(SD)for 3 months or longer. For phase Ib study, 24 patients had been enrolled. One ABC, 2 CRC and 3 ICC patients progressed after 2 months of medication. Among 7 HCC patients already evaluated, 1 obtained PR and progressed after one year of treatment and 2 remained in the study, stable for 5 months. Similar drug related toxicity profile was noted in phase Ib. Conclusions: Icaritin was generally well-tolerated without DLT across tested dose levels. Evidence of promising antitumor activity was observed in ABC and HCC. Final results will be presented at the meeting. Clinical trial information: NCT01278810.

A phase I/II study of cetuximab (cet) in combination with S-1 and oxaliplatin (SOX) in first-line treatment for metastatic colorectal cancer (mCRC) (JACCRO CC-06).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 571-571 ◽  
Author(s):  
Akihito Tsuji ◽  
Yu Sunakawa ◽  
Tadamichi Denda ◽  
Yasutaka Takinishi ◽  
Masahito Kotaka ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Maximum Tolerated Dose ◽  
Safety And Efficacy ◽  
Dose Adaptation ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Early Tumor ◽  
Ecog Ps ◽  
Level 2

571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC. COIN trial indicated that the use of cet in combination with capacitabine and oxaliplatin should not be recommended. However, the safety and efficacy of cet plus SOX are not clear. To evaluate the safety and clinical efficacy of the combination, we conducted a multi-center phase I/II study. Methods: In this trial, we assigned pts with KRAS wild type (wt), EGFR-expressing tumor and no prior chemotherapy to receive cet (initial dose 400, and 250 mg/m2 weekly) followed by SOX (oxaliplatin on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. The phase I part was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) according to the dose adaptation schedule of oxaliplatin (100 mg/m2 for level 1 and 130 mg/m2 for level 2). In the following phase II part, the enrolled pts were treated with the RD. The primary endpoint was response rate (RR) evaluated by the external review board according to RECIST criteria v1.1. Secondary endpoints included PFS, OS, and safety. In addition, we prospectively evaluated early tumor shrinkage (ETS). Results: A total of 67 pts were enrolled from January 2012 to February 2013. In the phase I part, level 2 was determined to be the RD. The MTD was not determined because dose limiting toxicity was not confirmed in level 2. In the phase II part, 59 pts including 6 pts of phase I cohort were assessable for the efficacy. The median age was 64 years, 51% of pts were male, and ECOG PS 0 was observed in 85% of pts. The median course of treatment was 5 (range 1-14). The RR was 62.7% (95%CI, 50.4 to 75.1) and ETS was observed in 72% of pts. In safety analysis, grade 3 or worse adverse events were platelet count decreased (13.1%), neutropenia (8.2%), anorexia (11.7%), rash acneform (6.7%) and peripheral neuropathy (3.3%). Conclusions: We determined the RD of cet plus SOX treatment in pts with mCRC. This combination is tolerable at full doses of cet and SOX, with manageable toxicities, and demonstrates advantages in RR for pts with KRAS wt tumor. Updated safety and efficacy data will be presented. Clinical trial information: UMIN000007022.

Phase Ib trial of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC): Final data including long-term outcomes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4087-4087 ◽  
Author(s):  
Shukui Qin ◽  
Tae-You Kim ◽  
Ho Yeong Lim ◽  
Baek-Yeol Ryoo ◽  
Jürgen Scheele ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Progression Free Survival ◽  
Response Duration ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Modest Improvement ◽  
Phase Ib ◽  
Advanced Hcc ◽  
Ecog Ps

4087 Background: The incidence of hepatocellular carcinoma (HCC), a leading cause of cancer death, is increasing with the increasing incidence of chronic liver disease. Sorafenib, the only approved systemic therapy for advanced HCC, provides modest improvement in overall survival. Preclinical studies suggest c-Met is a valid target in HCC, but non-selective TKIs with c-Met inhibitory activity have not shown efficacy in trials, possibly due to lack of c-Met inhibition. Tepotinib (MSC2156119J) is a highly selective c-Met inhibitor that has favorable safety and promising activity, particularly against c-Met+ solid tumors. We report the final results of a phase Ib trial of tepotinib in patients (pts) with advanced HCC. Methods: Pts were Asian adults with confirmed HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG PS 0–2. Pts received tepotinib 300, 500 (the RP2D) or 1,000 mg/day on a 21-day cycle. c-Met expression status was retrospectively determined by IHC. Results: 27 pts were enrolled (median age 57 [38-69]; male 23; ECOG PS 0/1 11/16); 7 received tepotinib 300 mg/day, 14 500 mg/day, and 6 1,000 mg/day (3 with dose reduction). No DLTs were observed. 22 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), most commonly diarrhea (n = 10), nausea (8), elevated AST (7), and elevated ALT (6). 9 pts had grade ≥3 TRTEAEs, including elevated AST (3) and elevated ALT (3). Best overall response (BOR) was partial response (PR) in 2 pts, one of whom received tepotinib 500 mg (response duration 16.1 months) and one 1,000 mg (4.4 months); both had c-Met+ tumors. A further 8 pts had a BOR of stable disease (SD), 1 pt non-complete response (CR)/non-progressive disease (PD), and 14 pts had PD (2 pts not evaluable). Five pts had progression free survival > 8 months. PK were as expected from previous studies. Conclusions: Tepotinib at doses of up to 1,000 mg/day was well tolerated by Asian pts with advanced HCC and a maximum tolerated dose was not reached. Antitumor activity was observed, particularly in pts with c-Met+ tumors. The ongoing phase II part of this study is comparing the efficacy and safety of first-line tepotinib and sorafenib in pts with c-Met+ HCC. Clinical trial information: NCT01988493.

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