A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors

• Published in: Annals of oncology Vol. 24; no. 5; pp. 1392 - 1400
• Main Authors: Vermorken, J.B., Rottey, S., Ehrnrooth, E., Pelling, K., Lahogue, A., Wind, S., Machiels, J.-P.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.05.2013; Oxford University Press
• Subjects: Adult; Afatinib; Aged; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Cisplatin - therapeutic use; Drug Administration Schedule; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - therapeutic use; Humans; Maximum Tolerated Dose; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Paclitaxel - therapeutic use; Pharmacology. Drug treatments; phase Ib; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - therapeutic use; Tumors; afatinib; paclitaxel; phase Ib; cisplatin; Antineoplastic agent; Solid tumor; Toxicity; Taxane derivatives; Paclitaxel; Advanced stage; Safety; Antimitotic; Platinum II Complexes; Fluorouracil; Human; Drug combination; Enzyme; Fluoropyrimidine derivatives; Transferases; Oral administration; Enzyme inhibitor; Patient; Malignant tumor; Thymidylate synthase; Cisplatin; Alkylating agent; Antimetabolic; Methyltransferases; Afatinib; Pyrimidine derivatives; Combined treatment; Therapeutic protocol; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mds633

In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m2/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m2 (regimen A) or cisplatin 75–100 mg/m2/5-fluorouracil 750–1000 mg/m2 (regimen B) in patients with advanced solid tumors. The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design). The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents. The MTD of afatinib was 20 mg with cisplatin–paclitaxel and 30 mg with cisplatin–5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment.