| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Basal Cell Carcinoma in adult patients with Nevoid Basal Cell Carcinoma Syndrome |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004146 |
| E.1.2 | Term | Basal cell carcinoma |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is: • To demonstrate the superiority of topical LDE225 versus vehicle in terms of treatment success in patients with NBCCS, 4 weeks after LDE225 treatment for 8 weeks or 12 weeks. |
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| E.2.2 | Secondary objectives of the trial |
| All secondary objectives are key objectives. The secondary objectives are: • To assess the safety of topical treatment with LDE225, compared to vehicle in terms of reported systemic adverse events in patients with NBCCS. • To evaluate the local tolerability of topical treatment with LDE225, compared to vehicle in terms of reported local adverse events in patients with NBCCS. • To assess the rate of complete clinical clearance of the Target BCC in patients with NBCCS in the LDE225 treatment group versus vehicle, 4 weeks after LDE225 treatment for 8 weeks or 12 weeks. • To assess the rate of complete histological clearance of the Target BCC in patients with NBCCS in the LDE225 treatment group versus vehicle, 4 weeks after LDE225 treatment for 8 weeks or 12 weeks. • To assess the rate of complete clinical clearance of the Nodular BCC in patients with NBCCS in the LDE225 treatment group versus vehicle, 4 weeks after LDE225 treatment for 12 weeks. • PLS SEE PROTOCOL |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1 to 6 must be met at the Screening Visit. Criteria 7 and 8 must be met at the Baseline Visit. 1. Written informed consent, which includes consent for PTCH1 genetic mutation testing, consent for at least 3 and up to 12 2-mm punch biopsies, and three surgical excisions must be obtained before any study-related assessment is performed. 2. Male or female patient, of any race or ethnicity, at least 18 years of age. 3. Patient is able to understand and communicate with the investigator and comply with the requirements of the study. If not, a caregiver or legal representative who is able to understand, communicate with the investigator and comply with the requirements of the study must be present at all visits. 4. Typical presentation of NBCCS in the opinion of the investigator, based on clinical criteria such as Kimonis et al (Kimonis et al 1997). 5. At least one of the criteria below characteristic of NBCCS: • Odontogenic keratocysts of the jaws • Palmar or plantar pits (3 or more in any combination) • Bilamellar calcification of the falx cerebri • Bifid, fused or markedly splayed ribs • First degree relatives with NBCCS (a biologically related parent, sibling or child) • PTCH1 mutation identified in DNA from non-tumor tissue. 6. Presence of multiple BCCs at the Screening Visit (and the Rescreening Visit, if applicable) to be biopsied, including: o At least three BCCs that appear to be of superficial type clinically of at least (≥) 8 mm and less (<) than 20 mm in their longest dimension, that are located in a body location in which a surgical excision with a peri-tumoral margin of approximately 4 mm is technically feasible. These BCCs must not be recurring tumors, and must not have been previously treated (and must not be treated until Baseline). There must be at least 20 mm healthy looking surrounding skin bordering each tumor that will be biopsied. 7. Presence of multiple BCCs at the Baseline Visit, including: a. At least two superficial BCCs confirmed histologically from tumors biopsied at the Screening/Rescreening Visits. At the Baseline Visit, the longest dimension of each superficial BCC (Target BCC) must be less (<) than 20 mm and must not have decreased from the measurement prior to the biopsy performed during the screening period. The Target BCCs must not have been treated between Screening and Baseline. b. Preferably one superficial and partly nodular BCC confirmed histologically (Nodular BCC) from the tumors biopsies at the Screening/Rescreening Visits. At the Baseline Visit, the longest dimension of the Nodular BCC must be less (<) than 20 mm and must not have decreased from the measurement prior to the biopsy performed during the screening period. The Nodular BCC must not have been treated between Screening and Baseline. c. Preferably up to 8 Additional superficial BCCs of less (<) than 20 mm at Baseline in their longest dimension. These BCCs must clinically appear to be of superficial type, and must not be recurring tumors, and must not have been previously treated. If they have been biopsied, the type can be either of superficial or superficial and partly nodular histologically. 8. The BCCs where biopsies were taken at the Screening (or Rescreening) Visit and that will be treated during the study must be completely healed at the Baseline Visit. |
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| E.4 | Principal exclusion criteria |
| Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 1. BCCs to be treated must not be: superficial BCCs ≥ 20 mm, any type of BCC other than superficial or superficial and partly nodular, including sclerodermiform, clinically unclear diagnosis of BCC, such as hyperkeratotic lesion that could correspond to a metatypic BCC or Squamous Cell Carcinoma or Actinic Keratosis. 2. Any concomitant dermatological disease that could confound the evaluations, based on the discretion of the investigator. 3. Participation in a prior LDE225 study in which active LDE225 was a treatment arm. The patient can not have been exposed to LDE225 prior to this study. 4. Use of systemic treatment for BCC (e.g., retinoid, chemotherapy, celecoxib, …) in the 4 weeks prior to Baseline. 5. Use of any topical treatment (imiquimod or 5-fluorouracil (5-FU)) in the Treated Area of any of the BCCs (area of BCC + 10 mm surrounding BCC) to be treated in the 12 weeks prior to Baseline. 6. Use of PDT in the Treated Area (area of BCC + 10 mm surrounding skin) of any of the BCCs in the 12 weeks prior to Baseline. 7. Use of other investigational drugs at Baseline, or within 30 days or 5 half-lives prior to Baseline, whichever is longer. 8. Clinically significant medical condition, as per judgment of the investigator, including metastatic BCC. 9. History of hypersensitivity to any of the ingredient of the study drug. 10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive βhCG laboratory test (> 5 mIU/mL). 11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods from the time they sign the informed consent form. The double method contraception can be a double-barrier method or a barrier method plus a hormonal method. o Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent. o Reliable contraception should be maintained throughout the treatment period and for at least 6 weeks after study drug discontinuation. o Woman are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. 12. Fertile males, defined as all males physiologically capable of conceiving offspring UNLESS the patient and his partner agree to comply with acceptable double method contraception defined above from the time the male patient signs the informed consent form. Double-method contraception is not required if the partner is considered postmenopausal or not of child bearing potential as described in exclusion criterion #11. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to demonstrate superiority of LDE225 versus vehicle with respect to treatment success assessed 4 weeks after treating for 8 or 12 weeks. The study will be considered positive if superiority of LDE225 versus vehicle will be shown for at least one treatment duration with regard to the primary endpoint (treatment success rate). |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 33 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| 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 | 0 |
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