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Updated: Jun 13, 2026
Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer
Published on: February 12, 2017
Phase I dose-escalation study of brostallicin, a minor groove binder, in combination with cisplatin in patients with
F Caponigro1, D Lorusso, G Fornari
1National Tumor Institute, Naples, Italy. caponigrof@libero.it
Purpose:
Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin-brostallicin combination paved the way to clinical combination studies. In particular, we set up the first clinical combination study of brostallicin and cisplatin in patients with advanced solid tumors. This study was to be followed by a phase II study in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN).
Methods:
Escalating doses of brostallicin were administered in combination with a fixed dose of cisplatin (75 mg/m(2)) in patients with recurrent or metastatic advanced solid tumors who had previously received a cumulative dose of cisplatin not higher than 475 mg/m(2). The recommended dose of brostallicin was expanded in order to have a better estimate of antitumor activity and to better define the safety profile of the combination.
Results:
Twenty-one patients were treated. Two DLTs (grade 3 fatigue and febrile neutropenia) were observed at dose level 3 (brostallicin 9 mg/m(2)). Dose level 2 (brostallicin 7 mg/m(2) and cisplatin 75 mg/m(2)) was recommended for future phase II studies. Main toxicity was hematologic; in fact, only 1 patient out of 21 did not develop neutropenia and only 2 patients did not have thrombocytopenia. Grade 3-4 neutropenia was observed in 90.5% of patients, grade 3-4 thrombocytopenia in 38.1%, grade 3-4 anemia in 23.8%. The cycle 1 nadir (ANC < 500 x 10(9)/L) for neutrophils was Day 14 (median; range 11-17) with recovery to an ANC of >1,500 3.5 days after nadir (median; range 2-4) at dose level 3. The cycle 1 nadir (median of 51,000 x 10(9)/L) for platelets occurred on Day 13 (median; range 10-15) with recovery to a platelet count of >100,000 4 days after nadir (median; range 2-8). No objective responses were observed, but seven patients had a long lasting (>18 weeks) stable disease.
Conclusions:
Further studies of the combination of brostallicin and cisplatin are warranted.
Insights
This study combined brostallicin with cisplatin in advanced solid tumors. The combination showed significant hematologic toxicities, with dose level 2 recommended for future trials despite no objective responses observed.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Brostallicin, a DNA minor groove binder, demonstrates efficacy in drug-resistant cancers.
- Previous trials indicated myelotoxicity as the dose-limiting toxicity for brostallicin.
- Preclinical data suggested a synergistic effect between brostallicin and cisplatin.
Purpose of the Study:
- To evaluate the safety and efficacy of combining brostallicin with cisplatin in advanced solid tumors.
- To determine the recommended dose for future Phase II studies.
- To explore the combination's potential in recurrent squamous cell carcinoma of the head and neck (SCCHN).
Main Methods:
- A dose-escalation study of brostallicin combined with fixed-dose cisplatin (75 mg/m²).
- Patients with recurrent or metastatic advanced solid tumors were enrolled.
- The study aimed to identify dose-limiting toxicities (DLTs) and assess antitumor activity.
Main Results:
- Hematologic toxicities, including neutropenia and thrombocytopenia, were prevalent.
- Grade 3-4 neutropenia occurred in 90.5% of patients.
- Seven patients achieved stable disease for over 18 weeks; no objective responses were observed.
Conclusions:
- The combination of brostallicin and cisplatin warrants further investigation.
- Dose level 2 (brostallicin 7 mg/m² and cisplatin 75 mg/m²) was recommended for Phase II studies.
- The study highlights the need for careful toxicity monitoring in future trials.
