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Clinical Phase I study with an Insulin-like Growth Factor-1 receptor inhibitor: experiences in patients with squamous
Simon Ekman1, Jan-Erik Frödin, Johan Harmenberg
1Section of Oncology, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Sweden. Simon.Ekman@onkologi.uu.se
Background:
Inhibition of the Insulin-like Growth Factor-1 receptor (IGF-1R) has resulted in extensive anti-tumor effects. Picropdophyllin (PPP, AXL1717) is a small-molecule inhibitor of the IGF-1R without inhibition of closely related receptors including the insulin receptor and has shown extensive effects against a wide range of tumors in animals. PPP is currently tested as an orally administrated single agent treatment in an open-label combined Phase I/II clinical study in advanced cancer patients with solid tumors which progress in spite of several lines of treatment.
Patients And Methods:
The first part (Phase IA) consisted of single day BID dosing every three weeks with consecutive dose escalations. The second part (Phase IB) consists of seven days or longer BID dosing every three weeks, dosing range being 520-700 mg BID. Non-progressing patients could continue treatment within a compassionate use setting.
Results And Discussion:
The present report describes our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with PPP. Despite more than seven months of PPP treatment as third or fourth line treatment, the reported patients did not develop any additional metastases. Furthermore, CT scans as well as (18)FDG-Positron Emission Tomography (PET) scans of the patients demonstrated large central necrotic areas, which may suggest tumor response. At the same time, the study drug is so far well tolerated. The phenomenon of necrosis in the tumors suggestive of tumor response has not been reported before in anti-IGF-1R treatment and will be subject to further studies in the present clinical trial.
Insights
Picropdophyllin (PPP) shows promise in treating advanced cancers by inhibiting the Insulin-like Growth Factor-1 receptor (IGF-1R). Early clinical trials indicate potential tumor response and good tolerability in patients with non-small cell lung cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Inhibition of the Insulin-like Growth Factor-1 receptor (IGF-1R) demonstrates significant anti-tumor activity.
- Picropdophyllin (PPP, AXL1717) is a novel small-molecule IGF-1R inhibitor with broad anti-cancer effects in preclinical models.
- PPP is being evaluated as an oral monotherapy in advanced solid tumors refractory to prior treatments.
Purpose of the Study:
- To assess the safety and preliminary efficacy of Picropdophyllin (PPP) in patients with advanced solid tumors.
- To evaluate the anti-tumor effects of PPP in patients with progressive squamous non-small cell lung cancer (NSCLC).
Main Methods:
- Phase I/II open-label clinical study involving dose escalation (Phase IA) and longer dosing durations (Phase IB).
- Patients received Picropdophyllin (PPP) orally, BID, every three weeks, with doses ranging from 520-700 mg.
- Imaging studies including CT and (18)FDG-PET scans were utilized to assess tumor response.
Main Results:
- Four patients with progressive squamous non-small cell lung cancer (NSCLC) received PPP for over seven months.
- No additional metastases were observed in treated patients.
- CT and PET scans revealed extensive central necrosis, suggesting a potential tumor response to PPP.
- The drug was well-tolerated with no significant adverse events reported.
Conclusions:
- Picropdophyllin (PPP) demonstrated encouraging signs of tumor response, characterized by tumor necrosis, in advanced NSCLC patients.
- The observed necrosis phenomenon is novel for anti-IGF-1R therapies and warrants further investigation.
- PPP exhibits good tolerability, supporting its continued evaluation in clinical trials for solid tumors.
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