Introduction

Chemotherapy-induced alopecia (CIA), a non-cicatricial alopecia, is a common dermatologic adverse event (AE) associated with cytotoxic chemotherapeutic agent use in cancer patients [1, 2]. Many chemotherapies have shown to induce alopecia such as taxanes (paclitaxel, nab-paclitaxel, and docetaxel) in > 80% of patients and doxorubicin in 60-100% of patients, respectively [3]. CIA has been reported in up to 82% of patients undergoing monotherapy paclitaxel [4,5,6]. CIA is considered to be an adverse events associated with chemotherapy that negatively impacts quality of life, and may cause physical, psychological, and social distress. Therefore, approaches to mitigate these effects represent a significant unmet need [7].

There are currently no regulatory agency-approved pharmacologic agents to prevent CIA. Scalp-cooling devices have been cleared by the FDA to prevent CIA. Although these have shown safety in clinical trials, their availability, cost, and applicability to various tumor types or chemotherapy regimens represent barriers to their use [8, 9].

Pre-clinical studies have indicated that Vitamin D may represent a novel therapeutic to stimulate hair follicle growth [10]. Vitamin D plays a critical role in the regulation of several cellular functions, including cell proliferation, differentiation, and the synthesis and secretion of cytokines and other hormones [11]. Additionally, Vitamin D deficiency has been associated with alopecia [10, 12, 13]. It has been proposed that Vitamin D via receptor-mediated activation of WNT beta-catenin and hedgehog signaling pathways may be responsible for the initiation and completion of the hair cycle and differentiation of the follicular and interfollicular epidermis [14]. Results from knockout mice have demonstrate that expression of vitamin D receptors reverses alopecia [15].

Calcipotriol (or calcipotriene), a Vitamin D analog, possesses activities similar to calcitriol. It inhibits epidermal proliferation and modulates keratinization and inflammation; however, calcipotriol is much less potent in regulating calcium metabolism compared to calcitriol [16].

Early work demonstrated that topical calcitriol reduces alopecia. This effect was attributed to its ability to arrest the cell cycle and reduce the sensitivity of the epithelium to chemotherapy [17]. Subsequent clinical trials using topical calcitriol analogs have demonstrated its safety, yet have not observed efficacy signals possibly due to insufficient treatment duration [18, 19].

The current trial was designed such that topical calcitriol (BPM31543) would be applied for two weeks prior to chemotherapy to induce the catagen stage to protect against CIA. Patients unable to undergo the two-week pre-chemotherapy treatment period could elect to pre-treat with the investigational agent for 7 ± 2 days instead. Continued application on a daily basis was planned to ensure maintenance of the catagen stage and to extend protection throughout administration of multiple weekly doses of a taxane-containing regimen.

In this Phase 1 trial, adult female cancer patients receiving taxane-based chemotherapy for the treatment of advanced or recurrent disease were treated with a topical solution of calcitriol (BPM31543) dose range of 5 to 80 µg/mL to prevent CIA.

Methods

Patients

Patients were enrolled at Memorial Sloan Kettering Cancer Center in New York, NY and at Cedars-Sinai, Samuel Oschin Comprehensive Cancer Institute in Los Angeles, CA from September 2012 to February 2017. Of the twenty-eight female patients who provided informed consent, 27 were eligible for treatment.

Patients enrolled in the trial must be at least 18 years of age and able to provide informed consent for participation in the trial. In addition, patients were required to be scheduled to receive a weekly taxane-based regimen for a pathologically confirmed solid tumor. Patients should have no evidence of alopecia or mild alopecia, categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.0. Patients with female/male-pattern baldness or age-related alopecia were allowed if not > Grade 1 (hair loss of < 50% of normal for that individual that was not obvious from a distance but only on close inspection; a different hair style could be required to cover the alopecia but it does not require a wig or hair piece to camouflage) per NCI-CTCAE v4.0 and patients who had previously lost their hair could enroll if they had Grade 0 or 1 alopecia. Additional criteria included Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1 within 14 days prior to registration, baseline neutrophil counts o f > 1500 cells/mm3 within 72 h prior to registration, and serum calcium ≤ upper limit of normal, and ULN (for patients with an albumin  < 3.0, a corrected serum calcium = serum calcium + [0.8] [3.5- serum albumin]) within 72 h prior to registration. Patients were excluded if they met any of the following criteria: receiving calcium-lowering therapy or drugs that may affect calcium levels (e.g., calcitonin, mithramycin, phosphate, or denosumab) within 4 weeks of initiation of topical calcitriol or receiving bisphosphonates or calcium-lowering therapy for 3 months or greater prior to the start of the trial. Additional exclusion criteria included a history of drug or alcohol abuse within 1 year of study enrollment, patients who elected to shave the scalp hair prior to the initiation of chemotherapy or planning to do so during the chemotherapy treatment, and any dermatological condition that, in the opinion of the investigator, would impact the absorption of the study medication, e.g., atopic dermatitis, etc.

Patients were excluded if they received an investigational agent within 30 days or six half-lives of its biologic activity (whichever is shorter) before the start of study drug, had 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. Patients could take vitamin D supplements if they had been on them for 30 days or more prior to the initiation of the study, and the dose of the Vitamin D supplement had to remain the same throughout the study, received medications known to affect calcium levels within 4 weeks of initiation of topical therapy (> 500 international unit, IU, Vitamin A, calcium supplements, fluoride, or antiepileptics), with the exception of patients on stable therapy for > 6 months, or a history of hypercalcemia or kidney stones.

There also could be no self-report of significant hair breakage or hair damage and associated alopecia 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 v4.0), or significant alopecia or hair breakage, or prior radiation to the cranium. Finally, patients could not be pregnant or breastfeeding.

Study design

This was a multi-center, single arm, dose-escalation Phase 1 trial to determine the maximum tolerated dose (MTD), overall safety, tolerability, and pharmacokinetics (PK) of topical BPM31543 (calcitriol) in adult female patients with metastatic or recurrent cancer who were scheduled to receive a taxane-based chemotherapy regimen.

A standard 3 + 3 dose-escalation design was employed with three to six patients at each of six dose levels. Eligible patients applied a total of 1 ml of the topical formulation of BPM31543 to their entire scalp. It was applied separately to each of the four quadrants of the scalp (front right, front left, back right, and back left) with the provided metered pump spray unit twice daily for 2 weeks (or 7 days ± 2 days if the patient was unable to undergo 2 weeks of pre-treatment) prior to the first dose of chemotherapy. Patients continued the application twice daily until termination of chemotherapy treatment (up to a maximum of 54 weeks) or until they developed total alopecia.

To determine maximum tolerated dose (MTD), dose escalation was conducted in stepwise increments based on the immediate prior dose group, in the absence of Grade 3 or greater toxicities attributed to the topical BPM31543. Dose-limiting toxicity (DLT) considered possibly, probably, or definitely related to BPM31543, and not to the taxane-based regimen, was determined by the trial investigators. Determination of DLTs of topical BPM31543 was conducted during the first 28 days of topical application and subsequently every 4 weeks by a study clinician. Appropriate dose modifications or treatment interruption of the chemotherapeutic regimen was based on per patient’s oncologist and the current standard of care.

Safety assessments

Safety assessments included medical history, concomitant medications, physical exam (including weight), vital signs (blood pressure, temperature, respiration rate, and heart rate), and adverse events (AEs). Adverse events were analyzed for severity and relationship to BPM31543 by the investigator and coded using Medical Dictionary for Regulatory Activities (MedDRA) v. 19.1.

Following the start of topical BPM31543 application at 2 weeks or 7 ± 2 days prior to initiation of chemotherapy, patients were seen by an investigator for an interim medical history, concomitant medications, physical exam (including weight), vital signs (blood pressure, temperature, respiration rate, and heart rate), and adverse events at Weeks 1, 2, 3, 5, 7, 11, 15, 27, and 54.

Twenty-three patients who received treatment were included in the safety population; of these, 14 patients who completed at least one photographic assessment and completed their diary through Week 7 were included in the evaluable population.

Pharmacokinetics

Pharmacokinetics (PK) was evaluated at each dose level before escalating to the next dose level. PK blood samples were collected on Day 1 of topical BPM31543 treatment at the following time points: pre-dose and two hours (± 30 min), four hours (± 30 min), and eight hours (± 1 h) post-dose after the first morning application of topical BPM31543. PK samples were also collected 12 h after the last evening dose of (before the first Day 1 of the next 28-day treatment) Weeks 5, 9, 13, and 54.

Preliminary efficacy

Potential benefit of topical BPM31543 for prevention of chemotherapy-induced alopecia was evaluated by the principal investigator using photographic assessments. Photographs of the views of the front of head/face, bilateral sides of head, and back and top of head/scalp were taken using a Canon Power Shot G12 camera system. Additionally, close-up photographs were taken 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. Photographic assessments were performed based on a 7-point scale at baseline and at Weeks 7, 15, 27, and 54 (Fig. 2a, b). Based on the photographic assessments and patient self-assessments, patients were allowed to continue twice-daily topical application at the discretion of the investigator for the duration of their chemotherapy, up to a maximum of 54 weeks.

Patients were asked to use a diary throughout treatment that included self-assessments of hair thickness, fullness, volume, breakage, and cosmetic qualities (ease of styling, etc.) on an analog 10-point scale for each parameter.

Results

Safety

In this patient population, mean time since diagnosis was 3.7 years (range: 0–15 years). Primary cancers included breast (11/23; 47.8%), endometrial (6/23; 26.1%), and ovarian (6/23; 26.1%). Planned chemotherapy for the majority of patients was taxane-based paclitaxel (20/23; 82.6%), nab-paclitaxel (2/23, 2.9%), and docetaxel (1/23, 2.9%). Thirteen (13/23; 56.5%) received agent other than taxanes as part of their cancer treatment regimen, and 12 (12/20) patient treated with paclitaxel also had one or more agents included in their treatment (cisplatin or carboplatin, herceptin, bevacizumab). All ECOG performance scores were 0 or 1 within 14 days prior to enrollment.

Of the twenty-three patients treated, eight patients (35%) experienced treatment-related AEs. Of all treatment-related adverse event (20 total events), 16 were of mild severity and 4 were moderate in severity. Of these, elevated Vitamin D in 6 patients (26.1%) and pruritus in 2 patients (8.7%) were the most frequently experienced probably/possibly/definitely treatment-related AEs. Three patients discontinued from the study due to AE(s) and one patient had study drug interrupted due to AE(s). The AEs leading discontinuation were serious in two patients, and none of the events were considered related to treatment (Table 1).

Table 1 Patient demographics (n = 23)
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Twenty-two (22/23) treated patients (95.7%) experienced at least one treatment emergent adverse event (TEAE), and the total number of TEAEs reported during the study was 231 (Table 2). Overall, the most frequently experienced TEAEs were alopecia in fourteen patients (60.9%), fatigue in eleven patients (47.8%), nausea in nine patients (39.1%), and peripheral sensory neuropathy in seven patients (30.4%); maculopapular rash and Vitamin D increased each in six patients (26.1%; Supplemental Table 1). The majority of the events were mild or moderate (Grade 1 or Grade 2) in severity. The highest incidence of TEAEs categorized as severe (Grade 3) or higher when there were abdominal pain in three patients (13.0%) and vomiting and hypomagnesemia each in two patients (8.7%) (Supplemental Table 1).

Table 2 Summary of adverse events
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Nine patients (39.1%) experienced at least one SAE during the study (10 µg/mL, one patient; 20 µg/mL, one patient; 40 µg/mL, four patients; 60 µg/mL, one patient; 80 µg/mL, two patients). Abdominal pain, nausea, and vomiting were the most commonly occurring SAEs; each occurred in three patients (13.0%). Of these, one patient in the 40 µg/mL dose group experienced four moderate/Grade 2 SAEs (vomiting, nausea, fever, and flank pain), which were the only SAEs considered treatment related by the investigator, and occurred 13–14 days after the end of study treatment. All events resolved in 1–2 days with no actions taken. There were no deaths during this study.

Pharmacokinetics

Single- and multiple-dose PKs of BPM31543 were determined for the different dose levels in this study (Fig. 1). Non-compartmental PK parameters are shown in Table 3 for the 16 patients with sufficient data to calculate the parameters. Additional two patients with pre-dose concentration in Week 1, as well as pre-dose concentrations after repeat dosing (Week 5, 9, and/or 13) were included in the post-dose versus pre-treatment comparisons. Five (5) patients were excluded from the analysis due to missed sampling (outside of scheduled collection time, quality (hemolysis) or quantity of sample insufficient for the analysis or missing sample) resulting in inadequate data sufficient for pharmacokinetic analysis. The mean baseline concentrations (C0) ranged from 32.8 to 58.4 pg/mL, representing endogenous calcitriol. There was no apparent dose dependency for either Cmax or AUC0−t over the range of 5–80 µg/mL BPM31543 doses. The mean Cmax values for BPM31543 doses on Day 1 were similar or slightly greater than the pre-dose means for C0. The slopes of the regression lines of calcitriol concentrations versus BPM31543 doses were not significantly different from 0. The concentrations of the samples collected at Weeks 5, 9, and 13 were not statistically significantly different from the pre-treatment endogenous concentrations on Day 1.

Fig. 1
figure 1

Mean serum concentrations of calcitriol by dose level. Mean serum calcitriol concentrations for each dose level plotted over time. There was no consistent increase in mean serum concentrations with increasing dose

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Table 3 Non-compartmental PK parameters
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Preliminary efficacy

Photographic records of seven different views of hair and scalp showed similar or worsening alopecia between Week 7 (mean score range: − 1.3 to − 1.8) and Week 15 (range: − 1.7 to − 2.3) (Fig. 2c). Alopecia appeared to occur more in the top views of the head/scalp compared to the front, back, left, right, superior, and vertex views. Of the 14 patients who had photographic records at Week 7, < 50% alopecia was observed in 8 patients and two of the patients had alopecia maintained < 50% at Week 15. Insufficient data collection at 27 weeks and 54 weeks prevented objective assessment of efficacy signal in the treated population.

Fig. 2
figure 2

BPM31543 treatment shows signs of prevention of chemotherapy-induced alopecia in patients receiving taxane-based chemotherapy. a Representative images of patients at baseline (\(\ge\) 14 days prior to receiving chemotherapy) and after 7 and 15 weeks of twice-daily topical treatment at 20 μg/mL or 60 μg/mL. b Assessment Scale for Determination of Hair Loss/Gain; c Assessment of Overall Scores Averages of Hair Loss/Gain at doses of BPM31543 tested

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Patient-reported outcomes were evaluated based on self-assessment diaries. Mean scores for hair quality, overall confidence in hair condition, hair fallout after/during hair care, and overall feeling regarding health decreased over the course of the trial. The mean self-assessment scores for hair quality, in terms of hair fullness, thickness, volume, worsened from mean scores of 7.6, 7.5, and 7.2, respectively, at Week 1 to mean scores of 2.8, 2.6, and 2.6, respectively, at Week 7, and similar scores at Week 15 (2.7, 2.8, and 2.8, respectively). Patients’ overall confidence in hair condition was relatively high at Week 1 (mean score of 8.9), and then decreased to 4.28 at Week 7 and 3.8 at Week 15. Patients rating of their hair fallout after/during hair care (shampooing, combing, brushing, etc.) showed evidence of increasing fall out between Week 1 (mean score of 2.4) and Week 7 (mean score of 5.9), and then a lower mean score by Week 15 (2.2). Patient rating of the overall feeling regarding their health suggested a small decrease over the course of the study in the mean score (7.9 at Week 1, 6.7 at Week 7, and 6.5 at Week 15).

Discussion

CIA is one of the most common and distressing dermatologic AEs associated with the use of cytotoxic chemotherapeutic agents [1, 2]. This Phase I trial evaluated the effects of calcitriol (BPM31543) on CIA prevention in adult female cancer patients receiving taxane-based chemotherapy for the treatment of advanced or recurrent disease. Topical application appears to be well tolerated, as the vast majority of SAEs and significant AEs reported by patients were non-specific and considered unrelated to the study drug.

Vitamin D plays a critical role in calcium and phosphate homeostasis through its actions in the intestines, kidneys, and parathyroid glands, primarily via its metabolite, 1,25-dihydroxyvitamin D3 (calcitriol) [11]. Calcitriol also plays a role in regulating cell proliferation, differentiation, and the synthesis and secretion of cytokines and other hormones.

In concordance with our results, oral and topical calcitriol has an established safety and efficacy profile. As such, the first approval of oral and topical calcitriol by the FDA was in 1978 and 2009 for plaque psoriasis and hyperparathryroidism, respectively. AEs associated with calcitriol use have been well documented and range from topical/local effects to reversible alterations of calcium homeostasis.

While this study was not designed or powered to adequately assess the efficacy of BPM31543, we found a signal of efficacy at each dose. These preliminary results are in contrast to previous trials that have evaluated similar compounds. In a Phase 1 trial, Hidalgo et al. (1999) evaluated topical topitriol (a calcitriol analog) treatment in 14 patients with Stage II–IV breast cancer on a regimen of cyclophosphamide, doxorubicin, and 5-fluorouracil for 21 days [8]. They received 3 doses of topitriol (500, 1000, and 2000 μg/day) across 7 days prior to chemotherapy. The presence of alopecia was evaluated for 5 days prior and post-chemotherapy or until the appearance of Grade 2 alopecia. In this trial, all 14 patients developed Grade 2 alopecia within 20–30 days after their first course of chemotherapy. While mild pruritic maculopapular dermatitis on the scalp and surrounding skin exposed to topical topitriol was the most common TEAE, there were no effects on alopecia.

A second trial investigated the potential of calcipotriol in the prevention of CIA in patients with breast cancer who were receiving cyclophosphamide, methotrexate, and 5-fluorouracil [19]. Calcipotriol was applied twice daily for 4 days prior to chemotherapy and continued for 14 days during each treatment cycle. Similarly, there was no detectable effect of calcipotriol on the proportion of patients who experienced alopecia, hair shedding rates, and hair regrowth on hair density.

The lack of efficacy signals observed in the described trials may be attributed to insufficient treatment duration or the anthracyclines included in the regimen. A short course may have not allowed for treatment to induce the catagen stage in scalp hair follicles, as topical application of the calcitriol cream was only performed four to seven days prior to initiation of chemotherapy.

We found that BPM31543 applied topically twice daily to the scalp in patients receiving taxane-based chemotherapy appeared to be safe and well tolerated. There were no differences observed in safety, PK, and efficacy across BPM31543 doses (5–80 µg/mL). No DLT was observed up to 80 µg/mL dose, and no MTD level was reached. At Last, there was a signal of efficacy detected at each dose level.

As the utilization of scalp-cooling devices are limited due to availability and cost, there remains a significant unmet need to develop novel pharmacologic agents to prevent CIA [8, 9]. Based on the results of this study, future Phase 2/3 trials are warranted to further assess the safety and efficacy of topical BPM31543 for the prevention of CIA.