Compound 31543 (Calcitriol, USP) in Patients Receiving Taxane-based Chemotherapy Regimens for the Treatment of Chemotherapy-Induced Alopecia

Phase 1

Completed

Conditions: Chemotherapy-Induced Alopecia

Interventions: Drug: Compound 31543 Calcitriol 10 μg/mL
Drug: Compound 31543 Calcitriol 20 μg/mL
Drug: Compound 31543 Calcitriol 40 μg/mL
Drug: Compound 31543 Calcitriol 60 ug/mL
Drug: Compound 31543 Calcitriol 80 μg/mL
Drug: Compound 31543 Calcitriol 5 μg/mL

Registration Number: NCT01588522

Lead Sponsor: BPGbio

Brief Summary: The goal of this clinical trial is to learn if Compound 31543 (topical calcitriol) for treatment of hair-loss in patients with a diagnosis of breast cancer, gynecologic cancer or sarcomas receiving a taxane-based chemotherapy is safe. The main questions it aims to answer are:

* What medical problems do participants have when using compound 31543?

* How much Compound 31543 is in blood after treatment?

* How much hair is lost during treatment?

Participants will:

* Apply Compound 31543 to their scalp twice a day, starting at least 5 days before starting chemotherapy for at least 3 months or until chemotherapy treatment is completed.

* Have blood drawn on weeks 1, 5, 9, 13, and 54.

* Have photographs taken of their hair before starting and at weeks 7, 15, 27, and 54.

* Keep a diary of the condition of their hair.

Detailed Description: This was a multi-center, single arm, dose-escalation Phase 1 study to determine the maximum tolerated dose (MTD), PK, and the overall safety and tolerability of Compound 31543 in patients with a diagnosis of early-stage or locally advanced, unresectable and/or metastatic cancer, or patients with operable cancer, who were scheduled to receive follow up treatment with a taxane-based chemotherapy regimen, as per the physician's discretion. A standard 3+3 dose escalation design was employed, over 6 dose levels, with 3 to 6 patients at each dose level. Eligible patients in each cohort, \>18 years of age and scheduled to receive a taxane-based regimen with treatment breaks as per physician's discretion, initially received or applied the topical formulation of Compound 31543 to the scalp twice daily either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).To determine the MTD for Compound 31543, dose escalation was conducted in stepwise increments, in the absence of dose-limiting toxicity (DLT) defined as clinically significant Grade 3 or 4 non-hematologic toxicity assessed as possibly, probably, or definitely related to Compound 31543 and not to the taxane-based chemotherapy, as best determined by investigator; assessment of DLTs was made weekly during the first 28 days of Compound 31543 treatment and subsequently thereafter every 4 weeks.

Pharmacokinetic (PK) data were evaluated for each dose level before escalation of Compound 31543 to the next dose level in all patients. PK blood samples were collected on Day 1 prior (pre-dose) to the first-morning dose of topical Compound 31543 and at 2, 4, and 8 hours post-dose after the first application of Compound 31543 on Day 1. PK samples were also collected 12 hours after the last, evening dose of Compound 31543 (i.e., before the first Day 1 of the next 28-day treatment) on Weeks 5, 9, 13, and 54.

Potential efficacy of the Compound 31543 was evaluated by photographic assessments and self-assessment diaries performed at baseline and Weeks 7, 15, 27, and 54. Photographic assessments were performed using a Canon digital camera system on views of the front of head/face, bilateral sides of head, and back and top of head/scalp view, as well as close-up photographs of a superior view and a vertex view with hair parted in the center and combed away from the part. Photographs were standardized for lighting, camera angle, and position to the participant's head.

Additionally, patients maintained a medication application diary and a self-assessment diary. The patient completed diary collected patient-reported assessments of hair thickness, fullness, volume, breakage, and cosmetic qualities (ease of styling, etc.) based on a 10-point analog scale for each parameter/question during the first 15 weeks after initiating calcitriol Compound 31543 and at Weeks 19, 23, and 27.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

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:
1. Early stage and/or treatment naïve, or
2. Relapsed or is refractory to previous therapy, or
3. Operable and necessitates adjuvant or neo-adjuvant treatment
Have no evidence of alopecia or mild alopecia (NCI CTCAE v.4.0 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. Patients that have previously lost their hair may enroll if they currently have Grade 0 or 1 alopecia
Eastern Cooperative Oncology Group (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 upper limit of normal (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 patients on stable therapy for more than 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Compound 31543 Calcitriol - 10 μg/mL	Compound 31543 Calcitriol 10 μg/mL	Compound 31543 Calcitriol (10 μg/mL), 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 either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).
Compound 31543 Calcitriol - 20 μg/mL	Compound 31543 Calcitriol 20 μg/mL	Compound 31543 Calcitriol (20 μg/mL), 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 either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).
Compound 31543 Calcitriol - 40 μg/mL	Compound 31543 Calcitriol 40 μg/mL	Compound 31543 Calcitriol (40 ug/mL), 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 either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).
Compound 31543 Calcitriol - 60 μg/mL	Compound 31543 Calcitriol 60 ug/mL	Compound 31543 Calcitriol (60 μg/mL), 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 either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).
Compound 31543 Calcitriol - 80 μg/mL	Compound 31543 Calcitriol 80 μg/mL	Compound 31543 Calcitriol (80 μg/mL), 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 either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).
Compound 31543 Calcitriol - 5 μg/mL	Compound 31543 Calcitriol 5 μg/mL	Compound 31543 Calcitriol (5 μg/mL), 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 either for 2 weeks or 7 ± 2 days (if the patient was unable or unwilling to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy and continued the application twice daily for the duration of the individual patient's chemotherapy (up to a maximum of 54 weeks).

Primary Outcome Measures

Name	Time	Method
Dose-limiting Toxicities (DLT) of Topical Compound 31543	28 days	DLTs were graded according to the CTCAE v4.0. A DLT was defined as a clinically significant Grade 3 or 4 (severe or life-threatening, respectively) non-hematologic toxicity occurring during the first 28-day treatment cycle, and determined to be possibly, probably, or definitely related to BPM31543 and not the taxane-based regimen as best determined by investigators.

Secondary Outcome Measures

Name	Time	Method
Pre-dose Concentrations of Compound 31543	pre-dose on day 1 of Week 1	Pre-dose concentrations of Compound 31543 from serum samples collected on Week 1 Day 1.
Cmax of Compound 31543 on Week 1 Day 1	8 hours	Cmax of Compound 31543 was calculated using serum samples collected on Week 1 Day 1 pre-dose and at 2 ± 0.5 hours, 4 ± 0.5 hours, and 8 ± 1 hours post-dose. The 8-hour Week 1 Day 1 sample was collected before the second of the daily doses.
AUC0-t of Compound 31543 on Week 1 Day 1	8 hours	Area under the curve (AUC0-t) of Compound 31543 was calculated from serum samples collected on Week 1 Day 1 pre-dose and at 2 ± 0.5 hours, 4 ± 0.5 hours, and 8 ± 1 hours post-dose. The 8-hour Week 1 Day 1 sample was collected before the second of the daily doses.
Top View Photographic Review Score	7 and 15 weeks	Top of head/scalp view at 7 and 15 weeks were compared to baseline images and scored on a 7-point evaluation scale: -3 = \>75% great hair loss; -2 = 50-75% moderate hair loss; -1 = 25-49% slight hair loss; 0 = 0-24% hair loss/gain, 1 = 25-49% slight hair gain; 2 = 50-75% moderate hair gain; 3 = \>75% greatly increased/hair gain.
Right Side Photographic Review Score	7 and 15 weeks	Right side of head/scalp view at 7 and 15 weeks were compared to baseline images and scored on a 7-point evaluation scale: -3 = \>75% great hair loss; -2 = 50-75% moderate hair loss; -1 = 25-49% slight hair loss; 0 = 0-24% hair loss/gain, 1 = 25-49% slight hair gain; 2 = 50-75% moderate hair gain; 3 = \>75% greatly increased/hair gain.
Left Side Photographic Review Score	7 and 15 weeks	Left side of head/scalp view at 7 and 15 weeks were compared to baseline images and scored on a 7-point evaluation scale: -3 = \>75% great hair loss; -2 = 50-75% moderate hair loss; -1 = 25-49% slight hair loss; 0 = 0-24% hair loss/gain, 1 = 25-49% slight hair gain; 2 = 50-75% moderate hair gain; 3 = \>75% greatly increased/hair gain.
Front Photographic Review Score	7 and 15 weeks	Front of head/face view at 7 and 15 weeks were compared to baseline images and scored on a 7-point evaluation scale: -3 = \>75% great hair loss; -2 = 50-75% moderate hair loss; -1 = 25-49% slight hair loss; 0 = 0-24% hair loss/gain, 1 = 25-49% slight hair gain; 2 = 50-75% moderate hair gain; 3 = \>75% greatly increased/hair gain.
Back Photographic Review Score	7 and 15 weeks	Back of head/face view at 7 and 15 weeks were compared to baseline images and scored on a 7-point evaluation scale: -3 = \>75% great hair loss; -2 = 50-75% moderate hair loss; -1 = 25-49% slight hair loss; 0 = 0-24% hair loss/gain, 1 = 25-49% slight hair gain; 2 = 50-75% moderate hair gain; 3 = \>75% greatly increased/hair gain.
Superior (Mid Pattern) Photographic Review Score	7 and 15 weeks	Mid-pattern of the scalp from a superior view at 7 and 15 weeks were compared to baseline images and scored on a 7-point evaluation scale: -3 = \>75% great hair loss; -2 = 50-75% moderate hair loss; -1 = 25-49% slight hair loss; 0 = 0-24% hair loss/gain, 1 = 25-49% slight hair gain; 2 = 50-75% moderate hair gain; 3 = \>75% greatly increased/hair gain.
Vertex Photographic Review Score	7 and 15 weeks	Vertex view with hair parted in the center at 7 and 15 weeks were compared to baseline images and scored on a 7-point evaluation scale: -3 = \>75% great hair loss; -2 = 50-75% moderate hair loss; -1 = 25-49% slight hair loss; 0 = 0-24% hair loss/gain, 1 = 25-49% slight hair gain; 2 = 50-75% moderate hair gain; 3 = \>75% greatly increased/hair gain.

Trial Locations

Locations (2): Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai
🇺🇸
Los Angeles, California, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai
🇺🇸Los Angeles, California, United States