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

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.

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 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