Phase I study of MGCD265 administered intermittently to patients with advanced malignancies (Study 265–102)

e14516 Background: MGCD265 is an orally-available small molecule designed to inhibit c-Met, VEGFR-1, -2, -3, Tie-2 and Ron kinases. These targets are potentially relevant for the treatment of a variety of cancers. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of MGCD265 using an intermittent schedule of administration in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered on days 1–7 and 15–21 (1 week on, 1 week off schedule) of each 28-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Eleven patients with advanced solid tumors have been treated. Characteristics: age range 40–72; gender: 3 M/8F; ECOG: 1 (7 patients); 2 (4 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs have been reported during cycle 1. Six patients received treatment for 2 or more cycles. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax (Table below) with an approximate mean half-life of 30 hours and an approximate mean Tmax of 7 hours. At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Intermittent administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Treatment of patients at 192 mg/m2 is underway. [Table: see text] [Table: see text]

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Phase I study of daily administration of MGCD265 to patients with advanced malignancies (Study 265–101)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14525 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14525-e14525 ◽

Cited By ~ 3

Author(s):

C. K. Kollmannsberger ◽

H. Hurwitz ◽

G. Vlahovic ◽

C. Maroun ◽

J. Dumouchel ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Study ◽

Tumor Development ◽

Daily Administration ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose ◽

Grade 3

e14525 Background: MGCD265 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor that targets the mesenchymal epithelial transition (c-Met) and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3). Additional RTK targets include Tie-2, and Ron. Those kinases are known to be involved in tumor development and angiogenesis. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of daily administration of MGCD265 in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered as a continuous 21-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Ten patients with advanced solid tumors have been treated. Characteristics: age range 25–75; gender: 8 M/2F; ECOG: 0 (1 patient); 1 (9 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs during cycle 1 have been reported. Eight patients received treatment for 2 cycles or more. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax with an approximate mean half-life of 23 hours (see Table below). At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Daily oral administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Further dose escalation is underway. [Table: see text] [Table: see text]

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Abstract 1752: A phase I/IIa, first time in human, open-label dose-escalation study of GSK2636771 in subjects with advanced solid tumors with PTEN deficiency

10.1158/1538-7445.am2012-1752 ◽

2012 ◽

Cited By ~ 4

Author(s):

Samuel C. Blackman ◽

Shelby D. Gainer ◽

Benjamin B. Suttle ◽

Konstantine W. Skordos ◽

Joel D. Greshock ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose ◽

First Time

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Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2512 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2512-2512 ◽

Cited By ~ 41

Author(s):

Amita Patnaik ◽

Soonmo Peter Kang ◽

Anthony W. Tolcher ◽

Drew Warren Rasco ◽

Kyriakos P. Papadopoulos ◽

...

Keyword(s):

Antitumor Activity ◽

Phase I ◽

Preliminary Evidence ◽

Open Label ◽

Dose Escalation Study ◽

Advanced Malignancy ◽

Multiple Tumor ◽

Label Dose ◽

Grade 3 ◽

Tumor Types

2512 Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy >6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]

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Phase I study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of SC10914 in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6047 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6047-6047

Author(s):

Jifang Gong ◽

Jinhai Tang ◽

Yongmei Yin ◽

Dingwei Ye ◽

Jian Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase I ◽

Cancer Patients ◽

Solid Tumors ◽

Phase I Study ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Adequate Organ Function ◽

Grade 3 ◽

Wbc Count

6047 Background: SC10914 is a highly selective inhibitor of PARP enzymes, including PARP1 and PARP2. SC10914 has a similar structure with olaparib. We conducted a phase I study to assess the safety, tolerability, PK/PD and preliminary efficacy of SC10914 in patients with advanced solid tumors. Methods: This is a phase I dose-escalation study with 3+3 design, we enrolled patients at 4 sites in China. Eligible patients were diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists; had measurable disease; had adequate organ function. Patients received SC10914 daily at ten escalating doses from 30 mg QD to 500 mg TID in a 28-day cycle. We obtained blood for PK and CA125 assessments. Toxic effects were assessed by CTCAE 4.03 criteria and tumour responses ascribed by RECIST 1.1 and CA125 was assessed by GCIG criteria. Results: As of January 2020, 52 patients were enrolled, of which 14 were males and 38 were females. Ten doses were escalated to 500mg TID, and no DLT was observed, and MTD was not obtained. The incidence of grade 3/4 AEs and SAEs that were related to SC10914 were 34.6% (18/52) and 13.5% (7/52). Grade 3/4 adverse reaction happened in at least two patients were anaemia/reduced hemoglobin (10/52, 19.2%), decreased WBC count (5/52, 9.6%), neutropenia (3/52, 5.8%), thrombocytopenia (2/52, 3.8%), and decreased lymphocyte count (2/52, 3.8%). A total of 17 gBRCAm evaluable ovarian cancer patients were enrolled, 6 of them had PR, the ORR was 35.3% (6/17). 10 gBRCAm ovarian cancer patients were enrolled in TID groups (including 2 patients who received BID doses at the beginning and changed to 300 mg TID dose after several cycles of treatment), 5 of them had PR, the ORR was 50% (5/10). The ORR of 400 mg TID group was 66.7%(4/6). PK data showed that the exposure of SC10914 was increased with dose increasing at the dose of 30 mg to 250 mg. The half-life of SC10914 was about 2-5 hours. Conclusions: SC10914 was safe in patients with advanced solid tumors. The main toxicity was blood-related adverse reactions. SC10914 was effective in gBRCAm ovarian cancer patients. 400 mg TID might be RP2D. Clinical trial information: NCT02940132.

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