A Phase II Study of Oral Calcitriol in Combination With Ketoconazole in Castration Resistant Prostate Cancer, Progressing Despite Primary ADT and Abiraterone
Phase: PHASE2
Conditions: Castration-resistant Prostate Cancer
Sponsor: Donald Trump, MD

  
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A Phase II Study of Oral Calcitriol  
in Combination with Ketoconazole in Castration Resistant Prostate Cancer, Progressing 
despite Primary ADT and  Abiraterone 
 
 
 
 
 
 
Principal Investigator: 
Donald L. Trump, MD, FACP 
Co-Investigators:  
Jeanny Aragon-Ching, MD 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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PROTOCOL SYNOPSIS 
 
 
A Phase I/II Study of Oral Calcitriol in Combination with Ketoconazole in Castration 
Resistant Prostate Cancer Following Progression on Abiraterone 
 
 
 
 
 
 
 
 
 
 
Number of centers: 1 
 
Study period 
 
Phase of development 
Estimated date of first patient 
enrolled 
 Sept 2016 
II 
Estimated date of last patient 
completed 
 Sept 2017 
 
 
Objectives 
Primary Objective 
1.  To estimate the PSA response rate with the use of ketoconazole/hydrocortisone (400mg 
QD + hydrocortisone 20mg AM, 10 mg PM) + calcitriol (10mcg QD X3 weekly) among 
men with CRPC in whom disease has progressed despite abiraterone 
 
Secondary Objectives 
1. Describe objective tumor responses to the combination of oral calcitriol and ketoconazole 
and hydrocortisone-among patients with measurable disease using modified RECIST 1.1 
criteria.  
2. Determine toxicities, and tolerability of oral calcitriol combination with daily oral 
ketoconazole, and hydrocortisone in this patient population. 
 
Trial Design 
2. A single arm phase II trial of ketoconazole (400mg QD + hydrocortisone 20mg AM, 10 mg 
PM) + calcitriol (10mcg QD X3 weekly) among men with CRPC in whom disease has 
progressed despite abiraterone 
 
 
Background and Rationale 
In vitro, calcitriol has both antiproliferative and differentiating effects.  Growth inhibition 
following exposure to calcitriol has been demonstrated in melanoma, breast, colon, prostate,  
osteosarcoma, and leukemia  cell lines, and in xenografts of human colorectal carcinoma and 
melanoma in immunosuppressed mice. In vitro and in vivo maximum tumor response requires 
high calcitriol concentrations (>10 nM). These concentrations are not achievable with daily 
administration of calcitriol because dose-limiting hypercalcemia develops. Treatment with 

  
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calcitriol on an intermittent basis (once weekly or daily x 3/ week) is better tolerated than daily 
treatment and results in peak blood concentrations 1/5-1/10 those needed for activity in vivo.  
Dexamethasone and other glucocorticoids inhibit calcium absorption by the intestine and 
increase calcium excretion by the kidneys, thus ameliorating the hypercalcemic effects of 
calcitriol. Furthermore, when combined with calcitriol, glucocorticoids enhance vitamin-D 
receptor expression, cell cycle arrest, apoptosis and antitumor effects. 
 
One of the postulated mechanisms of resistance to calcitriol antitumor effects is intratumoral 
catabolism of calcitriol; the primary catabolic pathway is by 24-hydroxylation, mediated by 24 
hydroxylase (CYP 24). In vitro and more recently in vivo CYP 24 inhibition by the non-
specific cytochrome P450 inhibitor, ketoconazole, has been shown substantially to potentiate 
the antitumor activity of calcitriol in LNCaP, PC-3 and SCC models. 
 
Both ketoconazole and calcitriol are agents with definite antitumor activities in preclinical 
models. These agents are relatively well tolerated with acceptable toxicity profiles. Both 
ketoconazole and calcitriol have been evaluated clinically as single agents or in combination 
therapies. Ketoconazole in combination with glucocorticoids (the latter required because high 
dose ketoconazole can cause hypoadrenalism through inhibition of adrenal steroidogenesis) has 
shown definite antitumor activity manifested as prolonged stabilization and objective responses 
in patients with androgen independent prostate cancer (AIPC). Clinical data suggest efficacy of 
ketoconazole primarily at high dose, 400 mg TID. Calcitriol, on the other hand, has not shown 
significant antitumor activity when evaluated clinically as a single agent. It has been postulated 
that the reason for lack of responses with single-agent calcitriol is due to failure to achieve and 
maintain adequate serum concentrations for prolonged periods without experiencing dose-
limiting hypercalcemia; in addition, the potential for CYP24 inhibition to enhance intratumoral 
and intracellular calcitriol exposure is a potential advantage of this approach. When given 
intermittently, such as on a weekly basis or on 3 consecutive days a week, calcitriol serum 
concentrations ranging between 1 nM and 5 nM are achieved. Higher concentration of 
calcitriol could not be achieved with oral supplementation of liquid or pill formulations.  
 
Recent preclinical data suggest synergistic antitumor effect by combining calcitriol and 
ketoconazole. Recent work (Feldman and Peehl, unpublished data:  Johnson CS, Yu WD, 
Muindi J and Trump DL) supports a synergistic tumor inhibitory effect from combining 
calcitriol and ketoconazole. Ketoconazole is utilized to block androgen biosynthesis by 
inhibiting P450 enzymes involved in steroidogenesis and in addition, blocks other P450 
enzymes such as 24 hydroxylase (CYP24) involved in the catabolism of calcitriol.  Calcitriol-
mediated in vitro anti-tumor activity is significantly enhanced by ketoconazole in primary 
cultures of human prostatic cancer cells.  A significant increase in anti-proliferative activity is 
observed in human lung tumor cells treated with calcitriol and ketoconazole as compared to 
either agent alone after 72 hr as measured in an MTT assay. In addition in prostate cancer 
models in vivo and in vitro, ketoconazole and calcitriol are substantially more active than 
either agent alone. (See full protocol introduction) 
 

  
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Patient Population and Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
For inclusion in the trial, a patient must fulfill all of the following criteria: 
1. >=18 years of age. The effects of ketoconazole and high-dose calcitriol have not been  
studied adequately in patients <18 years of age and prostate cancer has not been described 
in children.  
2. Histologically or cytologically confirmed adenocarcinoma consistent clinically with 
androgen Independent prostate cancer 
3. Measurable disease with elevated PSA or evaluable disease (PSA elevation will constitute 
evaluable disease). 
4. No cytotoxic chemotherapy for extensive disease prior to study entry will be allowed; 
given the recent data regarding the role of docetaxel + ADT in patients beginning ADT for 
advanced disease, such “adjuvant chemotherapy will be allowed (no more than 6 cycles) 
retinoids, vitamin D analogues, PPARγ agonists or antagonists, antiandrogens, 
progestational agents, estrogens, PC-SPES, LHRH analogues, vaccines, cytokines will not 
be considered “cytotoxics.” Patients who have previously received ketoconazole + 
glucocorticoids will NOT be eligible for this trial. 
5. Patients who have received antiandrogens or progestational agents as therapy for prostate 
cancer must discontinue therapy and demonstrate a rising PSA > 28 days following 
discontinuation (antiandrogren withdrawal – AAW) (>42 days for bicalutamide or 
nilutamide). Patients who receive megestrol acetate as therapy for “hot flashes” at a dose of 
<40mg per day may continue this therapy during this trial. The dose of the megestrol 
acetate should not be changed during protocol treatment. Patients undergoing androgen 
deprivation using LHRH analogues must continue such agents or undergo orchiectomy to 
maintain castrate levels of testosterone.  
6. Patients must have prostate cancer that is advanced or recurrent. 
7. Patients should not have received any chemotherapy or investigational agents for at least 28 
days before entering the study.  
8. Eastern Clinical Oncology Group performance status 0 or 1  
9. Life expectancy >3 months. 
10. Patients must have normal organ and marrow function as defined below: patients may be 
transfused to meet these parameters at the physician’s discretion. 
− 
leukocytes: >3,000/μl 
− 
hemoglobin: > 8 g/dl 
− 
absolute neutrophil count (ANC):>1,500/μl 
− 
platelets: >75,000/μl 
− 
total bilirubin: within normal institutional limit  
− 
AST/ALT: <2.5 X institutional upper limit of normal 
− 
creatinine: < 2mg/dL 
− 
calcium:  not above normal institutional limit 
11. Patients should be able to receive oral medications. 
12. Patients with brain metastases which are stable and have been treated with surgery 
and/or irradiation will be eligible for this trial.  Stable is defined as being asymptomatic 

  
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and requiring no anticonvulsants or corticosteroids for >/= 28 days prior to the initiation 
of study therapy.  
 
13. The effects of high-dose calcitriol and ketoconazole on the developing human fetus are 
unknown.  For this reason and because these agents as well are known to be teratogenic, 
men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while her partner is 
participating in this study, she should inform the treating physician immediately. 
14. Ability to understand and the willingness to sign a written informed consent document. 
15. Progressive disease must have occurred on abiraterone within the prior 12 months and 
patient must not have received treatment with enzalutamide. 
 
Men of all ethnic groups are eligible for this trial.  Efforts will be made to include minority 
groups and all representative ethnicities and races in the community. 
 
Exclusion Criteria 
Any of the following is a criterion for exclusion from the trial: 
1. Known severe hypersensitivity to ketoconazole, calcitriol or any of the excipients of these 
products. 
2. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to calcitriol, ketoconazole, or other agents used in study. 
3. Evidence of any other significant clinical disorder or laboratory finding that makes it 
undesirable for the patient to participate in the trial. 
4. History of kidney, ureteral, or bladder stones within the last 5 years 
5. Heart failure or significant heart disease including significant arrhythmias, myocardial 
infarction within the last 3 months, unstable angina, documented ejection fraction <30%, or 
current digoxin therapy. 
6. Thiazide therapy within 7 days from entering the study. 
7. Requirement for concurrent systemic glucocorticoid therapy at greater than physiologic 
replacement doses 
8. Unwillingness to stop calcium or vitamin D supplementation, including when part of a 
multivitamin. As judged by the investigator, any evidence of severe or uncontrolled 
systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal 
disease) or intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
9. Human immunodeficiency virus-positive patients receiving combination anti-retroviral 
therapy are excluded from the study because of possible PK interactions with ketoconazole 
or other agents administered during the study. Appropriate studies will be undertaken in 
patients receiving combination anti-retroviral therapy when indicated. 
11. Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, or 
St John’s wort,  alfentanil, alfuzosin, almotriptan, alprazolam, amiodarone, amitriptyline, 
amprenavir, aprepitant, aripiprazole, bepridil, bortezomib, bosentan, budesonide, 
buprenorphine, buspirone, carbamazepine, cilostazol, cisapride, cyclosporine, delaviridine, 
didanosine, digoxin, disopyramidedofetilide, donepezil, eletriptan, elperenone, fluticasone, 

  
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fosamprenavir, galantamine, systemic griseofulvins, indinavir, levobupivacaine, lopinavir, 
midazolam, mifepristone, modafinil, nateglinide, nefazadone, nelfinavir, oxcarbazepine, 
pimozide, quetiapine, quinidine, repaglinide, rifabutin, rifampins, rifapentine, ritonavir, 
saquinavir, sildenafil, sirolimus, tacrolimus, tadalafil, tolterodine, theophyllines, 
tolterodine, trazolam, valdecoxib, vardenafil,  ziprasidone, zanisamide, statins, with the 
exception of pravastatin (Pravachol) or other "statins" which are not metabolized by 
or induce CYP3A4, calcium channel blockers,  and macrolides or other agents that will be 
significantly perturbed in a clinically important way by the P450 inhibitory properties of 
ketoconazole  
12. Concomitant use of proton pump inhibitors or H2 blockers 
13. Treatment with a non-approved or investigational drug or agent within 28 days before day 
1 of trial treatment. 
14. Any unresolved chronic toxicity greater then CTC Grade 2 from previous anticancer 
therapy.  
15. Incomplete healing from previous oncologic treatments or other major surgery. 
16. Inability to swallow oral capsules. 
17. Patients on digoxin will be excluded from this study. 
 
Products Dosage and Mode of Administration 
• Ketoconazole, 200 mg tablets, 2 tablets orally TID 
• Calcitriol (0.5 mcg caplets) given orally QD X3 consecutive days  every week 
• Hydrocortisone 20mg AM, 10mg PM orally starting in the evening before the first dose 
of Calcitriol. 
 
Number of Patients and Duration of Treatment 
Number of patients expected to be enrolled each month: 2-3 patients 
Total number of patients expected to enroll:  15 patients 
Treatment will continue as long as there is absence of prohibitive toxicities and lack of clinical 
or radiological progression.  
 
Estimated Time to Complete Accrual: 1 year 
 
Statistical Analysis: 
It is highly likely that the antitumor activity of ketoconazole and abiraterone in prostate cancer 
depend substantially on the ability of both agents to inhibit CYP 17A1 and disrupt androgen 
synthesis.  We and others have shown that antitumor effects of abiraterone are substantially 
reduced in patients in whom ketoconazole has previously failed to be effective.  In addition, 
enzalutamide, whose mechanism is not CYP17A1 dependent, does inhibit CRPC through 
disruption of androgen signaling. There are essentially no data regarding the success of 
ketoconazole therapy after abiraterone “failure”.  If ketoconazole and abiraterone share the 
same mechanism of action one would expect the same low PSA response rate in men with 
CRPC who receive (I) ketoconazole → abiraterone and those who receive (II) abiraterone → 
ketoconazole.  If the response rate among men treated with sequence (II) substantially exceeds 
the PSA RR of 10% we saw with sequence (I), this would suggest additional effects of 

  
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ketoconazole.  Further, the hypothesis of this trial is that ketoconazole also inhibits CYP24A1, 
the predominant vitamin D metabolizing enzyme and hence potentiates the antitumor effect of 
calcitriol (1,25 dihydroxycholecalciferol, 1,25 vitamin D3) - in a synergistic manner. 
 
This study proposes to treat men in whom abiraterone has proven to be ineffective within 12 
months of entry onto this portion of this study.  Based on the above, a PSA response rate of 
10% or less for this regimen following abiraterone failure would be considered to have too 
little activity to be of clinical significance in this patient population, whereas a response rate of 
40% or more would be of interest.  We utilize a flexible design  (Chen TT, NG T. Optimal 
flexible designs in phase II clinical trials. Stat Med. 
1998;17:2301-2312.) that permits the actual number of evaluable patients in each stage to vary 
slightly in order to accommodate the challenges of accruing precise numbers of evaluable 
patients. In the first stage, we target an accrual of 9 eligible and evaluable patients but permit 
accrual to range from 7 to 11 patients. If more than 0 patients respond and medical judgment 
indicates, accrual to the second stage of the trial will be initiated; otherwise, the study will be 
stopped and the treatment regimen will be classified as clinically uninteresting. If the study 
advances to the second stage, then an overall study accrual of 15 eligible and evaluable patients 
will be targeted but will be permitted to range from 13 to 17 patients. If more than 2 out of 13-
14 patients respond or 3 out of 15-17 patients respond then the regimen will be considered 
worthy for additional investigation. If the true response rate is 10% (H0), these decision rules 
limit the average probability of designating the treatment as active to 10% and the average 
probability of stopping after completing only the first stage of accrual is 39%. On the other 
hand, if the true response rate is 40% (H1) then the average probability of correctly classifying 
the treatment as active is 93%.  These are average probabilities computed from the individual 
probabilities averaged over all permitted accrual combinations and assuming each combination 
is equally likely. Limited investigations have indicated that the type I and type II errors are 
fairly insensitive to variations in the true probability distribution of accrual combinations. 
 
 
Stage of 
Accrual 
Targeted Cumulative 
Accrual 
Limits of Actual 
Accrual 
Max number of 
responses to reject H1 
1 
9 
7-11 
0/(7-11) 
2 
15 
13-17 
2/(13-14), 3/(15-17) 
 
 
Entry criteria for this addendum phase will be identical to the ongoing trial except that 
progressive disease will be required to have occurred on abiraterone within the prior 12 
months.  Patient may also not have received enzalutamide in order to, as much as possible, 
“standardize” prior manipulation of the androgen axis. 
 

  
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 Schedule  
Calcitriol 10mcg QD X3, weekly + Ketoconazole 400mg po TID and Hydrocortisone 20mg AM, 10mg PM 
Day 
 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
Calcitriol 
 
 
C 
C 
C 
 
 
 
 
C 
C 
C 
 
 
 
 
C 
C 
C 
 
 
 
 
C 
C 
C 
 
 
 
 
Ketoco 
Nazole 
 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
Hydro 
Cortisone 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
 
 
K = ketoconazole 400 mg TID (1200mg/day).  
C = Calcitriol.  
H =Hydrocortisone 20mg AM, 10mg PM (starting in the evening before the first dose of calcitriol)  
 

  
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Table of Contents 
 
Table of Contents ............................................................................................................................................ 9 
1. 
OBJECTIVES ................................................................................................................................. 13 
2. 
BACKGROUND ............................................................................................................................ 13 
2.1 
Calcitriol (Rocaltrol® for Oral Formulations) .............................................................................. 13 
2.2    Preclinical Studies .......................................................................................................................... 13 
2.3    Clinical Trials ................................................................................................................................. 14 
2.4    Effect of ketoconazole on calcitriol-mediated anti-tumor activity. ................................................ 18 
1.5 
Effect on CYP24 Activity ............................................................................................................. 19 
2.4 
Summary and Rationale for Calcitriol Starting Dose .................................................................... 20 
3.0 
PATIENT SELECTION ................................................................................................................. 21 
3.1 
Inclusion Criteria ........................................................................................................................... 21 
3.2    Exclusion Criteria ........................................................................................................................... 23 
3.3    Inclusion of Minorities ................................................................................................................... 24 
3.4     Restrictions .................................................................................................................................... 24 
4.0 
TREATMENT PLAN ..................................................................................................................... 24 
4.1    Agent Administration ..................................................................................................................... 24 
4.2   Treatment Schedule ......................................................................................................................... 25 
4.1 
Supportive Care Guidelines ........................................................................................................... 26 
4.2 
Duration of Experimental Therapy ................................................................................................ 26 
5.0 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................................. 26 
5.1 
Ketoconazole ................................................................................................................................. 26 
5.2 
Dose Interruption for Non-Hematopoeitic Toxicity ...................................................................... 26 
5.3 Nausea and/or Vomiting .................................................................................................................... 27 
5.4 Diarrhea ............................................................................................................................................. 27 
5.5 
Other Concomitant Therapy with Ketoconazole ........................................................................... 27 
5.6 
Skin Adverse Events ..................................................................................................................... 28 
5.7  
Hypercalcemia ........................................................................................................................... 28 
5.8 
Renal Dysfunction ......................................................................................................................... 29 
5.9 
Other Concomitant Therapy with Calcitriol .................................................................................. 29 
5.10 Criteria for Discontinuation ............................................................................................................. 29 
6.0 
AGENT FORMULATION AND PROCUREMENT ..................................................................... 30 
6.1 
Ketoconazole ................................................................................................................................. 30 
6.1.1 
Storage ............................................................................................................................... 31 
6.2 
Calcitriol ........................................................................................................................................ 31 
6.2.1 
Storage ............................................................................................................................... 31 
6.3 
Hydrocortisone .............................................................................................................................. 31 
6.4 
Expected Toxicities ....................................................................................................................... 31 
6.4.1 
Calcitriol ............................................................................................................................ 31 
6.4.2 
Ketoconazole ..................................................................................................................... 31 
6.4.3 
Hydrocortisone .................................................................................................................. 32 
7.0 
STUDY CALENDAR .................................................................................................................... 32 
8.0 
MEASUREMENT OF EFFECT ..................................................................................................... 35 
8.1 
RECIST ......................................................................................................................................... 35 
8.2 
PSA Response ............................................................................................................................... 35 
9.0 
SAFETY EVALUATION .............................................................................................................. 36 
9.1 
Adverse Events .............................................................................................................................. 36 
9.1.1 
Definitions ......................................................................................................................... 36 
9.1.2 
Grading and Relationship to drug ...................................................................................... 37 
9.1.3 
Reporting Adverse Events ................................................................................................. 38 
9.1.4 
Reporting Serious Adverse Events .................................................................................... 39 
9.1.5 
Follow-Up for Serious Adverse Events ............................................................................. 40 
10.0 
Unanticipated Problems .................................................................................................................. 40 

  
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10.1.1 
Definition ...................................................................................................................................... 40 
10.1.2 
Reporting Unanticipated Problems................................................................................................ 40 
11.0 
DATA SAFETY AND MONITORING ......................................................................................... 40 
12.0 
STATISTICAL CONSIDERATIONS ............................................................................................ 41 
12.1 Stratification Factors ....................................................................................................................... 42 
12.2 Analysis of Secondary Endpoints .................................................................................................... 43 
13.0 
TRIAL MANAGEMENT ............................................................................................................... 43 
13.1 Audits and Inspections .................................................................................................................... 43 
13.2 Changes to the Protocol ................................................................................................................... 43 
13.3 Ethics ............................................................................................................................................... 43 
13.4 
Emergency Procedures .............................................................................................................. 43 
13.4.1 Procedures in Case of a Medical Emergency ....................................................................... 43 
13.4.2 Procedures in Case of Pregnancy ......................................................................................... 43 
13.5 
Data Accessibility ..................................................................................................................... 44 
14.0 REFERENCES ...................................................................................................................................... 44 
APPENDIX A ............................................................................................................................................... 52 
APPENDIX B ............................................................................................................................................... 53 
1.1 Response outcomes in daily clinical practice of oncology ................................................................ 53 
1.2   Response outcomes in uncontrolled trials as a guide to further testing of a new therapy ................ 54 
1.3   Response outcomes in clinical trials as a surrogate for palliative effect .......................................... 54 
1.3.1 Use in nonrandomized clinical trials ...................................................................................... 54 
1.3.2 Use in randomized trials ........................................................................................................ 55 
2 MEASURABILITY OF TUMOR LESIONS AT BASELINE .................................................................. 55 
2.1   Definitions ....................................................................................................................................... 55 
2.2   Specifications by methods of measurements ................................................................................... 56 
2.2.1 Clinical examination .............................................................................................................. 56 
2.2.2 Chest x-ray ............................................................................................................................. 56 
2.2.3 Computed tomography (CT) and magnetic resonance imaging (MRI) .................................. 56 
2.2.4 Ultrasound .............................................................................................................................. 56 
2.2.5 Endoscopy and laparoscopy ................................................................................................... 56 
2.2.6 Tumor markers ....................................................................................................................... 57 
2.2.7 Cytology and histology .......................................................................................................... 57 
3 TUMOR RESPONSE EVALUATIONS ................................................................................................... 58 
3.1 Baseline evaluation ............................................................................................................................ 58 
3.1.1 Assessment of overall tumor burden and measurable disease ................................................ 58 
3.1.2 Baseline documentation of "target" and "nontarget" lesions .................................................. 58 
3.2 Response criteria ............................................................................................................................... 58 
3.2.1 Evaluation of target lesions .................................................................................................... 58 
3.2.2 Evaluation of nontarget lesions .............................................................................................. 59 
3.2.3 Evaluation of best overall response ........................................................................................ 59 
3.2.4 Frequency of tumor re-evaluation .......................................................................................... 59 
3.3 Confirmatory measurement/duration of response .............................................................................. 60 
3.3.1 Confirmation .......................................................................................................................... 60 
3.3.2 Duration of overall response .................................................................................................. 60 
3.3.3 Duration of stable disease ...................................................................................................... 61 
3.4 Progression-free survival/time to progression ................................................................................... 61 
4 RESPONSE REVIEW ............................................................................................................................... 61 
5 REPORTING OF RESULTS ..................................................................................................................... 62 

  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
 
adverse event 
ALT 
 
alanine transaminase 
ANC  
absolute neutrophil count 
AST 
 
aspartate transaminase 
AUC  
area under the curve 
BUN  
blood urea nitrogen 
CR 
 
complete response 
CRFs  
case report forms 
CSR 
 
clinical study report 
CTC 
common toxicity criteria 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DSMB 
data and safety monitoring board 
EGF 
epidermal growth factor 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HRPC 
hormone-refractory prostate cancer 
IC50 
inhibitory concentration 50% 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
 
intravenous 
LCS 
 
lung cancer symptom 
LHRH  
luteinizing hormone-releasing hormone 
MAPK  
mitogen-activated protein kinase 
MTD  
maximum tolerated dose 
NCI 
 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
OAE  
other significant adverse event 
PARP  
poly (ADP-ribose) polymerase  
PD 
 
progressive disease 
p-EGFR 
phosphorylated-EGFR 
PK 
 
pharmacokinetic 
p.o. 
given by mouth 
PPARγ  
peroxisome proliferators-activated receptor-gamma   
PR 
partial response 
PSA 
prostate-specific antigen 
PVC 
polyvinyl chloride 
QOD 
every other day 
RPCI 
Roswell Park Cancer Institute 
RR 
response rate 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 

  
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SD 
stable disease 
TCF 
T-cell transcription factor 
TGF 
transdermal growth factor 
VDR 
vitamin D receptor 
WOCBP 
women of childbearing potential 
WNY 
Western New York 
ZD1839 
IRESSA® 
 

  
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1. OBJECTIVES  
 
Primary Objective 
To estimate the PSA response rate with the use of ketoconazole (400mg QD + hydrocortisone 
20mg AM, 10 mg PM) + calcitriol (10mcg QD X3 weekly) among men with CRPC in whom 
disease has progressed despite abiraterone 
 
Secondary Objectives 
 
Describe objective tumor responses to the combination of oral calcitriol and ketoconazole and 
hydrocortisone-among patients with measurable disease using modified RECIST1.1 criteria.  
 
Determine toxicities, and tolerability of oral calcitriol combination with daily oral 
ketoconazole, and hydrocortisone in this patient population. 
 
2. BACKGROUND 
 
2.1  Calcitriol (Rocaltrol® for Oral Formulations)  
The clinically required vitamin D supply in humans depends mainly on exposure to ultraviolet 
(UV) light of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D3 
(cholecalciferol). Vitamin D3 must be metabolically activated in the liver and the kidney before 
it is fully activated as a regulator of calcium and phosphorous metabolism in target tissues. The 
initial transformation of vitamin D3 is catalyzed by 25-hydroxylase enzyme present in the liver, 
and the product of the reaction is 25-hydroxyvitamin D3 [25-(OH)D3]. Hydroxylation of 25-
(OH)D3 occurs in the mitochondria of kidney tissue (alpha-OHase), to produce 1,25-(OH)2D3 
(Calcitriol), the active form of vitamin D3. Physiologic daily production is normally 0.5 to 1.0 
mcg and is usually higher during periods of active bone synthesis. 
 
Epidemiologic evidence suggests that low calcitriol may play an important role in the 
development of colon and prostate cancer.  An inverse relationship between incidence and UV 
light exposure has been reported for these neoplasms.  UV exposure is the major route of 
metabolic activation of calcitriol, and increasing risk of malignancy is associated with 
decreasing serum levels of calcitriol (prostate) and its metabolic precursor 25-(OH)D3 (colon).  
There is also evidence that dietary supplementation with calcitriol can reduce the incidence of 
colon cancer (1-5). 
 
2.2    Preclinical Studies 
Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or 
calcitriol), a central factor in bone and mineral metabolism (1,2), has significant antitumor 
activity in vitro and in vivo in murine squamous cell carcinoma (SCC), human xenograft 
prostatic adenocarcinoma (PC-3) and rat metastatic prostatic adenocarcinoma Dunning (MLL) 
model systems (3-6). Calcitriol induces G0/G1 arrest, modulates p27Kipl and p21Waf1/Cipl, the 
cyclin dependent kinase (cdk) inhibitors implicated in G1 arrest (4,7,8) and induces cleavage of 
caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent 
manner (5,9).  Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases 

  
     7/10/2017 
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that regulate cell survival pathways and up-regulates the pro-apoptotic signaling molecule, 
MEKK-1 (10).  
  
Calcitriol significantly enhances the in vitro and in vivo antitumor efficacy of the platinum 
analogues and taxanes (6,7,11,12). Enhancement of drug-mediated apoptosis is associated with 
an increase in PARP, MEK and caspase3-cleavage, the expression of p73 and MEKK-1 and a 
decrease in P-Erk and P-Akt (6,12).  Based on these pre-clinical data, we performed two phase 
I clinical trials of calcitriol with either carboplatin or paclitaxel and administered higher doses 
of calcitriol than previously reported, without toxicity (13).  Pharmacokinetic (pk) data 
following oral administration indicate that the serum calcitriol AUC is not proportional to 
calcitriol dose suggesting a decrease in bioavailability and calcitriol exposure (14).  Oral 
administration of calcitriol at the highest dose studied results in an AUC in man (7.5ng/ml.hr) 
that is significantly lower than the AUC in mice (38.1ng/ml.hr) at doses that correlate with a 
significant antitumor effect in vivo (15). 
 
Glucocorticoids enhance calcitriol-mediated activities pre-clinically (in vitro and in vivo) and 
clinically. We have demonstrated that dexamethasone (dex) significantly potentiates the 
antitumor effect of calcitriol and decreases calcitriol-induced hypercalcemia (16,17). Both in 
vitro and in vivo, dex increases vitamin D receptor (VDR) ligand binding in the tumor while 
decreasing binding in intestinal mucosa (16), the site of calcium absorption (18). P-Erk and P-
Akt are also decreased with calcitriol/dex, as compared to either agent alone (17).  When the 
dex is added to calcitriol and a number of cytotoxic drugs, a greater antitumor effect is 
observed than with each drug alone or any two drug combination (19-21). Dex enhances 
VDRE transcriptional activity through a potential effect on coactivator stimulation of 
transcription. We have examined whether there are differences among various glucocorticoid 
preparations in potentiating calcitriol in vitro or in vivo effects. No convincing differences 
between dex, prednisone or hydrocortisone have been detected at equivalent glucocorticoid 
doses. In a phase II trial in androgen independent prostate cancer (AIPC) oral calcitriol (12 
µg/day QDx3, weekly) and dex (4 mg QDx4, weekly), we saw a 50% reduction in prostate 
specific antigen (PSA) in 28% of the patients, no hypercalcemia (22) and molecular changes in 
peripheral blood monocytes (PBM) similar to those observed in cell lines. Antitumor effects 
were also noted following calcitriol/dex in men with localized disease with a rising PSA 
following prostatectomy or irradiation. These trials utilized oral calcitriol – a route of 
administration where drug exposure and bioavailability may be an issue and limit response 
(14). Induction of CYP24, the enzyme primarily responsible for calcitriol catabolism (23), may 
be a factor in bioavailability and calcitriol exposure; therefore, studies were initiated to 
investigate the effect of ketoconazole, a CYP24 inhibitor (24,25), on in vitro and in vivo anti-
tumor effects of calcitriol/dex in the PC-3 prostate tumor model.  Ketoconazole enhanced the 
anti-tumor activity of calcitriol/dex and decreased CYP24 activity.  
 
2.3    Clinical Trials 
Since 1999, we initiated six clinical trials with one detailed below.  The first trial was a phase I 
study to evaluate the pharmacokinetics and MTD of calcitriol following subcutaneous (sc) 
QOD administration (93).  Thirty-six patients were entered at doses ranging from 2 µg to 10µg 
QOD; dose-limiting toxicity (hypercalcemia) occurred in 3 of 3 patients entered at the 10 µg 
QOD dose. Hypercalciuria occurred at all dose levels examined. No other toxicity was seen. 

  
     7/10/2017 
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changes in peak concentration, AUC or T 1/2 were noted.  To investigate the issue of 
bioavailability of calcitriol, patients were given escalating doses of calcitriol starting at 14µg 
using a liquid formulation of calcitriol with potentially greater bioavailability.  
 
2.3.3  Calcitriol plasma pharmacokinetics.  Pharmacokinetic studies were required in at least 
2 of 3 patients at each dose level of the calcitriol/paclitaxel clinical trial and were performed in 
26 of the 36 patients; six patients at the highest dose level (38 µg) underwent pharmacokinetic 
studies (14).  Baseline plasma calcitriol concentrations of the 26 cancer patients resulted in a 
median concentration of 26 pg/ml (range 13-81).  The normal range for this assay is 16-
74pg/ml.  Serum calcitriol concentrations higher than baseline occurred within an hour of oral 
calcitriol administration.  A scatter plot of the maximum concentration of calcitriol (Cmax) for 
each patient studied at each dose level is portrayed in Fig3A.  As shown in Fig3B, baseline-
subtracted serum calcitriol AUC0->24hr (area under the concentration-time curve for the 24 hour 
period after calcitriol administration) is plotted against dose. A fit to the Michaelis Menten 
function (AUC = a×dose/(1 + b×dose) indicates that AUC0->24hr is not proportional to dose (a = 
540 ± 140 pg-hr/ml-µg; if AUC were proportional to dose, b would equal 0).       
  
 
                A                                                                                     B 
 
 
 
 
 
 
 
 
 
 
 
Fig 3.  (A) Scatter plot of the maximum serum calcitriol concentration (Cmax) vs. calcitriol 
doses.  Closed symbols represent mean values at each dose level.  (B) Baseline-subtracted 
serum calcitriol AUC0->24hr (area under the concentration-time curve for the 24 hour period 
after calcitriol administration) plotted against dose, and a fit of the Michaelis-Menten function, 
p-value of 0.0014.  The effect of the nonlinearity over the range of doses studied is large: the 
fit value of AUC0->24hr at 38 µg was only 4 times that at 4 µg, instead of the 9.5 times expected 
for a proportional relationship.  However, no deviation from linearity can be detected up to a 
dose of 17 µg (p=0.4).  In addition, there is insufficient evidence for an association between 
serum calcium and dose. No patient became hypercalcemic. 
 
Clinical studies to date have predominantly utilized oral administration of capsules at 0.5 
µg/capsule.  At doses of 38 µg, the patients took 72 gel capsules at one time.  To investigate 
decreased bioavailability and lack of absorption due to the mass of gel caps in the stomach, we 
utilized a liquid formulation of calcitriol in palm oil (1 µg/ml) which was tasteless and easy to 
swallow. No significant difference was observed in Cmax or AUC in patients given liquid or 
capsules at various doses.    
 
10
20
30
200
600
1200
Calcitriol Dose (µg)
Calcitriol Cmax (pg/ml)
0
10
20
30
40
0
4000
8000
Calcitriol dose (µg)
Calcitriol AUC0->24hr (pg.hr/ml)

  
     7/10/2017 
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Fig 6 A, B, C.  CYP24 activity of PC-3 treated with calcitriol +/- ketoconazole  (A) Dose 
response for calcitriol inducible CYP24 of PC-3 cells either untreated (), 10nM (), or 
100nM () of calcitriol (B) Effect of various doses of ketoconazole (0-20µM) on calcitriol 
(100nM) inducible CYP24 levels (C) % inhibition of CYP24 by ketoconazole in PC-3 cells. 
 
Peripheral blood monocytes were also examined for changes in calcitriol oxidation activity 
(CYP24) in patients treated with calcitriol alone. (see above)  
 
2.4 Summary and Rationale for Calcitriol Starting Dose 
These data point out that high dose calcitriol is well tolerated when given weekly or daily up to 
3 consecutive days. Daily and every-other-day regimens of calcitriol are associated with 
substantial hypercalcemia which limits dose escalation. 
 
These clinical and preclinical data have led us to conclude that the oral route of administration 
of calcitriol is not the optimal route of administration through which to attempt to achieve the 
exposures in animals that are required for optimal antitumor activity because: 
 1. interpatient variation in systemic exposure is substantial 
 2. exposure-dose relationships are nonlinear and unpredictable at large oral doses 
 
Therefore we have initiated two clinical trials to establish the feasibility, toxicity pattern and 
pharmacokinetics of intravenous calcitriol administered either QD X2 monthly + docetaxel on 
day 2 or weekly + gefitinib. Three patients have been entered on these trials and the following 
data suggest that at the initial dose level (10 mcg) and the second dose level pharmacokinetics 
of oral and IV calcitriol are not dramatically different: 
 
Route/No. subjects/formulation 
Dose 
Cmax (pg/ml) 
AUC (pg.hr/ml) 
po, N=7 ,caplet 
11mcg 
437 +/- 180 
5751+/-1563 
 po, N=2, caplet 
11mcg 
588 +/- 280 
6942+/-250 
po, N=3, caplet 
13mcg 
523 +/- 332 
4557+/-1659 
po, N=4, liquid 
13mcg 
692 +/- 497 
7167 +/-2734 
Iv,  N=3  
10mcg 
438 +/- 30 
4000, 4131 
Iv,  N=2  
15mcg 
860 +.270 
 6290 + 330 
 
These data suggest that the starting dose for this trial of oral calcitriol + ketoconazole is a safe 
starting dose; 3x this dose has been given safely. AUC and Cmax following doses in the range 
10mcg-15mcg are similar following iv and oral administration. Since 38 mcg of calcitriol has 
been given QD X3, weekly without toxicity, we estimate that a starting dose of 10 mcg 
calcitriol will be a safe starting dose: a dose that is safe and non-toxic when given iv 15mcg 
achieves serum levels comparable to oral administration at 13 mcg and is 1/4 the dose that is 
safe and non-toxic when given orally weekly  
Time (min)
0
5
10
15
20
25
30
35
Metabolites (dpms/200 µg protein)
0
1000
2000
3000
30000
60000
90000
120000
    0 nM Calcitriol
  10 nM Calcitriol
100 nM Calcitriol
A
a
b
c
Time (min)
0
5
10
15
20
25
30
35
Metabolites (dpms/200 µg protein)
0
1000
2000
3000
30000
40000
50000
60000
  0 µM KETO
  5 µM KETO
20 µM KETO
B
a
b
c
0.1
1
10
100
0
20
40
60
80
100
Inhibitor (µM)
CYP24 Activity
 (% of uninhibited activity)
C

  
     7/10/2017 
 Page 21  
 
 
 
These preclinical data lend a strong rationale to explore clinically the combination of 
ketoconazole and calcitriol. To achieve calcitriol serum concentrations that are proven to have 
antitumor activity and to maximize intratumoral calcitriol content through inhibition of 
catabolism by ketoconazole calcitriol will be administered orally. This phase I dose escalation 
study will determine the MTD of po calcitriol in combination with hydrocortisone 20mg q AM, 
10mg q PM and ketoconazole 400 mg po TID. 
 
Recent preclinical data suggest a potential synergistic antitumor effect by combining calcitriol 
and ketoconazole. Synergistic antitumor activity was seen with calcitriol concentrations of 10 
nM. This has been delineated in detail above. This synergism forms the rationale for 
combining theses 2 agents in clinical studies. This phase I study will determine the feasibility, 
safety, and the MTD of a combination of calcitriol and hydrocortisone (30 mg total daily dose) 
with ketoconazole (400 mg TID) This study will determine a recommended dose of the 
combination for further investigation in phase II efficacy trials.  
The rationale for this study can be summarized by the following: 
 
1. Both calcitriol and ketoconazole have antitumor activity in AIPC 
2. Calcitriol and ketoconazole show synergistic antitumor activity in prostate models 
3. A mechanism of calcitriol resistance is catabolism mediated via CYP 24 activity 
4. Ketoconazole inhibits CYP 24 activity 
5. Higher calcitriol dosages are associated with improved antitumor activity and synergy.  
Adequate concentrations of calcitriol (>10 nM or higher) are not achieved with currently 
available oral formulations, hence the need to explore IV dosing or other approaches-such 
as inhibiting calcitriol catabolism- to enhance calcitriol exposure 
 
Glucocorticoids have shown protective effects against vitamin D induced hypercalcemia and 
exert a significant degree of pre-clinical antitumor synergy when combined with calcitriol. 
3.0 PATIENT SELECTION 
Patients will be enrolled from the urologic oncology practices at ISCI.  No additional 
recruitment procedures will be used.   
 
Screening for eligibility consists of standard evaluation for castration resistant prostate cancer 
(CRPC).  No such data will be recorded until after consent is given.  Screening will be done by 
the patient’s urologic oncology specialist and Clinical Research Services personnel.  Consent 
will be presented to the patient when CRPC is recognized and initial inquiry from the patient’s 
physician is answered favorably by the patient.  There is no time table/limit for consent though 
1-2 weeks is typically sufficient for completion of consent process which is followed by 
initiation of research-specific screening procedure. 
 
3.1 
Inclusion Criteria 
For inclusion in the trial, a patient must fulfill all of the following criteria: 
1. >=18 years of age. The effects of ketoconazole and high-dose calcitriol have not been  
studied adequately in patients <18 years of age and prostate cancer has not been 
described in children.  

  
     7/10/2017 
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2. Histologically or cytologically confirmed adenocarcinoma consistent clinically with 
androgen Independent prostate cancer 
3. Measurable disease with elevated PSA or evaluable disease (PSA elevation will constitute 
evaluable disease). 
4. No cytotoxic chemotherapy for extensive disease prior to study entry will be allowed; 
given the recent data regarding the role of docetaxel + ADT in patients beginning ADT for 
advanced disease, such “adjuvant chemotherapy will be allowed (no more than 6 cycles) 
retinoids, vitamin D analogues, PPARγ agonists or antagonists, antiandrogens, 
progestational agents, estrogens, PC-SPES, LHRH analogues, vaccines, cytokines will not 
be considered “cytotoxics.” Patients who have previously received ketoconazole + 
glucocorticoids will NOT be eligible for this trial. 
5. Patients who have received antiandrogens or progestational agents as therapy for prostate 
cancer must discontinue therapy and demonstrate a rising PSA > 28 days following 
discontinuation (antiandrogren withdrawal – AAW) (>42 days for bicalutamide or 
nilutamide). Patients who receive megestrol acetate as therapy for “hot flashes” at a dose of 
<40mg per day may continue this therapy during this trial. The dose of the megestrol 
acetate should not be changed during protocol treatment. Patients undergoing androgen 
deprivation using LHRH analogues must continue such agents or undergo orchiectomy to 
maintain castrate levels of testosterone.  
6. Patients must have prostate cancer that is advanced or recurrent. 
7. Patients should not have received any chemotherapy or investigational agents for at least 28 
days before entering the study.  
8. Eastern Clinical Oncology Group performance status 0 or 1  
9. Life expectancy >3 months. 
10. Patients must have normal organ and marrow function as defined below:  patients may be 
transfused to meet withese parameters at the physician’s discretion.   
− 
leukocytes: >3,000/μl 
− 
hemoglobin: > 8 g/dl 
− 
absolute neutrophil count (ANC):>1,500/μl 
− 
platelets: >75,000/μl 
− 
total bilirubin: within normal institutional limit  
− 
AST/ALT: <2.5 X institutional upper limit of normal 
− 
creatinine: < 2mg/dL 
− 
calcium:  not above normal institutional limit 
11. Patients should be able to receive oral medications. 
12. Patients with brain metastases which are stable and have been treated with surgery 
and/or irradiation will be eligible for this trial.  Stable is defined as being asymptomatic 
and requiring no anticonvulsants or corticosteroids for >/= 28 days prior to the initiation 
of study therapy.  
13. The effects of high-dose calcitriol and ketoconazole on the developing human fetus are 
unknown.  For this reason and because these agents as well are known to be teratogenic, 
men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while her partner is 
participating in this study, she should inform the treating physician immediately. 
14. Ability to understand and the willingness to sign a written informed consent document. 

  
     7/10/2017 
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15. Progressive disease must have occurred on abiraterone within the prior 12 months and 
patient must not have received treatment with enzalutamide. 
 
Men of all ethnic groups are eligible for this trial.  Efforts will be made to include minority 
groups and all representative ethnicities and races in the community. 
 
3.2    Exclusion Criteria 
Any of the following is a criterion for exclusion from the trial: 
1. Known severe hypersensitivity to ketoconazole, calcitriol or any of the excipients of these 
products. 
2. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to calcitriol, ketoconazole, or other agents used in study. 
3. Evidence of any other significant clinical disorder or laboratory finding that makes it 
undesirable for the patient to participate in the trial. 
4. History of kidney, ureteral, or bladder stones within the last 5 years 
5. Heart failure or significant heart disease including significant arrhythmias, myocardial 
infarction within the last 3 months, unstable angina, documented ejection fraction <30%, or 
current digoxin therapy. 
6. Thiazide therapy within 7 days from entering the study. 
7. Requirement for concurrent systemic glucocorticoid therapy at greater than physiologic 
replacement doses 
8. Unwillingness to stop calcium or vitamin D supplementation including when part of a 
multivitamin. 
9. As judged by the investigator, any evidence of severe or uncontrolled systemic disease 
(e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease) or 
intercurrent illness including, but not limited to, ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
10. Human immunodeficiency virus-positive patients receiving combination anti-retroviral 
therapy are excluded from the study because of possible PK interactions with ketoconazole 
or other agents administered during the study. Appropriate studies will be undertaken in 
patients receiving combination anti-retroviral therapy when indicated. 
11. Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, or 
St John’s wort,  alfentanil, alfuzosin, almotriptan, alprazolam, amiodarone, amitriptyline, 
amprenavir, aprepitant, aripiprazole, bepridil, bortezomib, bosentan, budesonide, 
buprenorphine, buspirone, carbamazepine, cilostazol, cisapride, cyclosporine, delaviridine, 
didanosine, digoxin, disopyramidedofetilide, donepezil, eletriptan, elperenone, fluticasone, 
fosamprenavir, galantamine, systemic griseofulvins, indinavir, levobupivacaine, lopinavir, 
midazolam, mifepristone, modafinil, nateglinide, nefazadone, nelfinavir, oxcarbazepine, 
pimozide, quetiapine, quinidine, repaglinide, rifabutin, rifampins, rifapentine, ritonavir, 
saquinavir, sildenafil, sirolimus, tacrolimus, tadalafil, tolterodine, theophyllines, 
tolterodine, trazolam, valdecoxib, vardenafil,  ziprasidone, zanisamide, statins, with the 
exception of pravastatin (Pravachol) or other "statins" which are not metabolized by 
or induce CYP3A4, calcium channel blockers,  and macrolides or other agents that will be 
significantly perturbed in a clinically important way by the P450 inhibitory properties of 
ketoconazole  

  
     7/10/2017 
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12. Concomitant use of proton pump inhibitors or H2 blockers 
13. Treatment with a non-approved or investigational drug or agent within 28 days before day 
1 of trial treatment. 
14. Any unresolved chronic toxicity greater then CTC Grade 2 from previous anticancer 
therapy.  
15. Incomplete healing from previous oncologic treatments or other major surgery. 
16. Inability to swallow oral capsules. 
17. Patients on digoxin will be excluded from this study. 
 
3.3    Inclusion of Minorities 
Only men are eligible for this trial.  Different races and ethnicities and minorities will be 
sought for participation in this study. 
 
3.4     Restrictions 
Men enrolled in this study must practice acceptable methods of birth control to prevent 
pregnancy. 
4.0 TREATMENT PLAN 
 
4.1    Agent Administration 
Treatment will be administered on an outpatient basis.  Reported AEs and potential risks for 
calcitriol and ketoconazole are described below. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient’s malignancy. Calcitriol will be administered orally as 0.5 mcg caplets. Patients will be 
instructed to take calcitriol over a period < 15 minutes. Ketoconazole will be administered 
orally TID. The dose of ketoconazole will be at a standard dose, 400 mg TID. Hydrocortisone 
will be administered orally 20mg in the AM and 10mg PM starting the night prior to the first 
dose of calcitriol. The scheduling is detailed below. 
 
 
Calcitriol will be given orally daily 10 mcg x 3 consecutive days per week starting on day 1 
subsequently. On Day 1, ketoconazole will be started orally at 400 mg TID (Table 1).  
Hydrocortisone 20 mg every morning and 10 mg every evening will be given starting the 
evening before the first dose of calcitriol. 
 

  
     7/10/2017 
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4.2   Treatment Schedule 
 
Table 1 
Calcitriol 10mcg QD X3, weekly + Ketoconazole 400mg po TID and Hydrocortisone 20mg AM, 10mg PM 
Day 
 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
Calcitriol 
 
 
C 
C 
C 
 
 
 
 
C 
C 
C 
 
 
 
 
C 
C 
C 
 
 
 
 
C 
C 
C 
 
 
 
 
Ketoco 
Nazole 
 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
K 
Hydro 
Cortisone 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
 
 
K = ketoconazole 400 mg TID (1200mg/day).  
C = Calcitriol.  
H =Hydrocortisone 20mg AM, 10mg PM (starting in the evening before the first dose of calcitriol)  
 

  
     7/10/2017 
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4.1 Supportive Care Guidelines 
Patients should receive full supportive care, including antiemetics, antibiotics, transfusions of 
blood and blood products, etc., when appropriate. Whenever any medications are administered, 
the reason(s) for treatment, dosage and date of treatment must be recorded on the case report 
forms (CRFs). 
 
Erythropoietin alpha can be administered concurrently.  
 
4.2 Duration of Experimental Therapy 
Experimental therapy consisting of calcitriol, hydrocortisone and ketoconazole will continue in 
the absence of disease progression and absence of unacceptable/ unmanageable drug-related 
AEs.  
 
There will be no rest period between cycles. Cycle 2 will start on day 29 in the absence of dose 
delays. 
 
 
Treatment will continue unless 1 of the following is satisfied: 
• Disease progression (see section 6.3) 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable AE 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• For up to one year if none of the above and if the treatment is still working at one year 
patients may discuss with the treating provider whether continuing calcitriol treatment 
is recommended but will not receive calcitriol as part of this study. 
5.0 DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1 Ketoconazole 
Dose interruptions should be the first approach to managing toxicity.  Repeat dose 
interruptions are allowed as required. No dose reduction is allowed.   
 
5.2 
Dose Interruption for Non-Hematopoeitic Toxicity  
In the event of CTC Grade 3 or 4 non-hematopoeitic AE(s) that the investigator considers due 
to suspected disease progression, re-evaluation of tumor status is indicated, irrespective of 
scheduled clinic visits.  
 
CTC Grade 3 or 4 believed to be drug related will be considered DLTs and will result in taking 
patients off study. One exception will be in the case of CTC Grade 3 diarrhea or Grade 3 
nausea that is not attributed to hypercalcemia. In those situations ketoconazole may be resumed 
after a period of interruption that does not exceed 2 weeks with full antiemetics or antidiarrheal 
medication. In the event that these toxicities recur at grade 3 or greater, despite adequate 
supportive medications, this will be a DLT and the patients will be taken off study.  
 

  
     7/10/2017 
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Ketoconazole may also be interrupted for a period that does not exceed 2 weeks in the event of 
symptomatic intolerable Grade 2 rash. At a minimum, reassessment of toxicity should be done 
twice weekly and more frequently if clinically indicated.  When the AE decreases in severity to 
CTC Grade 1, the patient may resume the assigned dose.   
 
5.3 Nausea and/or Vomiting 
In patients who have emesis and are unable to retain ketoconazole, every attempt should be 
made to obtain control of nausea and vomiting.  The dose of ketoconazole may be repeated if 
emesis occurs within 30 minutes of taking the tablets. 
 
5.4 Diarrhea 
Diarrhea can be debilitating and on rare occasions is potentially life-threatening.  Guidelines 
developed by an American Society of Clinical Oncology panel for treating chemotherapy-
induced diarrhea are abstracted below. 
 
Pharmacological approaches include the following: 
 
• Diarrhea has been successfully managed with anti-diarrheal agents such as loperamide. 
Loperamide administered as an initial 4-mg dose followed by 2-mg doses every 4 
hours.  This dose and regimen is moderately effective. 
• Clonidine, 
non-steroidal 
inflammatory 
drugs, 
and 
the 
serotonin 
antagonist 
cryoheptadine have been shown to be effective in controlling diarrhea associated with 
inflammation of the bowel. 
The synthetic octapeptide octreotide has been shown to be effective in the control of diarrhea 
induced by fluoropyrimidine-based chemotherapy regimens when administered as an 
escalating dose by continuous infusion or subcutaneous injection. Octreotide can be 
administered at doses ranging from 100 micrograms twice daily to 500 micrograms 3 times 
daily, with a MTD of 2000 micrograms 3 times daily in a 5-day regimen. 
 
In the event of: 
• CTC Grade 1 diarrhea. No specific supportive care is usually needed or indicated.   
• CTC Grade 2 or 3 diarrhea.  If this occurs and immediate supportive care measures 
are begun (e.g. loperamide) ketoconazole should be discontinued for up to a maximum 
of 14 days, until resolution or the diarrhea has decreased in severity to CTC Grade 1. 
• CTC Grade 4 diarrhea will be declared a DLT 
• If a Grade 4 diarrhea is associated with hemodynamic collapse, the investigator should 
report it as an SAE and remove the patient from the trial. 
 
5.5 
Other Concomitant Therapy with Ketoconazole 
If surgery is considered necessary for the patient, whenever possible at least 7 days should 
elapse after the last dose of ketoconazole before surgery is performed. Treatment may be 
restarted after adequate wound healing. 
 

  
     7/10/2017 
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No concomitant use of the following drugs is allowed: phenytoin, carbamazepine, rifampicin, 
barbiturates, or St John’s wort as these drugs induce CYP3A4 and may alter levels of 
ketoconazole and/or calcitriol.  
 
In addition patients cannot receive the following agents while on study since ketoconazole is 
known to impair the metabolism of these drugs. Patients on these agents may enter trial if the 
agent of concern can be discontinued or an alternative drug can be utilized:  alfentanil, 
alfuzosin, almotriptan, alprazolam, amiodarone, amitriptyline, amprenavir, aprepitant, 
aripiprazole, bepridil, bortezomib, bosentan, budesonide, buprenorphine, buspirone, 
carbamazepine, cilostazol, cisapride, cyclosporine, delaviridine, didanosine, digoxin, 
disopyramidedofetilide, 
donepezil, 
eletriptan, 
elperenone, 
fluticasone, 
fosamprenavir, 
galantamine, systemic griseofulvins, indinavir, levobupivacaine, lopinavir, midazolam, 
mifepristone, modafinil, nateglinide, nefazadone, nelfinavir, oxcarbazepine, pimozide, 
quetiapine, quinidine, repaglinide, rifabutin, rifampins, rifapentine, ritonavir, saquinavir, 
sildenafil, sirolimus, tacrolimus, tadalafil, tolterodine, theophyllines, tolterodine, trazolam, 
valdecoxib, vardenafil,  ziprasidone, zanisamide  
 
Ketoconazole requires acidity for dissolution and absorption.  Patients taking antacid should 
wait 2 hours before taking ketoconazole.  Patients may not take a proton pump inhibitor or H2 
blockers while on ketoconazole. 
 
Patients receiving oral hypoglycemic agents should be monitored carefully for hypoglycemia 
since the clearance of these agents may be reduced by ketoconazole. 
 
International normalized ratio (INR) elevations, and/or bleeding events have been reported in 
some patients taking warfarin. Patients taking warfarin should be monitored regularly for 
changes in prothrombin time or INR. 
 
5.6 
Skin Adverse Events 
A variety of agents can be used to manage skin rashes.  These include mild-to-moderate 
strength steroid creams, topical or systemic antibiotics, topical or systemic antihistamines, and 
occasionally retinoid creams. 
5.7  
Hypercalcemia 
A possible side effect of calcitriol is hypercalcemia; therefore all calcium levels used for the 
determination of toxicity will be corrected for serum albuim levels using the following 
formula: 
Ca+2cor = Ca+2ser + (0.8)(4.0 - Albser) 
Patients developing: 
a) Corrected serum calcium >12 mg/dl persisting >7 days or 
b) Any corrected calcium >13 mg/dl with symptoms secondary to hypercalcemia 
or 
c) Any corrected serum calcium >14 mg/dl  
 
Calcitriol will be stopped and calcium level will be repeated in 1 week. Treatment will resume 
when calcium level returns to < 10.5 mg/dl. Recovery from hypercalcemia must occur within 2 

  
     7/10/2017 
 Page 29  
 
 
weeks to continuation on study. If this toxicity recurs, the patient will be taken off study. 
Further therapy off study would then be at the discretion of the treating physician. 
5.8 
Renal Dysfunction 
In the event where creatinine levels increase ≥2 mg/dL, calcitriol therapy will be withheld until 
creatinine decreases <2.0 mg/dL. Sustained increases (>72 hours) in creatinine of >2.5mg/dL 
will constitute a DLT and will result in removal from study even in the absence of 
hypercalcemia 
 
5.9 
Other Concomitant Therapy with Calcitriol 
Caution should be exercised when calcitriol is co-administered with calcium supplements as 
this might enhance hypercalcemia. All patients will be instructed to discontinue calcium 
supplementation. Thiazides decrease urinary excretion of calcium and will be a 
contraindication to this treatment. 
 
Since hypercalcemia increases the risk of arrhythmias patients on digoxin will not be allowed 
on study. 
 
5.10 Criteria for Discontinuation 
Patients may be discontinued from trial treatment and assessments at any time at the discretion 
of the investigator(s). Specific reasons for discontinuing a patient from this trial are the 
following: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable AE 
• Patient develops kidney stones 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
PSA progression is an increase of 50% above the nadir at a minimum of 5 ng/mL. (i.e. PSA 
must rise a minimum of 5 units) 
 
 If that criterion is reached patients will be declared to have PSA Progressive Disease (PD), 
but: 
a.       If radiographs do not confirm PD 
b.      PSA and symptoms are stable or improved from baseline 
c.       Patient is in agreement 
 
Investigator will have the discretion to continue investigational therapy until: 
 
PSA achieves a level of >50% of baseline  
          or 
Radiographic or symptomatic PD 
          or 
   Patient wish to discontinue 
 

  
     7/10/2017 
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The two options for categorizing withdrawal are either progressive disease (PD) or an AE 
(>1AE may be documented as a reason for withdrawal). Only 1 event will be captured as the 
cause of death. Note that death is an outcome and not an AE.  
 
All trial treatment-related toxicities and SAEs must be followed up until resolution. 
 
All patients who have new or worsening CTC Grade 3 or 4 laboratory values at the time of 
withdrawal must have further tests performed, and the results must be recorded appropriately.  
Until the laboratory values have returned to CTC Grade 1 or 2, unless these values are not 
likely to improve because of the underlying disease. In these cases, the investigators must 
record their opinions in the patients’ medical records. Laboratory abnormalities should not be 
reported as AEs unless any criterion for a SAE is fulfilled, the laboratory abnormality causes 
the patient to discontinue from the study, or the investigator insists the abnormality should be 
reported as an AE.   
 
At withdrawal all ongoing study-related toxicities and SAEs must be followed until resolution, 
unless in the investigator’s opinion, the condition is unlikely to resolve due to the patient’s 
underlying disease. 
 
After withdrawal from treatment, patients must be followed up for existing AEs for  
30 calendar days after administration of the last dose of trial drug.  All AEs occurring during 
that period must be reported to the U.S. Food and Drug Administration and must be followed 
up until resolved, unless in the investigator’s opinion the condition is unlikely to resolve 
because of the patient’s underlying disease. 
6.0 AGENT FORMULATION AND PROCUREMENT 
 
6.1 Ketoconazole 
Ketoconazole will be obtained from commercial sources and provided by third party or patient 
resources. 
Ketoconazole Formulation 
Treatment 
Strength 
Description 
Daily dose 
 Tablets 
per dose 
Ketoconazole 
200-mg tablet 
Ketoconazole is a white to 
slightly beige, odorless  
powder, soluble in acids, with a 
molecular weight of 531.44. 
1200 mg 
2 tablets 
TID 
 
Ketoconazole is available under the brand name NizoralR. It is available generically as 
ketoconazole.  
 
Ketoconazole treatment will be taken 3 times per day (e.g. with meals), every day about the 
same time. It can be taken with or without food. If a patient forgets to take a dose, he should 
take the last missed dose as soon as they remember. However, do not double dose if it is time 
for the next dose.  
 

  
     7/ 1 0/ 2 0 1 7  
 Pa ge 3 1  
 
 
6. 1. 1  St or a ge 
Ket oc o naz ole s h o ul d be st ore d at r o o m te m perat ure bet wee n 1 5 a n d 3 0 ฀C ( 5 9 a n d 8 6 ฀F). 
Pr otect fr o m m oist ure.  
 
6. 2  C alcitri ol  
Calcitri ol will  be  pr o vi de d  t o  t he  st u d y  s u bjects  b y  st u d y  staff.   0. 5  mc g  ca plets  will  be  
e m pl o ye d.  O ur I S CI i n vesti gati o nal p har macist will or der t he calcitri ol a n d distri b ute it as 
i n vesti gati o nal f or t his st u d y. T he p har macist will f oll o w all G C P f or trac ki n g, mai ntai ni n g a n d 
distri b uti n g t he c alcitri ol as i n vesti gati o nal i n t his st u d y.  
 
6. 2. 1  St or a ge 
Please refer t o t he C o m plete Pr o d uct I nf or mati o n.  
 
6. 3  
H y dr oc ortis o ne 
H y dr oc ortis o ne is a vaila ble c o m merciall y i n 5, 1 0, 2 5 a n d 5 0 m g ta blets  a n d will be o btai ne d 
fr o m c o m mercial s o urces a n d pr o vi de d b y t hird part y or patie nt res o urces  
 
Please refer t o t he c o m plete pr o d uct i nf or mati o n.  
 
6. 4  
E x pecte d T o xicities  
 
6. 4. 1  C alcitri ol  
C o m m o nl y see n si de effects wit h hi g h d ose calcitri ol i ncl u de h y percalce mia, h y percal ci uria, 
a n d h y per p h os p hate mia. Cli nical t o xicit y has bee n m ostl y li n ke d t o t he le vel a n d d urati o n of  
ass ociate d  h y percalce mia.  Earl y  si g ns  of  h y percalce mia  i ncl u de  wea k ness,  hea dac he,  
s o m n ole nce, na usea, v o miti n g, dr y m o ut h, c o nsti pati o n, m uscle pai n, b o ne pai n, metallic taste, 
a n d a n ore xia.  
 
Late  si g ns  i ncl u de  p ol y uria,  p ol y di psia,  a n ore xia,  wei g ht  l oss,  n oct uria,  c o nj u ncti vit is  
(calcific),  pa ncreatitis,  p h ot o p h o bia,  r hi n orr hea,  pr uritis,  h y pert her mia,  decrease d  li bi d o,  
ele vate d  bl o o d  urea  nitr o ge n  ( B U N),  al b u mi n uria,  h y perc h olester ole mia,  ele vate d  as pa rtate  
transa mi nase ( A S T) a n d ala ni ne tra nsa mi nase ( A L T), ect o pic calcificati o n, ne p hr ocalci n osis, 
h y perte nsi o n,  car diac  arr h yt h mias,  d ystr o p h y,  se ns or y  dist ur ba nces,  de h y drati o n,  a pat h y,  
arreste d gr o wt h, uri nar y tract i nfecti o ns, a n d, rarel y, o vert ps yc h osis. C hr o n ic h y percalce mia 
has als o bee n ass ociate d wit h a n i ncrease i n creati ni ne le vels i n patie nts wit h n or ma l baseli ne 
re nal f u ncti o n. 
 
H y perse nsiti vit y reacti o ns t o calcitri ol are rare b ut ha ve bee n re p orte d. O ne case of  aller gic 
reacti o n  a n d  a n ot her  case  of  eryt he ma  m ultif or me  ha ve  bee n  c o nfir me d  b y  rec halle n ge  
( R ocaltr ol®  C o m plete Pr o d uct I nf or mati o n).  
 
6. 4. 2  Ket oc o n az ole  
Ket oc o naz ole is o ne of a series of i mi daz oles w hic h are acti ve a ntif u n gal a ge nts; ket oc o n az ole 
at a d ose of 2 0 0 m g dail y  is wi del y use d i n t he t hera p y of c uta ne o us, es o p ha geal a n d uri nar y 
tract f u n gal i nfecti o ns a n d at 4 0 0 m g TI D is fre q ue ntl y prescri be d i n t he  t hera p y of a n dr o ge n 
i n de pe n de nt  pr ostate  ca ncer  ( wit h  gl uc oc ortic oi ds  t o  pre ve nt  a dre nal  i ns ufficie nc y)  

  
     7/10/2017 
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Ketoconazole mechanism of antifungal and perhaps antitumor action depends on its ability to 
inhibit numerous cytochrome P450 enzymes, disrupting membrane lipid structure as well as 
modifying the activity of a number of other intracellular compounds: vitamin D, retinoids. 
Ketoconazole has demonstrated a broad range of antitumor effects in preclinical systems (in 
vitro), but has not been widely tested in the active therapy of any cancer other than prostate 
cancer, where its activity was originally believed to depend on disruption of androgen 
signaling. Ketoconazole is generally a well tolerated agent. The major toxicities are GI 
(nausea, vomiting, hepatotoxicity) constitutional toxicities (headache, dizziness, rash, lethargy, 
dry skin, pruritis, somnolence, diarrhea) and rare myelosuppression and anaphylaxis. 
 
6.4.3 Hydrocortisone 
Adverse reactions to hydrocortisone are those associated with glucocorticoid and 
mineralocorticoid use. Most occur with prolonged and high dose therapy and are somewhat 
reduced in patients receiving alternate day therapy where suppression of endogenous adrenal 
steroid production is reduced.  The hydrocortisone dose in this trial is intended as glucocorticoid 
replacement and is anticipated to have limited potential to cause any of the following side effects: 
electrolyte disturbances, fluid retention, and exacerbation of congestive heart failure increased 
risk of infection (esp. mucocutaneous candidiasis), polyuria, fluid retention, “moon faces”, 
centripetal obesity, mood alterations (depression or anxiety).  Long term use may cause 
myopathy, osteoporosis, impaired wound healing, fragile skin, and Cushingoid habitus.  Patients 
with mild glucose intolerance may develop frank diabetes, and glaucoma can be precipitated in 
patients with increased intraocular pressure.  Mood disturbances and increased appetite are also 
commonly reported.  This drug must not be abruptly discontinued following prolonged usage 
since adrenal insufficiency is common. 
   
7.0 STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy.   
Radiographs must be done within 6 weeks of entering the study. 
 

  
     7/10/2017 
 Page 33  
 
 
 
 
 
Cycle 1  
Cycle 2 
Cycle 3 
Cycles 4+ 
 
  
Pre- 
Study 
(-28 to -
1 days) 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
 
Off Study 
Ketoconazole 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weekly 
 
Calcitriol 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weekly 
 
Hydrocortisone 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weekly 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Every 4 wks 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Every 4 wks 
X 
Physical exam, 
Vital Signs, Weight 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Every 4 wks 
 
X 
 
CBC w/diff, plts 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Every 4 wks 
X 
 
Serum chemistrya 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Every 4 wks 
X 
Adverse event 
evaluation 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Every 4 wks 
 
 
Performance status 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Every 4 wks 
X 
PSA 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Every 4 wks 
 
Tumor 
measurements 
 
X 
Tumor measurements are repeated every 4-12 weeks (measurable disease).  Documentation 
(radiologic) must be provided for patients removed from study for progressive disease. 
Xc 
Radiologic 
evaluation b 
 
X 
 
Radiologic measurements should be performed every 12 weeks from the start of calcitriol 
Xc 

  
     7/10/2017 
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Ketoconazole:  400 mg given TID starting D 1 (except if participating in the PK portion begin day 4) 
Calcitriol:  10 mcg; Calcitriol will be given for 3 consecutive days starting the 1st day of each week, day 1,2,3,8,9,10,15,16,17   
Hydrocortisone: will be given 20mg AM, 10mg PM in the evening starting the day before the first dose of calcitriol  
a- Alkaline phosphatase, total bilirubin, LDH, total protein, SGOT(AST), SGPT(ALT) will be obtained monthly. Albumin, Bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, total protein, and phosphorous will be obtained monthly. 
b- Every12 weeks in patients with measurable disease. Every 12 weeks in the absence of measurable disease. 
c- If partial or complete response are assessed, repeat in 1 month for confirmation. Longer intervals as determined by the study protocol may 
also be appropriate.  
 
 

  
     7/10/2017 
 Page 35  
 
 
8.0 MEASUREMENT OF EFFECT 
 
 
8.1 RECIST 
 
The modified Response Evaluation Criteria in Solid Tumors (RECIST) and 
Recommended NCI PSA Response Criteria will be used for this trial for objective tumor 
response assessment.  The primary response objective of this trial is the PSA response 
rate. In patients with measurable disease CR and PR will be assessed by RECIST criteria. 
Measurable response is a seconary objective of the phase II portion of this study. 
 
Overall responses for all possible combinations of tumor responses in target and 
nontarget lesions with or without the appearance of new lesions* 
Target lesions 
 
Nontarget lesions 
 
New lesions 
 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
CR = complete response; PR = partial response; SD = stable disease; and PD = 
progressive disease. See Appendix B for more details.  
Responses should be confirmed at a follow-up visit at least 4 weeks later 
 
8.2 PSA Response  
PSA will be used as an indicator of response in all disease categories.  
Changes in PSA will be assessed utilizing the following guidelines: 
 
 
 
 
Assessment of response requires two PSA values >4 weeks apart. 
 
PSA must be assessed >4 weeks after prostatic biopsy. 
 
 
Complete response:   
 
Normalization (< 4 ng/ml (non prostatectomy) < 0.2ng/ml (prostatectomy) of  PSA on 
three successive determinations. 
  
Partial response:   
>50% decrease in PSA, persistent for >4 weeks and without clinical or 
radiological evidence of disease progression during this time period.  
 
 
 
Progression: Increase in PSA to >50% above baseline, if maintained >4  weeks. 
 
 

  
     7/10/2017 
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Relapse from response or progression: 
>50% increase above the nadir at a minimum of 5 ng/mL (i.e. PSA must rise a 
minimum of 5 units). 
  
If that criterion is reached patients will be declared to have PSA Progressive Disease 
(PD), but: 
a.       If radiographs do not confirm PD 
b.      PSA and symptoms are stable or improved from baseline 
c.       Patient is in agreement 
 
Investigator will have the discretion to continue investigational therapy until: 
       
PSA achieves a level of >50%  of  baseline  
    or 
Radiographic or symptomatic PD 
    or 
Patient wish to discontinue 
9.0 SAFETY EVALUATION 
 
9.1 
Adverse Events 
 
9.1.1 
Definitions 
An adverse event or adverse experience (AE) is any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related. 
Therefore, an AE can be ANY unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of ‘unrelated’, ‘unlikely’, ‘possible’, ‘probable’, or 
‘definite’). 
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed; or if an investigator brochure is 
not required or available, is not consistent with the risk information described in the 
general investigational plan in other study-related documents. 
 
9.1.1.1 Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
clinically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE on the CRF. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 

  
     7/10/2017 
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9.1.1.2  Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause. For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the CRF. 
However, clinically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF. For example, if a 
severe gastrointestinal hemorrhage leads to renal failure, both events should be recorded 
separately on the CRF. 
11.1.1.3    Abnormal Normal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will 
be recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, 
further diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse 
Event CRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE. For example, an elevated serum potassium level of 7 mEq/L 
should be recorded as “hyperkalemia” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, 
seriousness, or etiology changes. 
11.1.1.4    Preexisting Medical Conditions (Baseline Signs and Symptoms)  
 A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on an Adverse Event CRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
 
9.1.2   Grading and Relationship to drug 
The descriptions and grading scales found in the CTEP Version 4.3of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. 
CTEP Version 3 of the CTCAE is identified and located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE 
Version 3. 

  
     7/10/2017 
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The relationship of event to study drug will be documented by the Investigator as 
follows: 
• Unrelated: The event is clearly related to other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs administered to 
the participant. 
• Unlikely: The event is doubtfully related to investigational agent(s). The event 
was most likely related to other factors such as the participant’s clinical state, 
other therapeutic interventions, or concomitant drugs. 
• Possible: The event follows a reasonable temporal sequence from the time of 
drug administration, but could have been produced by other factors such as the 
participant’s clinical state, other therapeutic interventions or concomitant drugs. 
• Probable: The event follows a reasonable temporal sequence from the time of 
drug administration, and follows a known response pattern to the study drug. The 
event cannot be reasonably explained by other factors such as the participant’s 
clinical state, therapeutic interventions or concomitant drugs. 
• Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be 
reasonably explained by other factors such as the participant’s condition, 
therapeutic interventions or concomitant drugs; AND occurs immediately 
following study drug administration, improves upon stopping the drug, or 
reappears on re-exposure. 
 
9.1.3 Reporting Adverse Events 
 
Table 1 
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies 
(Regardless of Expectedness) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Unrelated 
X 
X 
X 
X 
Unlikely 
X 
X 
X 
X 
Possible 
X 
X 
X 
X 
Probable 
X 
X 
X 
X 
Definite 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 

  
     7/10/2017 
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Table 2 
Guidelines for Routine Adverse Event Reporting for Pilot, Phase 2, 
and Phase 3 Studies (Regardless of Expectedness) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Unrelated 
 
 
X 
X 
Unlikely 
 
 
X 
X 
Possible 
X 
X 
X 
X 
Probable 
X 
X 
X 
X 
Definite 
X 
X 
X 
X 
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention or until the event has resolved, the study participant is lost to follow-up, the 
start of a new treatment, or until the study investigator assesses the event(s) as stable or 
irreversible, will be reported. New information will be reported after it is received. 
9.2 
Serious Adverse Events 
 
11.2.1 Definition 
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of 
either the investigator or sponsor results in ANY of the following: 
• Death. 
• A life-threatening adverse event (experience). Any AE that places a participant or 
participant, in the view of the Investigator or sponsor, at immediate risk of death 
from the reaction as it occurred. It does NOT include an AE that, had it occurred 
in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization (for 
> 24 hours). 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly or birth defect. 
• Important Medical Event (IME) that, based upon medical judgment, may 
jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
9.1.4 Reporting Serious Adverse Events 
All new SAEs occurring from the date the participant signs the study consent until 
30 days after the last intervention or a new treatment is started, whichever comes first, 
will be reported. During the screening period, only SAEs related to study procedures 
need to be reported. The SAE Source Form is to be completed with all available 
information, including a brief narrative describing the SAE and any other relevant 
information.  

  
     7/10/2017 
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SAEs occurring after the 30 day follow-up period that the investigator determines to be 
possibly, probably or definitely related to the study intervention should be reported. 
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please 
refer to Section 10.0 for details on reporting Unanticipated Problems 
9.1.5 Follow-Up for Serious Adverse Events 
All related SAEs should be followed to their resolution, until the study participant is lost 
to follow-up, the start of a new treatment, or until the study investigator assesses the 
event(s) as stable or irreversible. New information will be reported when it is received. 
10.0 
Unanticipated Problems 
10.1.1 Definition 
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of 
the following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given: 
a) The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of 
participant privacy or confidentiality of data. 
b) The characteristics of the participant population being studied. 
• Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research). 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized and if in relation to an AE is also deemed serious  
10.1.2 Reporting Unanticipated Problems 
Unanticipated problem reporting will begin at the time of participant consent. The 
Unanticipated Problem Form will be submitted to the CRS Compliance Office within 
1 business day of becoming aware of the Unanticipated Problem. 
When becoming aware of new information about an Unanticipated Problem, submit the 
updated information to CRS Compliance with an updated Unanticipated Problem Form. 
The site Investigator or designated research personnel will report all unanticipated 
problems, whether related or unrelated to the investigational agent(s) to the IRB in 
accordance with their local institutional guidelines. 
 
11.0 
DATA SAFETY AND MONITORING 
 
The Principal Investigator, Sub-Investigator, and Clinical Research Coordinators shall 
meet on a monthly basis to review toxicities and follow up on results of patients enrolled 
on the study. 

  
     7/10/2017 
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The adequacy of the data and safety monitoring plan will be reviewed by the Inova Schar 
Cancer Institute’s Protocol Review and Monitoring Committee (PRMC).  The PRMC 
shall also determine the risk level of the proposed trial, which in turn determines the 
frequency of review by the Data and Safety Monitoring Committee (DSMC).   
All Severe Adverse Events (SAEs) are required to be reported to the appropriate 
Institutional Review Board (IRB).    Based on SAEs, the IRB retains the authority to 
close the study to further accrual pending more detailed reporting and/or modifications to 
further reduce risk and maximize the safety of participating patients. 
Progress on the trial and the toxicities experienced will be reviewed by the DSMC.  The 
DSMC shall review trial progress, protocol adherence, data management, and patient 
safety parameters, including rates of adverse events and serious adverse events, on a 
scheduled determined by the trial’s risk level. They shall also include reviews performed 
by selected reviewers and auditors.  Results from these DSMC reviews and the 
Committee’s recommendations shall be forward to the Principal Investigator, the 
Research Oversight Committee, and the appropriate Institutional Review Board.   
If the DSMC recommends a study change for patient safety or efficacy reasons, or that 
accrual be halted, the PI will be notified immediately, as will the PRMC and IRB.   
In the unlikely event that the trial PI does not concur with the DSMC, the ISCI CEO/ 
Director must be informed of the reason for the disagreement.  The trial PI, DSMC Chair, 
and ISCI Director will be responsible for reaching a mutually acceptable decision about 
the study.  Confidentiality must be preserved during these discussions.  However, in some 
cases, relevant data may be shared with other selected trial investigators and staff to seek 
advice to assist in reaching a mutually acceptable decision. 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
It is highly likely that the antitumor activity of ketoconazole and abiraterone in prostate 
cancer depend substantially on the ability of both agents to inhibit CYP 17A1 and disrupt 
androgen synthesis.  We and others have shown that antitumor effects of abiraterone are 
substantially reduced in patients in whom ketoconazole has previously failed to be 
effective.  In addition, enzalutamide, whose mechanism is not CYP17A1 dependent, does 
inhibit CRPC through disruption of androgen signalingThere are essentially no data 
regarding the success of ketoconazole therapy after abiraterone “failure”.  If ketoconazole 
and abiraterone share the same mechanism of action one would expect the same low PSA 
response rate in men with CRPC who receive (I) ketoconazole → abiraterone and those 
who receive (II) abiraterone → ketoconazole.  If the response rate among men treated 
with sequence (II) substantially exceeds the PSA RR of 10% we saw with sequence (I), 
this would suggest additional effects of ketoconazole.  Further, the hypothesis of RPCI 
I68905 is that ketoconazole also inhibits CYP24A1, the predominant vitamin D 
metabolizing enzyme and hence potentiates the antitumor effect of calcitriol (1,25 
dihydroxycholecalciferol, 1,25 vitamin D3) - in a synergistic manner. 

  
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This study proposes to treat men in whom abiraterone has proven to be ineffective within 
12 months of entry onto this portion of this study.  Based on the above, a PSA response 
rate of 10% or less for this regimen following abiraterone failure would be considered to 
have too little activity to be of clinical significance in this patient population, whereas a 
response rate of 40% or more would be of interest.  We utilize a flexible design  (Chen 
TT, NG T. Optimal flexible designs in phase II clinical trials. Stat Med. 
1998;17:2301-2312.) that permits the actual number of evaluable patients in each stage to 
vary slightly in order to accommodate the challenges of accruing precise numbers of 
evaluable patients. In the first stage, we target an accrual of 9 eligible and evaluable 
patients but permit accrual to range from 7 to 11 patients. If more than 0 patients respond 
and medical judgment indicates, accrual to the second stage of the trial will be initiated; 
otherwise, the study will be stopped and the treatment regimen will be classified as 
clinically uninteresting. If the study advances to the second stage, then an overall study 
accrual of 15 eligible and evaluable patients will be targeted but will be permitted to 
range from 13 to 17 patients. If more than 2 out of 13-14 patients respond or 3 out of 15-
17 patients respond then the regimen will be considered worthy for additional 
investigation. If the true response rate is 10% (H0), these decision rules limit the average 
probability of designating the treatment as active to 10% and the average probability of 
stopping after completing only the first stage of accrual is 39%. On the other hand, if the 
true response rate is 40% (H1) then the average probability of correctly classifying the 
treatment as active is 93%.  These are average probabilities computed from the individual 
probabilities averaged over all permitted accrual combinations and assuming each 
combination is equally likely. Limited investigations have indicated that the type I and 
type II errors are fairly insensitive to variations in the true probability distribution of 
accrual combinations. 
 
 
Stage of 
Accrual 
Targeted Cumulative 
Accrual 
Limits of Actual 
Accrual 
Max number of 
responses to reject H1 
1 
9 
7-11 
0/(7-11) 
2 
15 
13-17 
2/(13-14), 3/(15-17) 
 
 
Entry criteria for this addendum phase will be identical to the ongoing trial except that 
progressive disease will be required to have occurred on abiraterone within the prior 12 
months.  Patient may also not have received enzalutamide in order to, as much as 
possible, “standardize” prior manipulation of the androgen axis. 
 
 
12.1 Stratification Factors 
 
No stratifications are planned in either phase of the study. 
 
 

  
     7/10/2017 
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12.2 Analysis of Secondary Endpoints 
 
Toxicity will be graded according to the NCI CTC version 4.03 and relationship to study 
drug will be assessed. Toxicities will be tabulated by dose of calcitriol.  All patients who 
receive study drug will be considered evaluable for toxicity.  
 
Objective tumor response will be judged by monthly physical exam and radiographic 
evaluation which will be done q12 weeks.   Patients will be considered evaluable for tumor 
response if they have at least two post-baseline tumor assessments at least 4 weeks apart, 
received study medication for 8 weeks or if they have evidence of disease progression. 
Analysis of the correlative studies in section 8.0 will be descriptive.  
 
13.0 
TRIAL MANAGEMENT 
 
13.1 Audits and Inspections 
 
Audits and data management will be overseen by the ISCI CTO 
 
13.2 Changes to the Protocol 
 
If it is necessary for the trial protocol to be amended, the amendment or a new version of 
the trial protocol must be notified to or approved by the IRB.  If a protocol amendment 
requires a change to theInformed Consent Form the IRB will be notified.  Approval of the 
revised Written Informed Consent Form by the IRB is required before the revised form is 
used. 
 
 
13.3 Ethics 
 
The principal investigator is responsible for providing the IRB with reports of any SAEs 
from any other trial conducted with the investigational product.  The trial will be 
performed in accordance with Good Clinical Practice. 
 
Amendments, reporting deviations, AE reports will be reported to the Institutional 
Review Board. 
 
13.4 
Emergency Procedures 
 
13.4.1 Procedures in Case of a Medical Emergency 
 
The principal investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. 
 
13.4.2 Procedures in Case of Pregnancy 
 

  
     7/10/2017 
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Pregnancy itself is not regarded as an AE unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  However, the outcome of all pregnancies (spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality) must be 
followed up and documented even if the patient was discontinued from the study.  
 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages 
should also be reported and handled as SAEs.  Elective abortions without complications 
should not be handled as AEs. 
 
13.5 
Data Accessibility 
 
Data are stored in locked files in Clinical Research Services (CRS), access to which is 
limited to authorized CRS personnel only.  Research data are also maintained in the ISCI 
clinical trials data base and secured, password protected and not connected to a network.   
 
         
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APPENDIX A 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 

  
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APPENDIX B 
Response Criteria 
 
1 Introduction 
The introduction explores the definitions, assumptions, and purposes of tumor response 
criteria.  Below, guidelines that are offered may lead to more uniform reporting of 
outcomes of clinical trials.  Note that, although single investigational agents are 
discussed, the principles are the same for drug combinations, non-investigational agents, 
or approaches that do not involve drugs.  
 
Tumor response associated with the administration of anticancer agents can be evaluated 
for at least three important purposes that are conceptually distinct:  
 
• Tumor response as a prospective end point in early clinical trials.  In this situation, 
objective tumor response is employed to determine whether the agent/regimen 
demonstrates sufficiently encouraging results to warrant further testing.  These trials 
are typically Phase II trials of investigational agents/regimens (see Section 1.2), and it 
is for use in this precise context that these guidelines have been developed.  
• Tumor response as a prospective end point in more definitive clinical trials designed 
to provide an estimate of benefit for a specific cohort of patients.  These trials are 
often randomized comparative trials or single-arm comparisons of combinations of 
agents with historical control subjects.  In this setting, objective tumor response is 
used as a surrogate end point for other measures of clinical benefit, including time to 
event (death or disease progression) and symptom control (see Section 1.3).  
• Tumor response as a guide for the clinician and patient or study subject in decisions 
about continuation of current therapy.  This purpose is applicable both to clinical 
trials and to routine practice (see Section 1.1), but use in the context of decisions 
regarding continuation of therapy is not the primary focus of this document.  
However, in day-to-day usage, the distinction among these uses of the term "tumor 
response" can easily be missed, unless an effort is made to be explicit.  When these 
differences are ignored, inappropriate methodology may be used and incorrect 
conclusions may result.  
1.1 Response outcomes in daily clinical practice of oncology  
The evaluation of tumor response in the daily clinical practice of oncology may not be 
performed according to predefined criteria.  It may, rather, be based on a subjective 
medical judgment that results from clinical and laboratory data that are used to assess the  
treatment benefit for the patient.  The defined criteria developed further in this document 
are not necessarily applicable or complete in such a context.  It might be appropriate to 

  
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make a distinction between "clinical improvement" and "objective tumor response" in 
routine patient management outside the context of a clinical trial.  
1.2   Response outcomes in uncontrolled trials as a guide to further testing of a new 
therapy  
"Observed response rate" is often employed in single-arm studies as a "screen" for new 
anticancer agents that warrant further testing.  Related outcomes, such as response 
duration or proportion of patients with complete response, are sometimes employed in a 
similar fashion.  The utilization of a response rate in this way is not encumbered by an 
implied assumption about the therapeutic benefit of such responses but rather implies 
some degree of biologic antitumor activity of the investigated agent.  
 
For certain types of agents (ie, cytotoxic drugs and hormones), experience has 
demonstrated that objective antitumor responses observed at a rate higher than would 
have been expected to occur spontaneously can be useful in selecting anticancer agents 
for further study.  Some agents selected in this way have eventually proven to be 
clinically useful.  Furthermore, criteria for "screening" new agents in this way can be 
modified by accumulated experience and eventually validated in terms of the efficiency 
by which agents so screened are shown to be of clinical value by later, more definitive, 
trials.  
 
In most circumstances, however, a new agent achieving a response rate determined a 
priori to be sufficiently interesting to warrant further testing may not prove to be an 
effective treatment for the studied disease in subsequent randomized Phase III trials.  
Random variables and selection biases, both known and unknown, can have an 
overwhelming effect in small, uncontrolled trials.  These trials are an efficient and 
economic step for initial evaluation of the activity of a new agent or combination in a 
given disease setting.  However, many such trials are performed, and the proportion that 
will provide false-positive results is necessarily substantial. In many circumstances, it 
would be appropriate to perform a second small confirmatory trial before initiating large 
resource-intensive Phase III trials.  
 
Sometimes, several new therapeutic approaches are studied in a randomized Phase II trial.  
The purpose of randomization in this setting, as in Phase III studies, is to minimize the 
impact of random imbalances in prognostic variables.  However, randomized Phase II 
studies are, by definition, not intended to provide an adequately powered comparison 
between arms (regimens).  Rather, the goal is simply to identify one or more arms for 
further testing, and the sample size is chosen so to provide reasonable confidence that a 
truly inferior arm is not likely to be selected.  Therefore, reporting the results of such 
randomized Phase II trials should not imply statistical comparisons between treatment 
arms.  
1.3   Response outcomes in clinical trials as a surrogate for palliative effect  
1.3.1 Use in nonrandomized clinical trials  
The only circumstance in which objective responses in a nonrandomized trial can permit a 
tentative assumption of a palliative effect (ie, beyond a purely clinical measure of benefit) 

  
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is when there is an actual or implied comparison with historical series of similar patients.  
This assumption is strongest when the prospectively determined statistical analysis plan 
provides for matching of relevant prognostic variables between case subjects and a 
defined series of control subjects.  Otherwise, there must be, at the very least, 
prospectively determined statistical criteria that provide a very strong justification for 
assumptions about the response rate that would have been expected in the appropriate 
"control" population (untreated or treated with conventional therapy, as fits the clinical 
setting).  However, even under these circumstances, a high rate of observed objective 
response does not constitute proof or confirmation of clinical therapeutic benefit.  
Because of unavoidable and non-quantifiable biases inherent in nonrandomized trials, 
proof of benefit still requires eventual confirmation in a prospectively randomized, 
controlled trial of adequate size.  The appropriate end points of therapeutic benefit for 
such a trial are survival, progression-free survival, or symptom control (including quality 
of life).  
 
1.3.2 Use in randomized trials  
Even in the context of prospectively randomized Phase III comparative trials, "observed 
response rate" should not be the sole, or major, end point.  The trial should be large 
enough that differences in response rate can be validated by association with more 
definitive end points reflecting therapeutic benefit, such as survival, progression-free 
survival, reduction in symptoms, or improvement (or maintenance) of quality of life. 
2 MEASURABILITY OF TUMOR LESIONS AT BASELINE 
2.1   Definitions  
At baseline, tumor lesions will be categorized as follows: measurable (lesions that can be 
accurately measured in at least one dimension [longest diameter to be recorded] as 20 mm 
with conventional techniques or as 10 mm with spiral CT scan [see Section 2.2]) or 
nonmeasurable (all other lesions, including small lesions [longest diameter <20 mm with 
conventional techniques or <10 mm with spiral CT scan] and truly non-measurable 
lesions).  
 
The term "evaluable" in reference to measurability is not recommended and will not be 
used because it does not provide additional meaning or accuracy.  
 
All measurements should be recorded in metric notation by use of a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of treatment.  
 
Lesions considered to be truly non-measurable include the following: bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by 
imaging techniques, and cystic lesions.  
 

  
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(Note: Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable, and the conditions under which such lesions should be 
considered must be defined in the protocol when appropriate.)  
2.2   Specifications by methods of measurements  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment.  
 
2.2.1 Clinical examination  
Clinically detected lesions will only be considered measurable when they are superficial 
(eg, skin nodules and palpable lymph nodes).  For the case of skin lesions, documentation 
by color photography—including a ruler to estimate the size of the lesion—is 
recommended.  
 
2.2.2 Chest x-ray 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung.  However, CT is preferable.  
 
2.2.3 Computed tomography (CT) and magnetic resonance imaging (MRI) 
CT and MRI are the best currently available and most reproducible methods for 
measuring target lesions selected for response assessment. Conventional CT and MRI 
should be performed with contiguous cuts of 10 mm or less in slice thickness.  Spiral CT 
should be performed by use of a 5-mm contiguous reconstruction algorithm; this 
specification applies to the tumors of the chest, abdomen, and pelvis, while head and neck 
tumors and those of the extremities usually require specific protocols.  
 
2.2.4 Ultrasound 
When the primary end point of the study is objective response evaluation, ultrasound 
should not be used to measure tumor lesions that are clinically not easily accessible.  It 
may be used as a possible alternative to clinical measurements for superficial palpable 
lymph nodes, subcutaneous lesions, and thyroid nodules.  Ultrasound might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.  
 
2.2.5 Endoscopy and laparoscopy  
The utilization of these techniques for objective tumor evaluation has not yet been fully 
or widely validated.  Their uses in this specific context require sophisticated equipment 
and a high level of expertise that may be available only in some centers.  Therefore, 
utilization of such techniques for objective tumor response should be restricted to 
validation purposes in specialized centers.  However, such techniques can be useful in 
confirming complete histopathologic response when biopsy specimens are obtained.  
 

  
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2.2.6 Tumor markers 
PSA will be used as a measure of response in this trial. 
PSA will be used as an indicator of response in all disease categories.  
Changes in PSA will be assessed utilizing the following guidelines: 
 
 
 
 
Assessment of response requires two PSA values >4 weeks apart. 
 
PSA must be assessed >4 weeks after prostatic biopsy. 
 
 
 
Complete response:   
Normalization (<4 ng/ml [non prostatectomy], <0.2ng/ml [Prostatectomy] of 
PSA on three successive determinations. 
 
 
 
Partial response:   
 
>50% decrease in PSA, persistent for >4 weeks. 
 
 
 
 
 
Progression:   
 
 Increase in PSA to >50% above baseline, if maintained >4 weeks. 
 
 
 
Relapse from response or progression: 
PSA progression is an increase of 50% above the nadir at a minimum of  5 ng/mL 
(i.e. PSA must rise a minimum of 5 units) 
 
 If that criterion is reached patients will be declared to have PSA Progressive Disease 
(PD), but: 
a.       If radiographs do not confirm PD 
b.      PSA and symptoms are stable or improved from baseline 
c.       Patient is in agreement 
 
Investigator will have the discretion to continue investigational therapy until: 
      PSA achieves a level of >50% of  baseline  
    or 
Radiographic or symptomatic PD 
    or 
  Patient wish to discontinue 
 
Progression of disease will be defined as any progression as assessed by criteria for 
measurable disease, evaluable disease, osseous disease, or performance status. 
 
2.2.7 Cytology and histology 
Cytologic and histologic techniques can be used to differentiate between partial response 
and complete response in rare cases (eg, after treatment to differentiate between residual 
benign lesions and residual malignant lesions in tumor types such as germ cell tumors).  
Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or 
stable disease.  Under such circumstances, the cytologic examination of the fluid 
collected will permit differentiation between response or stable disease (an effusion may  

  
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be a side effect of the treatment) and progressive disease (if the neoplastic origin of the 
fluid is confirmed).  New techniques designed to better establish objective tumor response 
will be integrated into these criteria when they are fully validated; they will be used in the 
context of tumor response evaluation. 
3 TUMOR RESPONSE EVALUATIONS 
3.1 Baseline evaluation  
3.1.1 Assessment of overall tumor burden and measurable disease  
To assess objective response, it is necessary to estimate the overall tumor burden at 
baseline to which subsequent measurements will be compared.  Only patients with 
measurable disease at baseline should be included in protocols where objective tumor 
response is the primary end point.  Measurable disease is defined by the presence of at 
least one measurable lesion (as defined in Section 2.1).  If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
 
3.1.2 Baseline documentation of "target" and "nontarget" lesions 
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size 
(those with the longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically).  A sum of the longest diameter for all target 
lesions will be calculated and reported as the baseline sum longest diameter.  The baseline 
sum of the longest diameter will be used as the reference by which to characterize the 
objective tumor response. 
  
All other lesions (or sites of disease) should be identified as nontarget lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
3.2 Response criteria  
3.2.1 Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.  The criteria have been adapted from the original WHO 
Handbook, taking into account the measurement of the longest diameter only for all target 
lesions: complete response—the disappearance of all target lesions; partial response—at 
least a 30% decrease in the sum of the longest diameter of target lesions, taking as 
reference the baseline sum longest diameter; progressive disease—at least a 20% increase 
in the sum of the longest diameter of target lesions, taking as reference the smallest sum 
longest diameter recorded since the treatment started or the appearance of one or more 
new lesions; stable disease—neither sufficient shrinkage to qualify for partial response  
nor sufficient increase to qualify for progressive disease, taking as reference the smallest 
sum longest diameter since the treatment started.  

  
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3.2.2 Evaluation of nontarget lesions 
This section provides the definitions of the criteria used to determine the objective tumor 
response for nontarget lesions: complete response—the disappearance of all nontarget 
lesions and normalization of tumor marker level; incomplete response/stable disease—the 
persistence of one or more nontarget lesion(s) and/or the maintenance of tumor marker 
level above the normal limits; and progressive disease—the appearance of one or more 
new lesions and/or unequivocal progression of existing nontarget lesions.  
(Note: Although a clear progression of "nontarget" lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression 
status should be confirmed later by the review panel [or study chair]).  
 
3.2.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  In general, the patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria (see Section 3.3.1).  Table 1 provides overall responses for all 
possible combinations of tumor responses in target and nontarget lesions with or without 
the appearance of new lesions.  
Notes:  
• Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration."  Every effort should be made to 
document the objective disease progression, even after discontinuation of treatment.  
• Conditions that may define early progression, early death, and nonevaluability are 
study specific and should be clearly defined in each protocol (depending on treatment 
duration and treatment periodicity).  
• In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine-needle aspiration/biopsy) 
before confirming the complete response status.)  
3.2.4 Frequency of tumor re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and 
adapted to the type and schedule of treatment.  However, in the context of Phase II 
studies where the beneficial effect of therapy is not known, follow-up of every other cycle 
(ie, 6-8 weeks) seems reasonable.  Smaller or greater time intervals than these could be 
justified in specific regimens or circumstances.  
After the end of the treatment, the need for repetitive tumor evaluations depends on 
whether the Phase II trial has, as a goal, the response rate or the time to an event (disease 
progression/death).  If time to an event is the main end point of the study, then routine re-
evaluation is warranted of those patients who went off the study for reasons other than the 

  
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expected event at frequencies to be determined by the protocol.  Intervals between 
evaluations twice as long as on study are often used, but no strict rule can be made.  
 
Table 1 
Overall responses for all possible combinations of tumor responses in  
 target and nontarget lesions with or without the appearance of new  
 lesions*  
Target lesions 
 
Nontarget lesions 
 
New lesions 
 
Overall response 
 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; and PD = 
progressive disease. See text for more details. 
3.3 Confirmatory measurement/duration of response  
3.3.1 Confirmation  
The main goal of confirmation of objective response in clinical trials is to avoid 
overestimating the response rate observed.  This aspect of response evaluation is 
particularly important in nonrandomized trials where response is the primary end point.  
In this setting, to be assigned a status of partial response or complete response, changes in 
tumor measurements must be confirmed by repeat assessments that should be performed 
no less than 4 weeks after the criteria for response are first met.  Longer intervals as 
determined by the study protocol may also be appropriate.  
 
In the case of stable disease, measurements must have met the stable disease criteria at 
least once after study entry at a minimum interval (in general, not less than 6-8 weeks) 
that is defined in the study protocol (see Section 3.3.3).  
 
(Note: Repeat studies to confirm changes in tumor size may not always be feasible or 
may not be part of the standard practice in protocols where progression-free survival and 
overall survival are the key end points.  In such cases, patients will not have "confirmed 
response." This distinction should be made clear when reporting the outcome of such 
studies.)  
 
3.3.2 Duration of overall response 
The duration of overall response is measured from the time that measurement criteria are 
met for complete response or partial response (whichever status is recorded first) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started).  The duration of overall complete response is measured from the time 

  
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measurement criteria are first met for complete response until the first date that recurrent 
disease is objectively documented.  
 
3.3.3 Duration of stable disease 
Stable disease is measured from the start of the treatment until the response criteria for 
disease progression is met (taking as reference the smallest measurements recorded since 
the treatment started).  The clinical relevance of the duration of stable disease varies for 
different tumor types and grades.  Therefore, it is highly recommended that the protocol 
specify the minimal time interval required between two measurements for determination 
of stable disease.  This time interval should take into account the expected clinical benefit 
that such a status may bring to the population under study.  
 
(Note: The duration of response or stable disease as well as the progression-free survival 
are influenced by the frequency of follow-up after baseline evaluation. It is not in the 
scope of this guideline to define a standard follow-up frequency that should take into 
account many parameters, including disease types and stages, treatment periodicity, and 
standard practice.  However, these limitations to the precision of the measured end point 
should be taken into account if comparisons among trials are to be made.)  
3.4 Progression-free survival/time to progression  
This document focuses primarily on the use of objective response end points.  In some 
circumstances (eg, brain tumors or investigation of noncytoreductive anticancer agents), 
response evaluation may not be the optimal method to assess the potential anticancer 
activity of new agents/regimens.  In such cases, progression-free survival/time to 
progression can be considered valuable alternatives to provide an initial estimate of 
biologic effect of new agents that may work by a noncytotoxic mechanism.  It is clear 
though that, in an uncontrolled trial proposing to utilize progression-free survival/time to 
progression, it will be necessary to document with care the basis for estimating what 
magnitude of progression-free survival/time to progression would be expected in the 
absence of a treatment effect. It is also recommended that the analysis be quite 
conservative in recognition of the likelihood of confounding biases, e.g., with regard to 
selection and ascertainment.  Uncontrolled trials using progression-free survival or time 
to progression as a primary end point should be considered on a case-by-case basis, and 
the methodology to be applied should be thoroughly described in the protocol.  
4 RESPONSE REVIEW  
For trials where the response rate is the primary end point, it is strongly recommended 
that all responses are reviewed by an expert or experts independent of the study at the 
study's completion.  Simultaneous review of the patients' files and radiologic images is 
the best approach.  
 
(Note: When a review of the radiologic images is to take place, it is also recommended 
that images be free of marks that might obscure the lesions or bias the evaluation of the 
reviewer[s]).  

  
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5 REPORTING OF RESULTS  
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  (Note: By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database.)  
 
All of the patients who met the eligibility criteria should be included in the main analysis 
of the response rate.  Patients in response categories 4-9 should be considered as failing to 
respond to treatment (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  
 
Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.  The 95% confidence intervals should be provided.