| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Basal cell carcinoma (BCC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Rodent ulcer - small, fair papules, flesh-colored, round or oval translucent nodule, or scaly, localized plaque in frequently sun-exposed skin |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10004146 |
| E.1.2 | Term | Basal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is to compare the efficacy of BF-200 ALA containing 7.8% 5-aminolevulinic acid (ALA) as active ingredient with the comparator Metvix®, containing 16% methyl-aminolevulinate in the treatment of thin, non-aggressive BCC with photodynamic therapy. Clinical efficacy and safety of BF-200 ALA in PDT were proven for the treatment of mild and moderate AK in 1 dose-finding and 2 confirmatory studies encompassing a total of 798 enrolled patients comprising 357 patients (2,114 lesions) exposed to BF-200 ALA.
A phase II study in BCC using a preliminary 10% 5-ALA nanoemulsion formulation showed a promising complete lesion response rate in superficial basal cell carcinoma (sBCC) of 85% 6 months after a single PDT. In the study, BCC lesions were located in different body regions.
For the treatment of non-aggressive BCC, side effects are expected to be similar to those observed in the PDT of AK, mainly self-limiting pain and erythema at the application site. Based |
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| E.2.2 | Secondary objectives of the trial |
• Lesion complete response (completely cleared individual lesions) assessed 12 weeks after the last PDT,
• Reduction of total lesion area (summation of sizes of all treated lesions) per patient, assessed 12 weeks after the last PDT,
• Patient complete response (complete clearance of all treated lesions) assessed 12 weeks after PDT-2,
• The overall cosmetic outcome 12 weeks after the last PDT.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Willing and able to sign the informed consent form. A study-specific informed consent must be obtained in writing for all patients before any study procedures.
• Men or women ≥18 years of age (inclusive).
• Presence of 1 to 3 thin (≤2 mm thickness), non-aggressive, primary BCC lesions (comprising primary superficial, nodular, or mixed superficial/nodular) in the face/forehead outside the H-zone (see Appendix B), bald scalp, extremities and/or neck/trunk. Confirmation of non-aggressiveness and thickness of BCC through biopsies of all lesions taken at screening.
To document and confirm the investigator’s clinical diagnosis of non-aggressive behavior of the lesions:
Pre-study biopsies must be taken from all BCC lesions at the screening visit (Visit 1). Investigators are requested to take the 3 mm biopsy at the region of the tumor which, according to clinical judgment, appears thickest.
- The biopsy material will be histopathologically evaluated by a dermatopathological expert according to the WHO classification/subtyping(2). In case no clear histopathological assessment can be performed a second biopsy may be taken after approval of the sponsor. Hence, the time interval between Visit 1 and Visit 2 has to be expanded accordingly.
The result of the biopsies will ultimately determine whether the patient is eligible for the study; the patient may only be enrolled if the investigator’s clinical diagnosis of non-aggressive BCC is confirmed for all lesions by the histopathological evaluation according to WHO classification guideline(2) and the lesion thickness is ≤2 mm.
• The diameter of each lesion should range between ≥0.5 cm and ≤2 cm; the total maximal treated area must be not larger than approximately 10 cm² (including a 0.5 – 1.0 cm margin surrounding each lesion). The maximal thickness of a lesion should not exceed 2 mm (by means of histopathological confirmation).
The size of each baseline BCC lesion is determined by measuring the two largest perpendicular diameters. To describe irregular lesions (ellipsoidal), investigators must measure the major and minor axes, which must both be within the acceptable limits defined above.
• Target BCC lesions must be discrete and quantifiable and have to be located within 1 to 2 treatment areas.
• Willingness to undergo biopsy at the end-of-study visit 12 weeks after the last PDT in case of partial or non-responding lesions.
• Willingness to receive up to 4 PDTs within 3.5 months.
• Free of significant physical abnormalities (eg tattoos, dermatoses) in the potential treatment area that may cause difficulty with examination or final evaluation.
• Willingness to stop the use of moisturizers and any other topical treatments within the treatment area (during the observer blind part of the study), including anti-aging products, vitamin A-, vitamin D-, and/or vitamin E-containing ointments and creams, and green tea preparations during the study. Sunscreens will be allowed, but should not be applied in the treatment area within approximately 24 h before a clinical visit that involves a lesion count.
• Accept to abstain from extensive sunbathing and use of a solarium during the observer blind part of the study. Patients with sunburn within the treatment areas cannot be included until fully recovered.
• Healthy patients or patients with clinically stable medical conditions as confirmed by physical examination and by medical history, including but not limited to controlled hypertension, diabetes mellitus type II, hypercholesterolemia, and osteoarthritis, will be permitted to be included in the study if their medication is not prohibited by this protocol.
• Women of childbearing potential are permitted to participate in this study only if they have a negative serum pregnancy test at screening and a willingness to use a highly effective method of contraception during the observer blind part of the study. A woman is considered to be of childbearing potential if she possesses a uterus and at least one ovary, has not had a tubal ligation, or is not postmenopausal for at least 3 years. Highly effective methods of birth control are defined as resulting in a low failure rate (Pearl Index below 1, failure rate less than 1% per year) when properly used. This includes methods such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or sexual intercourse with a vasectomized partner. The use of condoms without spermicide coating is not considered to be a highly effective method of contraception.
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| E.4 | Principal exclusion criteria |
• History of hypersensitivity to 5-ALA or any ingredient of BF-200 ALA.
• History of hypersensitivity to MAL or any ingredient of Metvix® cream including arachis oil, or to peanut or soya.
• Current treatment with immunosuppression therapy.
• Presence of porphyria.
• Hypersensitivity to porphyrins.
• Presence of BCC lesions on embryonic fusion planes (H-zone, see Appendix B).
• Presence of more than 3 BCCs.
• Presence of malignant or benign tumors or precancerous lesions of the skin other than non-aggressive BCC within the treatment area (eg malignant melanoma, squamous cell carcinoma (SCC)) within the last 12 weeks.
• Gorlin Syndrome or Xeroderma pigmentosum.
• Presence of photodermatoses.
• Confirmed histopathological diagnosis of other than non-aggressive BCC.
• Treatment of recurrent BCCs, pigmented or aggressive BCCs including morpheiform BCC.
• Treatment of lesions (AK, BCC, SCC, Bowens disease, melanoma) ≤12 weeks prior to first PDT, except physical treatments (eg cryosurgery, excision surgery) that will not be allowed ≤4 weeks prior to screening visit (Visit 1).
• Presence of inherited or acquired coagulation defect.
• Start of intake of medication with hypericin or systemically-acting drugs with phototoxic or photoallergic potential, such as psoralenes, tetracyclines, nalidixic acid, furosemide, amiodarone, phenothiacines, chinolones, fibrates, or phytotherapy with St. John’s wort, arnica, or valerian, or topically applied phototoxic substances like tar, pitch, psoralenes or some dyes like thiazide, methylene blue, toluidine blue, eosine, Bengal rose, or Acridine within 8 weeks prior to screening. Patients may, however, be enrolled if such medication was taken for more than 8 weeks prior to screening without evidence of a phototoxic/photoallergic reaction. Within 8 weeks prior to screening and during the observer-blind part of the study, such medication must not be newly prescribed. Should such a prescription become unavoidable for medical reasons during the clinical part of the trial, the investigator has to consult with the sponsor, who may discontinue the patient’s study participation, if deemed necessary.
• Clinically relevant cardiovascular, hepatic, renal, neurologic, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult.
• Evidence of clinically significant (CS), unstable medical conditions, such as:
- Metastatic tumor or tumor with high probability of metastatic spread.
- Cardiovascular disease (New York Heart Association (NYHA) class III, IV).
- Immunosuppressive condition.
- Hematologic, hepatic, renal, neurologic, or endocrine condition.
- Collagen-vascular condition.
- Gastrointestinal condition.
• Topical treatment with 5-ALA or MAL outside the treatment area during the observer blind part of the study.
• Any topical treatment including diclofenac and immunomodulatory agents (eg imiquimod, ingenol mebutate) 12 weeks prior to the first PDT session and during the observer blind part of the study.
• Any physical treatment during the observer blind part of the study within the treated target areas.
• None of the following systemic treatments within the designated period prior to the first PDT session and during the observer blind part of the study:
- Interferon (6 weeks)
- Immunomodulators or immunosuppressive therapies (10 weeks)
- Cytotoxic drugs (6 months)
- Investigational drugs (8 weeks)
- Drugs known to have major organ toxicity (8 weeks)
- Corticosteroids (oral or injectable) (6 weeks)
- Inhaled corticosteroids (>1200 µg/day for beclomethasone, or >600 µg/day for fluticasone) (4 weeks)
- MAL or 5-ALA (12 weeks)
• Pregnancy.
• Breast feeding.
• Patients with any dermatological disease in the treatment region or surrounding region that may be exacerbated by treatment with topical 5-ALA or MAL or that may cause difficulty with examinations (eg psoriasis, eczema).
• Patients showing cornu cutaneum-like alterations of the skin in the face or on the bald scalp (ie target region).
• Participation in a clinical study within 2 months prior to screening.
• Drug or alcohol abuse in the preceding 2 years.
• Patient is the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff, or relative thereof directly involved in the conduct of the protocol.
• Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study.
• Patient is unlikely to comply with protocol, eg uncooperative attitude, inability to return for FU visits, and unlikelihood of completing the study.
• Confirmed diagnosis of human immunodeficiency virus (HIV) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable will be the overall patient complete response assessed clinically 12 weeks after the last PDT. An overall complete responder is defined as a patient in whom all treated lesions were cleared 12 weeks after the last PDT. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| See definition in sec. E.5.1 |
|
| E.5.2 | Secondary end point(s) |
• Lesion complete response (completely cleared individual lesions) assessed 12 weeks after the last PDT,
• Reduction of total lesion area (summation of sizes of all treated lesions) per patient, assessed 12 weeks after the last PDT,
• Patient complete response (complete clearance of all treated lesions) assessed 12 weeks after PDT-2,
• The overall cosmetic outcome 12 weeks after the last PDT. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See definition in sec. E.5.2 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the date of the last FU visit of the last patient. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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