Fixed dose-rate gemcitabine as radiosensitizer for newly diagnosed glioblastoma: a dose-finding study

Abstract Trotabresib (CC-90010) demonstrated antitumor activity as monotherapy in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270) and enhanced the antiproliferative effects of temozolomide in preclinical studies. CC-90010-GBM-002 (NCT04324840) is a phase 1B dose-finding study investigating standard-of-care temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide or concomitant trotabresib + temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide, post-resection, in patients with newly diagnosed glioblastoma. We present interim results for adjuvant trotabresib + temozolomide. Patients received trotabresib 15, 30, or 45 mg daily (4 days on/24 days off) + temozolomide administered per label for 6 cycles, followed by trotabresib 45 mg monotherapy daily (4 days on/24 days off). Primary objectives are to establish the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of trotabresib. Preliminary efficacy, pharmacokinetics, and pharmacodynamics are also being investigated. Of 13 patients enrolled, 5, 6, and 2 received trotabresib 15, 30, and 45 mg, respectively, plus temozolomide. Grade 3/4 treatment-related adverse events were reported in 2, 4, and 1 patients receiving trotabresib 15, 30, and 45 mg, respectively. MTD and RP2D are not yet reached; dose limiting toxicity (grade 4 thrombocytopenia) was reported in 1 patient in the 30-mg group. Of 10 evaluable patients, 1 had complete response and 7 had stable disease per RANO criteria. Trotabresib exposure increased proportionally with dose. Day 4 time to peak trotabresib concentration was 0.5–2.0 hours; mean terminal half life was 60–70 hours. Day 4 blood CCR1 RNA 2–4 hours post-dose was downregulated below baseline in the 15-mg group and ≥ 50% in the 30-mg group. Adjuvant trotabresib + temozolomide appears well tolerated, with promising preliminary efficacy. Treatment was ongoing at data cutoff in 9 patients in the adjuvant cohort; enrollment is continuing in the adjuvant and concomitant therapy dose-escalation cohorts.

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Development of a Subcutaneous Fixed‐Dose Combination of Pertuzumab and Trastuzumab: Results From the Phase Ib Dose‐Finding Study

The Journal of Clinical Pharmacology ◽

10.1002/jcph.1362 ◽

2018 ◽

Vol 59 (5) ◽

pp. 702-716 ◽

Cited By ~ 4

Author(s):

Whitney P. Kirschbrown ◽

Chris Wynne ◽

Matts Kågedal ◽

Russ Wada ◽

Hanbin Li ◽

...

Keyword(s):

Dose Finding ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Phase Ib ◽

Finding Study ◽

Dose Combination ◽

Dose Finding Study

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Fixed dose rate (FDR) gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme (GBM): Preliminary results of a phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.12502 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 12502-12502

Author(s):

A. Fabi ◽

A. Felici ◽

M. A. Mirri ◽

G. Metro ◽

A. Vidiri ◽

...

Keyword(s):

Combined Treatment ◽

Maximum Tolerated Dose ◽

Fixed Dose ◽

Newly Diagnosed ◽

Preliminary Results ◽

Activity Assessment ◽

Fixed Dose Rate ◽

Newly Diagnosed Glioblastoma ◽

Assessment Standard

12502 Background: In a previous phase I study (ASCO 2006), where FDR Gemcitabine at 10/mg/m2/min was tested in association with radiotherapy (RT) for the treatment of newly diagnosed GBM, a maximum tolerated dose of 175 mg/m2/wk was identified. Methods: After surgery for GBM (either citoreduction or sterebiopsy), patients were treated with fractionated focal RT at a daily dose of 2.0 Gy per fraction, five days per week for six weeks (total dose of 60 Gy). FDR Gemcitabine at 175 mg/m2/wk was given concomitantly starting 24–72 hours prior to RT and then for the whole duration of RT. An MRI performed at 7 and 40 days from the end of chemo-radiotherapy was used for activity assessment. Standard oral temozolamide 150–200 mg/m2 was administrated following the combined treatment. Results: From 07/2004 16 patients (9 male, 7 female) have been enrolled. Characteristics of patients were: median age 57 years (42–72), median KPS at baseline 90 (70–100), surgery/stereobiopsy 14/2. Median time from diagnosis to initiation of Gemcitabine was 45 days (28–54). Among the 14 evaluable patients 3 (21.4%) partial responses, 7 (50%) stable disease and 4 (28.5%) progressive diseases were recorded. At a median follow up of 18 months (2–33) time to progression was 6 months (1.5–24). Toxicity was manageable with only one G3 neutropenia and hypertransaminasemia in two patients respectively. Grade 1 hypertransaminasemia was registered in 6 patients (43%). Conclusions: These preliminary results show that in patients with newly diagnosed GBM, radiosensitizing FDR Gemcitabine at 175 mg/m2/wk is a well tolerated regimen with an interesting activity. Accrual is ongoing and final results will be presented at the meeting. No significant financial relationships to disclose.

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