Phase I Dose-Escalation Study of Afatinib, An ErbB Family Blocker, Plus Docetaxel in Patients with Advanced Cancer

Marshall, John L.; Shapiro, Geoffrey I.; Uttenreuther-Fischer, Martina; Ould-Kaci, Mahmoud; Stopfer, Peter; Gordon, Michael

doi:10.2217/fon.12.195

Cited by 16 publications

(8 citation statements)

References 34 publications

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“…The PK assessments and analysis in this study do not provide evidence of any drug–drug interactions between cabazitaxel and abiraterone. Mean trough plasma concentrations of cabazitaxel plus abiraterone were similar to those observed in previous combination therapy and monotherapy studies [15, 16]. …”

Section: Discussionsupporting

confidence: 83%

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

et al. 2017

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BackgroundAbiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536).Patients and methodsThe primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II).ResultsTen patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1–28). Grade 3–4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6–66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1–10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors.ConclusionsThe combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.

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Section: Discussionsupporting

confidence: 83%

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

et al. 2017

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“…Nevertheless, both AUC and C max values of afatinib and nintedanib were comparable to those reported previously for each agent when administered as monotherapy or in combination [26][27][29][30][31][32][35][36][37]. These findings suggest that there were no pharmacokinetic interactions between afatinib and nintedanib in the applied dosing schedule.…”

Section: • • Antitumor Activitysupporting

confidence: 83%

A Phase I Dose-Escalation Study of Afatinib Combined with Nintedanib in Patients with Advanced Solid Tumors

Gordon¹,

Springett²,

Su³

et al. 2015

Future Oncol.

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“…Although PX-866 has not been associated with neutropenia as a single agent, a drug–drug interaction that enhances docetaxel's myelosuppressive effects cannot be ruled out. Unexpected increases in neutropenia have been seen in other docetaxel combination trials with agents thought not to be myelosuppressive (Janne et al , 2013; Marshall et al , 2013). This may have been compounded by PX-866's introduction at the neutrophil nadir on day 8 of cycle 1.…”

Section: Discussionmentioning

confidence: 99%

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours

Bowles

Senzer

et al. 2013

Br J Cancer

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Background:This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours.Methods:PX-866 was administered at escalating doses (4–8 mg daily) with docetaxel 75 mg m−2 intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers.Results:Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1–569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed.Conclusion:Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.

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Phase I Dose-Escalation Study of Afatinib, An ErbB Family Blocker, Plus Docetaxel in Patients with Advanced Cancer

Abstract: Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

Cited by 16 publications

References 34 publications

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

A Phase I Dose-Escalation Study of Afatinib Combined with Nintedanib in Patients with Advanced Solid Tumors

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours

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