A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a for the Treatment of Non–Small Cell Carcinoma In Situ or Non–Small Cell Microinvasive Bronchogenic Carcinoma: A Dose Ranging Study

Abstract

Introduction We report a phase I trial of photodynamic therapy (PDT) of carcinoma-insitu (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used PS porfimer sodium (Photofrin®). Methods The objectives of this study were 1) to determine the maximally tolerated light dose at a fixed PS dose and 2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was done at one and six months, respectively. Results The rate of pathological complete response (CR) was 82.4% (14/17 evaluable lesions; 14 patients) at one-month and 72.7% (8/11 lesions; 8 patients) at 6 months. Only 4 patients developed mild skin erythema. One of the three patients in 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress due to mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The third sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose not exceed 125J/cm2. Conclusions PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies.

Oncologic Photodynamic Therapy: Basic Principles, Current Clinical Status and Future Directions

“…HPPH is a chlorin based PS which absorbs light at 665 nm and has a lower risk of skin sensitivity due to its shorter half-life compared to Photofrin ® [ 144 ]. A Phase I dose escalation study showed HPPH-PDT is capable of achieving high rates of CR that is retained for months in patients with carcinoma in situ (CIS) and micro invasive cancer (MIC) of the central airways [ 145 ]. Minor photosensitivity was reported but overall AEs were limited.…”

A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

“…Also,t his compound is soluble in water and activated using red light, whereas most PACT compounds reported to date require UV, blue or green light for activation. Thes teric hindrance of [2]Cl 2 is high enough to obtain activation using clinically relevant red-light doses (21 Jcm À2 ), [28] but low enough to maintain thermal stability.I nc ontrast, [1]Cl 2 is too labile in the dark, which make it unsuitable for PACT.Altogether this study represents the first example of PACT where the phototoxicity index measured in hypoxic cancer cells with red light can be explained by al ow 1 O 2 quantum yield, an efficient oxygen-independent photosubstitution reaction, and enzyme inhibition.…”

“…Also, this compound is soluble in water and activated using red light, whereas most PACT compounds reported to date require UV, blue or green light for activation. The steric hindrance of [ 2 ]Cl 2 is high enough to obtain activation using clinically relevant red‐light doses (21 J cm −2 ),28 but low enough to maintain thermal stability. In contrast, [ 1 ]Cl 2 is too labile in the dark, which make it unsuitable for PACT.…”

Novel theranostic nanoporphyrins for photodynamic diagnosis and trimodal therapy for bladder cancer

“…Given that PLZ4 also interacts with integrin αvβ3, it would be interesting to explore the potential similar vascular effects through PLZ4-tumor endothelial cell interaction. Additionally, another relevant photosensitizer 3-(1′-hexyloxyethyl) pyropheophorbide-a (HPPH) is current in clinical trials for non-small cell bronchogenic carcinoma and early stage cancer of the larynx [50, 51] and was previously reported to have 100% tumor response in xenograft mice bladder cancer model at the dose of 0.5 mg/kg. In our study, we used 5 mg pyropheophorbide a /kg, which was chosen to match polymer concentration used to achieve the therapeutic DOX dose (2.5 mg/kg) in mice with our standard formulation (1 mg DOX/10 mg PNP or 2 mg pyropheophorbide a /ml).…”