Compound 31543 (Calcitriol, USP) in Patients Receiving Taxane-based Chemotherapy Regimens for Advanced or Recurrent Disease

Study Overview
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Brief Summary
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This will be a dose escalation study to determine the maximum tolerated dose (MTD) and the overall safety and tolerability of a topical compound 31543 (Calcitriol) in patients with metastatic or recurrent cancer who are undergoing chemotherapy with a taxane-based regimen.

Detailed Description
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This will be a dose escalation study to determine the maximum tolerated dose (MTD) and the overall safety and tolerability of a topical compound 31543 (Calcitriol) in patients with metastatic or recurrent cancer who are undergoing chemotherapy with a taxane-based regimen. A standard 3+3 dose escalation design will be employed with 3-6 patients at each dose level. Eligible patients ≥18 years of age and scheduled to receive a taxane-based regimen with treatment breaks as per physician's discretion, will start applying the topical solution twice a day at each cohort dose level two weeks or 7 days ± 2 days prior to initiation of chemotherapy and then continue twice daily for 3 months or until termination of chemotherapy treatment. If topical calcitriol is found to be effective in preventing and/or diminishing taxane chemotherapy-induced alopecia as determined by the photographic assessments and patient self-assessments, patients will be allowed to continue topical application for the duration of their chemotherapy treatment, assuming no dose limiting toxicities (DLTs) related to the topical agent or intolerable side effects are observed. Toxicity to the topical compound 31543 (calcitriol) will be assessed on a weekly basis during the first 28 days of topical treatment and subsequently every four weeks by a study clinician, either a physician or a nurse. For the purpose of pharmacokinetic studies (PKs), blood samples will be collected on Day 1 of topical treatment at the following time points: pre-dose, at 2 hrs (±30 minutes), 4 hrs (±30 minutes), and 8 hrs (±1 hr post dose) after a single application on the morning of Day 1. The second application of drug product will be applied 10-14 hrs after the initial application and after the 8 hr PK sample. Thereafter, topical application frequency will be twice daily, morning and night. Subsequently, a PK sample will be taken 12 hrs (±2 hrs) after the last dose of each 28-day treatment, before the first application of Day 1 of the next 28-day treatment cycle. This schedule will continue for three consecutive 28-day topical treatment cycles. (PKs will be drawn at Weeks 1, 5, 9, and 13. In addition, if patients are still on study, a PK will also be drawn at Week 54.) As a secondary objective, potential efficacy of the topical calcitriol will be evaluated by photographic assessment. Photographic assessment will be performed using a Canon digital camera system to ensure standardization and uniformity among all enrolled patients. The following five views will be obtained at each photographic assessment: bilateral sides of head/scalp view, front of head/face view, back of head/scalp view, and top of head/scalp view.Additionally, close-up photographs will be taken at the same time points. They will include the mid-pattern of the scalp from a superior view and a vertex view with hair parted in the center and combed away from the center part. Photographs will be standardized for lighting, camera angle, and position to the participant's head.These assessments will be performed at the following time points: at baseline, Weeks 7, 15, 27, and 54. Photographs for patients in each cohort representing baseline, and treatment Weeks 7 and 15 will be presented blind to the study PI and dermatologist, Mario Lacouture, after at least 3 patients have completed 15 weeks of treatment. Photographs will also be taken at Week 27 and Week 54 of the study but will be included in the final photographic assessment as secondary information. In addition, all patients will be asked to maintain an application log throughout treatment to ensure compliance. Additionally patients will maintain a medication application diary and a self-assessment diary. The medication application diary will collect daily application details of the medication. This will include application dates and times, chemotherapy cycle, and whether the medication was applied (or reason if the medication was not applied). The self-assessment diary will require assessment of hair thickness, hair fullness, hair breakage, and hair cosmetic qualities (ease of styling, etc.) on an analog 10 point scale to assess patient-reported efficacy. The PI clinical assessment of baseline, Weeks 7 and 15 photographs will be used, together with the patient diary information, for the primary assessment of alopecia. The study is expected to take place over a period of approximately 12 months, including the screening period.

Official Title
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Phase I Dose-Escalation Study, to Evaluate the Safety, Tolerability and Pharmacokinetics of a Topical Compound 31543 (Calcitriol, USP) in Adult Cancer Patients Receiving Taxane-based Chemotherapy Regimens for the Treatment of Advanced or Recurrent Disease

Conditions
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Breast Cancer, Cervical Cancer, Endometrial Cancer, Ovarian Cancer, Primary Peritoneal Carcinoma, Bone Sarcoma, Cancer, Solid Tumor

Intervention / Treatment
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* Drug: compound 31543 Calcitriol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients at least 18 years of age Able to fully understand and participate in the informed consent process Patients who are scheduled to receive a taxane-based regimen for a histologically confirmed solid tumor that is: Early stage and/or treatment naïve, or Relapsed or is refractory to previous therapy, or Operable and necessitates adjuvant or neo-adjuvant treatment Have no evidence of alopecia or mild alopecia (NCI CTCAE grade 1 alopecia defined as hair loss of <50% of normal for that individual that is not obvious from a distance but only on close inspection; a different hair style may be required to cover the hair loss but it does not require a wig or hair piece to camouflage). Female/male-pattern baldness or age-related hair loss are allowed if not greater than grade 1, per NCI-CTCAE v. 4.0. Subjects that have previously lost their hair may enroll if they currently have Grade 0 or 1 alopecia ECOG Performance Score of 0 or 1 within 14 days prior to registration Has baseline neutrophil counts of > 1500 cells/mm3 within 72 hours prior to registration Has serum calcium less than or equal to ULN (for patients with an albumin lower than 3.0, a corrected calcium serum calcium = serum calcium +[0.8][3.5-serum albumin]) within 72 hours prior to registration Exclusion Criteria: Patients receiving calcium-lowering therapy or drugs that may affect calcium levels (e.g., calcitonin, mithramycin, phosphate, denosumab) within 4 weeks of initiation of topical calcitriol. Patients who have been managed with bisphosphonates or calcium-lowering therapy for 3 months or greater prior to the start of the trial and have demonstrated evidence for stability of calcium metabolism would be considered eligible for participation in the trial. Has a history of drug or alcohol abuse within 1 year of study enrollment as determined by the investigator. Patients who elect to shave the scalp hair prior to the initiation of chemotherapy or who plan to do so during the chemotherapy treatment. Any dermatological condition that in the opinion of the investigator will affect the absorption of the study medication, e.g. Atopic Dermatitis, etc. Has been treated with an investigational agent within 30 days or six half-lives of its biologic activity whichever is longer, before the start of study. (Patients may not be concurrently enrolled on another trial or concurrently treated with another investigational agent) Patients with a history of hypercalcemia or vitamin D toxicity, or hospitalization for treatment of angina, myocardial infarction, or congestive heart failure or psychiatric illness currently or within 30 days of study entry as determined by the investigator. Has a history of significant allergy to calcitriol as determined by the investigator. Has any condition that interferes with the ability of the subject to understand or comply with the requirements of the study. Patients taking Vitamin D supplements during the study, unless they have been taking Vitamin D supplements for 30 days or more prior to the start of the study and that the dose of the Vitamin D supplement remain the same throughout the study. Patients treated with medications that are known to affect calcium levels within 4 weeks of initiation of topical therapy (>500 IU vitamin A, calcium supplements, fluoride, antiepileptics).with the exception of subjects on stable therapy for more than six months Patients receiving thiazides or furosemide diuretics, with the exception of subjects who have stable doses and have been on therapy for over six months Patients with hypercalcemia or kidney stones Patients that indicate they have significant hair breakage or hair damage and associated hair loss from hair over-processing within the last 30 days due to peroxide applications, permanent hair coloring, bleaches, streaking, perms, relaxers and/or hair oxidative dyes. Current alopecia grade 2 or greater as per NCI-CTCAE v.4.0, or significant hair loss or hair breakage Prior radiation to the cranium Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dose-escalation of compound 31543<br>compound 31543 Calcitriol, Topical application, 0.25 mL to be applied to each of the four quadrants of the scalp twice daily, morning and night with 10-14 hours between applications | Drug: compound 31543 Calcitriol<br>* topical compound 31543 will be applied to the scalp twice daily 7 +/- 2 days prior to the dose of chemotherapy and continue the application twice daily for 3 months or until termination of chemotherapy treatment.<br>* Other names: Calcitriol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose (MTD) of Topical Compound 31543 | To determine the maximum tolerated dose (MTD) and the overall safety and tolerability of topical Compound 31543(Calcitriol, USP)in adult cancer patients receiving taxane-based chemotherapy regimens. | up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Record and observe adverse events in patient use of topical compound 31543 to determine overall safety and tolerability |  | up to 52 weeks | 
| Observe and determine potential efficacy of topical calcitriol | As a secondary objective, potential efficacy of the topical Calcitriol will be evaluated by photographic assessment. Photographic assessment will be performed using a Canon Power Shot G12 camera system to ensure standardization and uniformity among all enrolled patients. The following five views will be obtained at each photographic assessment: bilateral sides of head/scalp view, front of head/face view, back of head/scalp view, and top of head/scalp view. Additionally, close up photographs will be taken at the same time points. They will include the mid-pattern of the scalp from a superior view and a vertex view with hair parted in the center and combed away from the center part. Photographs will be standardized for lighting, camera angle, and position to the participant's head. These assessments will be performed at the following time points: at baseline, weeks 7, 15, 27, and 54. | weeks 7, 15, 27, and 54 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alopecia