A first-in-human phase I study of intravenous PI3K inhibitor BAY 80-6946 in patients with advanced solid tumors: Results of dose-escalation phase.

2578 Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p<0.01) and CZ48 Cmax(ϱ =0.51, p<0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.

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Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

Cancer Discovery ◽

10.1158/2159-8290.cd-16-1080 ◽

2017 ◽

Vol 7 (7) ◽

pp. 704-715 ◽

Cited By ~ 72

Author(s):

Dejan Juric ◽

Ian Krop ◽

Ramesh K. Ramanathan ◽

Timothy R. Wilson ◽

Joseph A. Ware ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Pi3k Inhibitor ◽

Advanced Solid Tumors ◽

Dose Escalation Study

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Preliminary biomarker and pharmacokinetic analysis from the completed dose escalation part of the first-in-human Phase I study evaluating MP0250, a multi-DARPin® blocking HGF and VEGF-A, in patients with advanced solid tumors

European Journal of Cancer ◽

10.1016/s0959-8049(16)32995-1 ◽

2016 ◽

Vol 69 ◽

pp. S133

Author(s):

K. Dawson ◽

D. Feurstein ◽

U. Fiedler ◽

K. Kuster ◽

M. Bez ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Study ◽

Pharmacokinetic Analysis ◽

Advanced Solid Tumors

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A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.3021 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 3021-3021 ◽

Cited By ~ 18

Author(s):

V. Moreno Garcia ◽

R. D. Baird ◽

K. J. Shah ◽

B. Basu ◽

N. Tunariu ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Pi3k Inhibitor ◽

Advanced Solid Tumors ◽

Phosphoinositide 3 Kinase

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A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts) with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3076 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3076-3076 ◽

Cited By ~ 4

Author(s):

Tae Min Kim ◽

Keun-Wook Lee ◽

Do-Youn Oh ◽

Jong-Seok Lee ◽

Seock-Ah Im ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Study ◽

Advanced Solid Tumors ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Expansion Cohort ◽

Positive Breast Cancer

3076 Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR L858R/T790M double mutant cells. A phase I study was conducted to determine the MTD, pharmacokinetics, and antitumor activity. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation part, and additional 12 pts were enrolled in the expansion cohort of molecular enrichment. Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82), M:F=25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4) were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24 mg, and two at 32 mg. The MTD was determined as 24mg. The most common drug-related adverse events were diarrhea, stomatitis, rash, pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1 unconfirmed, duration of response: 11.9 mo, 7.07 mo+, 4.5 mo+), and 19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17) months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics proportional to dose-escalation, relatively short half-life, and little accumulation. Additional 12 pts in the expansion cohort are under treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer). Conclusions: HM781-36B was safe and well tolerable in advanced solid tumors. Preliminary evidence of anticancer activity has been observed. Updated data will be presented at the meeting.

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